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Circular RNAs in Cancer: emerging functions in hallmarks, stemness, resistance and roles as potential biomarkers

Circular RNAs in Cancer: emerging functions in hallmarks, stemness, resistance and roles as... Circular RNAs (circRNAs) are a class of RNA molecules with closed loops and high stability. CircRNAs are abundantly expressed in eukaryotic organisms and exhibit both location- and step-specificity. In recent years, circRNAs are attracting considerable research attention attributed to their possible contributions to gene regulation through a variety of actions, including sponging microRNAs, interacting with RNA-binding proteins, regulating transcription and splicing, and protein translation. Growing evidence has revealed that circRNAs play critical roles in the development and progression of diseases, especially in cancers. Without doubt, expanding our understanding of circRNAs will enrich knowledge of cancer and provide new opportunities for cancer therapy. In this review, we provide an overview of the characteristics, functions and functional mechanisms of circRNAs. In particular, we summarize current knowledge regarding the functions of circRNAs in the hallmarks, stemness, resistance of cancer, as well as the possibility of circRNAs as biomarkers in cancer. Keywords: CircRNAs, Cancer, Function, Hallmarks, Stemness, Resistance, Biomarker Introduction revealed that more than 10% of expressed genes are able CircRNAs are a class of single-stranded closed circular to produce circRNAs. In 2013, Hansen et al. [6] and RNA molecules that lack 5′-3′ ends and poly (A) tails Memczak et al. [7] reported that circular transcripts of [1]. Four decades have elapsed since circular RNAs (cir- cerebellar degeneration-related protein 1 antisense RNA cRNAs) were first found in plant-based viruses in 1976 (CDR1as, also known as ciRS-7) can serve as miRNA [2]. CircRNAs were later found in eukaryotes as an en- sponges for miR-7. These works transformed circRNAs dogenous RNA splicing product in 1979 and in humans into a focal point of scientific research and rising stars in following hepatitis delta virus infection in 1986 [3, 4]. the noncoding RNA field. However, circRNAs were initially considered as func- In recent years, following the development and appli- tionless byproducts of aberrant RNA splicing and thus cation of high-throughput deep RNA sequencing and have not garnered sufficient scientific attention. In 2012, bioinformatics technology, circRNAs have been found to Salzman et al. [5] identified the abundance of circRNA be widespread in eukaryotic cells and dynamically species in both normal and mammalian cells and expressed in various developmental stages and physio- logical conditions [8, 9]. A large number of researchers have demonstrated that circRNAs are correlated with * Correspondence: hnchw11@163.com; liaoqianjin@hnszlyy.com the pathogenesis of various human diseases, including Min Su and Yuhang Xiao contributed equally to this work. nervous system disorders [10], cardiovascular disorders Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, [11], Alzheimer’s disease [12], osteoarthritis [13], dia- Central South University, Changsha, China betes [14], silicosis [15] and cancer [16, 17]. In particular, Department of the 2nd Department of Thoracic Surgery, Hunan Cancer circRNAs have been reported to play critical roles in Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, People’s Republic of cancer growth, metastasis, stemness and resistance to China therapy [18, 19]. Natural circRNA, which plays an Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Su et al. Molecular Cancer (2019) 18:90 Page 2 of 17 important role in the RNA interaction network, was stretches initially characterized by the action of the proven to be extremely abundant, relatively stable, di- Arthrobacterluteus restriction endonuclease) across verse and conserved [8]. Emerging evidence suggests exon-flanking introns. Intron paring place the splice sites that circRNAs are responsible for complicated functions close to each other, followed by back-splicing of pre- such as serving as endogenous RNAs to sponge miRNAs, mRNAs and exon circularization. Unlike ecircRNAs, regulating expression of parental genes, modulating alter- EIciRNAs retain the introns that are not spliced out com- native splicing, regulating RNA–protein interactions, and pletely [29]. Pre-mRNAs that contain flanking Alu com- acting as scaffolds in the assembly of protein complexes plementary pairs or flanking complementary sequence [20, 21]. In this review, we describe the characteristics, pairs other than Alu could facilitate the production of functions and functional mechanisms of circRNA. Specif- EIciRNAs [29]. In addition, ciRNAs are derived from in- ically, we discuss the role of circRNA in the hallmarks, tron lariats that escape the normal intron debranching stemness, resistance of cancer, as well as the possibility of and degradation [30]. The formation of ciRNAs are circRNAs as biomarkers in cancer. dependent on the presence of a 7 nt GU-rich sequence near the 5′ splicing site and a 11 nt C-rich motifs near the Characteristics and biogenesis of circRNAs 3′ branch point site. Up to today, several sequence fea- According to recent research, circRNAs are typically tures have been indicated to influence the biosynthesis of generated from one to five exons with length between a circRNA, such as length of intron and exon, repetitive se- few hundred to thousands of nucleotides (nt) [22, 23]. quences and RNA-binding proteins (RBPs) [31, 32]. The There are several important properties of circRNAs gen- RBPs that include muscleblind (MBL), quaking (QKI), SR erated by back-splicing: (1) circRNAs have a closed ring protein, adenosine deaminases that act on RNA (ADAR1), structure—without either 5′–3′ polarity or a polyadeny- fused in sarcoma (FUS), heterogeneous nuclear ribonu- lated tail—and are thus insusceptible to degradation by cleoprotein (hnRNP), NF90/NF110, heterogeneous nucle- exonucleases and much more stable than linear RNA arribonucleoprotein L (HNRNPL) and muscleblind [24]; (2) circRNAs are widely expressed in eukaryotic (MBL), could positively or negatively regulate the forma- cells, and more than one million circRNAs exist in hu- tion of circRNAs [32–35](Fig. 1). man tissues as detected by high-throughput sequencing [25]; (3) circRNAs primarily reside in the cytoplasm, Functional mechanisms of circRNAs whereas a small number of circRNAs are located in the Act as miRNA sponges nucleus [7]; (4) most circRNAs have highly conserved se- Multiple lines of evidence have proven that some cir- quences between different species [26]; (5) circRNAs exhibit cRNAs are rich in miRNA response elements (MREs) tissue-specific and dynamic developmental stage-expression and may serve as miRNA sponges. MiRNAs are small, patterns [9]; (6)circRNAsplayaregulatoryrole atthe level noncoding RNAs with approximately 22 nt lengths that of transcription or posttranscription [7]. play an important role in posttranscriptional gene ex- Both circRNAs and linear RNAs are originated from pression through binding to specific target sites within precursor mRNAs (pre-mRNAs), but in contrast to linear the mRNA 3′-untranslated region (3′-UTR), leading to RNAs that are generated by classical splicing, circRNAs decreased mRNA stability and suppression of translation are usually formed by back-splicing [8]. CircRNAs can be [36, 37]. CircRNAs may regulate gene expression derived from all regions of the genome, including inter- through binding to and releasing miRNAs from their genic, intronic, antisense and untranslational regions [7]. downstream target genes [38, 39]. In comparison with There are three major categories of circRNAs base on other miRNA sponges, some circRNAs exhibit a super- their origin: exonic circRNAs (ecircRNAs), exon-intron ior ability to bind with miRNAs and have been referred circRNAs (EIciRNAs), and circular intronic RNAs (ciR- to as “super sponge” [21]. The best example is CDR1as, NAs) [27]. EcircRNAs are derived from exons and ac- which harbors more than 70 selectively conserved miR-7 count for the main part of identified circRNAs [28]. Two binding sites [40]. In addition, there are a large number of models of ecircRNA formation have been proposed [8]. examples of circRNAs able to act as miRNA sponges, includ- (1) Iariat-driven circularization model: the introns in a lar- ing circRNA ZNF609 [41], circ-SRY [42], mm9_circ_012559 iat intermediate that consists several exons and introns [43], circDOCK1 [44], and many others. are removed, followed by the connection between the 3′ splice site of an upstream exon (splice acceptor) and the Interact with RNA binding proteins 5′ splice site of a downstream of exon (splice donor), In addition to acting as miRNA sponges, some circRNAs resulting in the formation of ecircRNAs. (2) Intron that harbor binding sites for RNA-binding proteins may pairing-driven circularizing model: a circular structure is serve as protein sponges or decoys and thus regulate formed by base-paring between reverse complementary gene expression. For instance, the circRNA originating sequences (such as Alu repeats, which are short DNA from the PABPN1 locus (circ-PABPN1) binds to human Su et al. Molecular Cancer (2019) 18:90 Page 3 of 17 Fig. 1 Formation of three types of circRNAs. a Exonic circular RNA (ecircRNA) is formed through back-splicing of the 5’splice site (splice donor site) to a 3’splice site (splice acceptor site); (b) The intron 1 is removed and bring the 5′ splice site of Exon 2 close to 3′ splice site of Exon 1, to form a ecircRNA that contains multiple exons. Exons can also skip splicing, exon 1 can also link with exon 3; (c) Circular intronic RNA (ciRNA) are derived from intron lariats that escape the normal intron debranching and degradation. Reverse complementary sequences of lariat intron excised from pre-mRNA can pair to produce close loop structure termed as ciRNA; (d) Exon–intron circRNAs (EIciRNAs) are circularized with introns‘retained’between the exons. Intron 3 retaines with Exon 3 and Exon 4 to form an EIciRNAs antigen R/ELAV-like protein 1 (HuR) and prevents HuR shown that some circRNAs possess translational ability. from binding to PABPN1 mRNA, subsequently sup- To this point, at least four circRNA molecules have been pressing PABPN1 translation [45]. The other examples, proven to be translatable. Legnini I. et al. [50] revealed including circ-Foxo3 [46] and circ-Mbl [31], primarily that circ-ZNF609 contains an open reading frame (ORF) interact with RNA binding proteins. and could be translated into a protein in murine myo- blasts when driven by IRES. Additionally, circ-SHPRH Regulate transcription or splicing [51] and circ-FBXW7 [52], as well as proteins encoded Some circRNAs have been demonstrated to regulate gene by them, are found to be abundantly expressed in nor- transcription through combining with RNA polymerase II mal human brains but downregulated in glioma. Both of complex and translating related proteins [47]. For example, the circRNAs have an ORF driven by the IRES to trans- circ-EIF3J and circ-PAIP2 were found to interact with the late a functional protein. Analogously, Pamudurti N. R. U1 snRNPs and RNA polymerase II in the promoter region et al. [53] found that circMbl can also translate protein of the host gene to realize enhanced transcription of their in a cap-independent manner. parental genes, such as PAIP2 and EIF3J [29]. Studies have also suggested that circRNAs can contrib- Regulate epigenetic alterations ute to the regulation of selective splicing. A study by Aberrant DNA methylation and histone modifications Ashwal-Fluss et al. [31] showed that circMbl is derived that associated with epigenetic gene expression are fre- from the circularization of the second exon of the spli- quently found in cancer [54, 55]. Some circRNAs have cing factor muscleblind (MBL) and could compete with been found to regulate these epigenetic alterations. Chen linear MBL mRNA for selective splicing. Notably, due to et al. [56] reported that circFECR1 induced extensive the presence of functional circMbl binding sites in the CpG DNA demethylation in the promoter of FLI1 and MBL protein, MBL could interact with circMbl and pro- thus epigenetically activated FLI1. CircFECR1 was dem- mote circMbl production. Thus, circMbl negatively af- onstrated to downregulate the transcription of DNMT1, fects canonical splicing and decreases the production of a critical methyltransferase required for the maintenance the parental mRNA. of DNA methylation, through binding to the DNMT1 promoter. In addition, circFECR1 could recruit TET1 Translate proteins DNA demethylase to the FLI1 promoter and induce Because of lacking 5′-3′ polarity and polyadenylated DNA demethylation. Enhancer of zeste homolog 2 tails, as well as internal ribosome entry sites (IRES), cir- (EZH2) is a subunit of polycomb-repressive complex 2 cRNAs were initially defined as a distinct class of en- (PRC2), which functions as a H3K27 methyltransferase dogenous noncoding RNA that could not translate and regulates histone methylation [57, 58]. Several cir- proteins [48, 49]. However, convincing evidence has cRNAs have been reported to regulate EZH2 expression Su et al. Molecular Cancer (2019) 18:90 Page 4 of 17 through acting as miRNA sponges, subsequently regulate factors and regulate cell growth [63, 64]. A variety of studies histone methylation indirectly. For example, circBCRC4 is have shown that EGFR is a target of miR-7, which is a tumor able to promote the expression of EZH2 by binding with suppressor regulating various biological processes [65, 66]. miR-101 [59], hsa_circ_0020123 is able to upregulate EZH2 One of the most well-known circRNAs, CDR1as, harbors and ZEB1 through sponging miR-144 [60], hsa_circ_0071589 more than 70 selectively conserved miR-7 target sites, thus can regulate the miR-600/EZH2 signaling [61](Fig. 2). acting as a sponge of miR-7 [6, 7]. CDR1as, predominantly found in human brain, is approximately 1500 nt in length CircRNAs regulate the hallmarks of cancer [67]. CDR1as has been reported to be involved in pulmonary In 2000, Hanahan and Weinberg proposed six hallmarks fibrosis, myocardial infarction, insulin secretion, neuropsychi- of cancer that result in the progressive conversion of atric disorders, and cancer [68–71]. Zhang et al. [72]re- normal cells into cancerous cells [62]. Most and perhaps ported that CDR1as was highly expressed in non-small cell all types of human cancer shared these acquired capabil- lung cancer (NSCLC) tissues, correlated with TNM stage, ities, including self-sufficiency in growth signals, evasion lymph node metastasis and survival time, and acted as an in- of antigrowth signals, resistance to cell death, limitless dependent prognostic factor for the NSCLC patients. Knock- replicative potential, sustained angiogenesis, tissue inva- down of CDR1as promotes cell vitality and growth through sion and metastasis. In recent years, some circRNAs induction of cell apoptosis and cell cycle arrest in G1/S have been shown to be involved in these properties of phase. Mechanical assays revealed that CDR1as functioned cancer (Fig. 3 and Table 1). as a miR-7 sponge to increase the expression levels of miR-7 targeting proto-oncogenes (EGFR, CCNE1 and PIK3CD). In Self-sufficiency in growth signals addition, CDR1as was also markedly overexpressed in colo- Normal cells acquire self-sufficiency in growth signals to rectal cancer (CRC) tissues and correlated with advanced change into an active proliferative state [62]. The mito- tumor stage, lymph node involvement, distant metastasis genic growth signals are transmitted into the cell interior and poor patient survival of CRC patients [73]. Overexpres- by binding to the transmembrane receptors. Cancer cells sion of CDR1as led to blocking of the tumor suppressive ef- could produce dysregulated growth factors and/or the fects of miR-7 and resulted in a more aggressive oncogenic corresponding receptor molecules themselves to lead to phenotype. Overexpression of CDR1as induced inhibition of an autocrine stimulation. miR-7 and subsequent activation of miR-7 target oncogenes Epidermal growth factor receptor (EGFR), highly expressed EGFR and RAF1. However, in another study, CDR1as ex- in a variety of solid tumors, is a critical molecular signal that pression was shown to be downregulated in hepatocellular can trigger an intracellular transduction cascade of growth carcinoma (HCC) tissues and cell lines [74]. The expression Fig. 2 The functional mechanisms of CircRNAs. a Acting as miRNA sponge; (b) Binding with RNA binding protein (RBP); (c) Regulating transcription; (d) Regulating splicing; (e) Translated into Protein; (f) Regulating epigenetic alterations Su et al. Molecular Cancer (2019) 18:90 Page 5 of 17 Fig. 3 CircRNAs involved in the hallmarks of cancer. a CDR1as and circHIPK3 active cell proliferative through regulating EGFR; (b) Circ-ITCH et al. promote cancer cells evading antigrowth signals by preventing expression or activation of tumor suppressors,suchasPTEN andCDK;(c) Hsa_circ_0007534 et al. promote cancer cells evading cell death via regulating cellular apoptosis or autophagy; (d) Has-circ-0020397 limits replicative potential of cancer cell trough regulating TERT; (e) CircRNA-MYLK et al. sustain angiogenesis trough regulating VEGF; (f) Dirc-10,720 et al. regulate the process of EMT and thus tissue invasion and metastasis of cancer profiles differ between NSCLC, CRC and HCC, possibly due migration of cells. Following binding to specific moieties to the tissue-specificity of circRNAs. Ectopic expression of of the ECM, the integrin receptors are able to transduce CDR1as could increase cell growth and adhesion while inhi- signals into the cell that mediate cell behavior. Integrin biting the migration of HCC cells. CDR1as exhibited these subunit beta 8 (ITGB8) is an important member of the functions through regulating the expression of EGFR. An- integrin family [79]. A recently study showed that hsa_- other circRNA that regulates EGFR is circHIPK3 (hsa_- circ_0046701, which was highly expressed in glioma tis- circ_0000284), which originates from the HIPK3 gene exon sues and cell lines, was able to promote cell proliferation 2, with the length of 1099 nt [75, 76]. CircHIPK3 is a particu- and invasion through regulating ITGB8 expression by larly abundant circRNA that has been proposed to be in- sponging miR-142-3p [80]. volved in tumorigenesis [76, 77]. It was shown to be C-myc, an important transcription factor, acts as an markedly overexpressed in CRC tissues and cell lines and oncogene to regulate various cellular processes including positively associated with advanced clinical stage and poor cell proliferation, differentiation, and apoptosis [81, 82]. survival of CRC patients [75]. CircHIPK3 knockdown signifi- It has been reported that c-myc can regulate up to 15% cantly inhibited CRC cell proliferation while inducing cell of gene expression [83]. Yang and coworkers [52]conducted apoptosis. Interestingly, miR-7 was identified and confirmed the RNA-expression profiling from glioblastoma and to be the only miRNA that directly interacts with circHIPK3 matched noncancerous tissues and characterized the circular [75]. Furthermore, overexpression of circHIPK3 effectively form of the FBXW7 gene, circ-FBXW7. Circ-FBXW7 was reversed miR-7-induced attenuation of CRC cell progression downregulated in glioblastoma tissues and correlated with through upregulating the expression of several key miR-7 tar- overall survival of glioblastoma patients. The spanning junc- get genes, including EGFR, IGF1R, FAK and YY1. tion open reading frame in circ-FBXW7 driven by internal However, EGFR is not the only growth signal regulated ribosome entry site encoded a novel 185-amino acid protein, by circRNAs. Integrins are transmembrane receptors which was termed as FBXW7-185aa. FBXW7-185aa, but not and mediators of the interactions between cells and the circ-FBXW7, could function as a tumor suppressor to induce extracellular matrix (ECM) [78]. Integrin-mediated inter- cell cycle arrest and inhibit proliferation in glioma cells actions are required for the cytoskeletal organization, at- through reducing the half-life of c-myc. FBXW7-185aa was tachment, survival, proliferation, differentiation and shown to directly interact with de-ubiquitinating enzyme Su et al. Molecular Cancer (2019) 18:90 Page 6 of 17 Table 1 CircRNAs involved in the hallmarks of cancer Function CircRNA Cancer type expression Associated clinical features Associated cell process Targets Ref. Sustaining growth CDR1as NSCLC up TNM stage, lymph nodes metastasis promote cell vitalities and growth, inhibit miR-7/EGFR, CCNE1, [72] signaling and survival time apoptosis and cell cycle arrest PIK3CD. CDR1as CRC up advanced tumor stage, tumor depth, – miR-7/EGFR, RAF1 [73] and survival time CDR1as HCC down – promote cell growth, adhesion, and inhibit miR-7/EGFR [74] migration circHIPK3 CRC up metastasis, clinical stage and survival inhibite cell proliferation, migration, invasion, and miR-7/EGFR, FAK, IGF1R, [75] time induce apoptosis YY1 hsa_circ_0046701 glioma up – promote cell proliferation and invasion miR-142-3p/ITGB8 [80] circ-FBXW7 glioblastoma down survival time inhibit cell proliferation and cell cycle acceleration FBXW7-185aa/c-Myc [52] Circ-Amotl1 – up – promote cell proliferation c-myc [84] Evading growth circ-ITCH Bca down histological grade and survival time inhibite cell proliferation, migration, invasio, induce miR-17, miR-224/p21, [90] inhibitors G1/S cell cycle arrest and apoptosis PTEN axis circ-ZFR GC down – inhibit cell propagation, cell cycle and promote miR-130a, miR-107/PTEN [91] apoptosis CDR1as GC up lymph nodes metastasis and survival promote cell proliferation, migration and inhibit miR-7/PTEN/PI3K/AKT [92] time apoptosis circRNA-000425 GC down – inhibit cell growth miR-17,miR-106/p21, BIM [93] Circ100284 – up – promote cell cycle acceleration miR-217/EZH2/cyclin D1, [97] CDK4 hsa_circ_0016788 HCC up – promote cell proliferation, invasion and inhibit miR-486/CDK4 axis [98] apoptosis circHIPK3 gallbladder up – promote cell survival and proliferation, inhibit cell miR-124/ROCK1, CDK6 [99] cancer apoptosis Resisting apoptosis hsa_circ_0007534 CRC up tumor stage and lymph node ptomote cell proliferation and inhibit apoptosis Bcl-2, Bax [104] metastasis circUBAP2 osteosarcoma up tumor progression and prognosis promote cell growth and inhibit apoptosis miR-143/Bcl-2 [105] hsa_circ_0009910 osteosarcoma up – promote cell proliferation inhibition, inhibit cell miR-449a/IL6R/Bcl-2/Bax [106] cycle arrest, and inhibit apoptosis hsa_circRNA_103809 CRC down – promote apoptosis miR-532-3p/FOXO4 axis [107] circNFIX glima up – promote cell propagation, migration and inhibit miR-34a-5p/NOTCH1 [108] apoptosis circ-DNMT1 BC up – inhibit autophagy, promote cell proliferation and p53, AUF1 [110] survival Uncontrolled has-circ-0020397 CRC up – promote cell viability and inhibit apoptosis mir-138/TERT, PD-L1 [114] replicative immortality Promoting circRNA-MYLK Bca up pathological stage, T and N promote cell growth, angiogenesis and metastasis miR-29a/VEGFA/VEGFR2 [118] angiogenesis classifications and survival time Su et al. Molecular Cancer (2019) 18:90 Page 7 of 17 Table 1 CircRNAs involved in the hallmarks of cancer (Continued) Function CircRNA Cancer type expression Associated clinical features Associated cell process Targets Ref. cZNF292 Glima up – promote cell proliferation, tube formation and VEGF-A, EGF, TGF-β1[122] angiogenic potential circHIPK3 Bca down tumor grade, invasion, lymph node inhibit migration, invasion, and angiogenesis miR-558/HPSE/VEGF [119] metastasis Activating invasion circ-10,720 HCC up Tumor metastasis and survival time promote cell proliferation, migration, invasion and Vimentin [129] and metastasis EMT circPTK2 NSCLC down – inhibit cell invasion and EMT miR-429, miR-200b-3p/ [132] TIF1y circSMAD2 HCC down – inhibit cell migration, invasion, and EMT miR-629 [137] hsa_circ_0061140 ovarian up – promote cell proliferation, migration, invasion and miR-370/FOXM1 [141] cancer EMT circ_0067934 NSCLC up TNM stage, lymph node statu, distant promote cell proliferation, migration, invasion and N-cadherin, vimentin [142] metastasis and survival time EMT snail, and E-cadherin circRNA_0023642 GC up – pormote cell proliferation, migration, invasion and N-cadherin, vimentin [143]` EMT snail, and E-cadherin Su et al. Molecular Cancer (2019) 18:90 Page 8 of 17 USP28, and thus antagonize the USP28-induced de-ubiquiti- HNRNPH1, which codes for circRNA-000425. nation of c-Myc and increase c-Myc ubiquitination. Another CircRNA-000425 was identified as a sponge of miR-17/ circRNA that could regulate c-myc is circRNA derived from miR-106b and indirectly modulated their targets, such as angiomotin-like1 (circ-Amotl1) [84]. Circ-Amotl1 was highly p21 and BIM, thus suppressing GC cell growth. expressed in breast cancer (BC) tissues and cell lines. Knock- In addition to these well-known tumor suppressors, down of circ-Amotl1 promoted cell proliferation and inhib- some circRNAs could also regulate tumor growth by ited apoptosis of BC cells. In addition, circ-Amotl1 was regulating cell cycle mediators, such as Cyclin D1, a demonstrated to bind to c-myc, translocate into nucleus and well-known regulator of the cell cycle that promotes the prevented degradation of c-myc. Ectopic expression of transition from G1 to S phase by activating CDK4 or circ-Amotl1 enhanced the binding affinity of c-myc to the CDK6 [96]. Xue and coworkers [97] performed a cir- promoters of a number of its targets, including HIF-1α, cRNA microarray to analyze the variability of circRNAs Cdc25a, ELK-1, and JUN. However, how circ-Amotl1 pre- in arsenite-treated HaCaT (As-HaCaT) cells and in vents c-myc degradation is not clear and awaits further arsenite-transformed cells compared to normal HaCaT cells investigation. and identify cirRNAs that involved in arsenite-induced ac- celeration of the cell cycle. Circ100284 was greatest Insensitivity antigrowth signals up-regulated in As-HaCaT cells and showed the most There are multiple antiproliferative signals in normal change following arsenite treatment. Knockdown of cells that operate to maintain cells in a quiescent state circ100284 inhibited G1/S transition in As-HaCaT cells. [62]. These signals can block cell proliferation through Circ100284 was demonstrated to be involved in the arresting the cell cycle [85]. However, cancer cells can arsenite-promoted cell cycle through regulation of EZH2 evade antigrowth signals by preventing expression or ac- via sponging miR-217. EZH2 subsequently bind to the pro- tivation of tumor suppressors. moter of CCND1, the host gene of cyclin D1. Knockdown Phosphatase and tensin homolog (PTEN), deleted of EZH2 suppressed the expression of cyclin D1 and from chromosome ten and mutated at high frequency in CDK4. Although EZH2 frequently acts through methyla- a variety of cancers, can contribute to the G0-G1 cell tion of H3K27 as discussed above, here, it functions cycle regulation and additional cellular functional activ- through the methylase-independent pathway. These results ities [86, 87]. Cyclin-dependent kinase (CDK) inhibitor suggested that, in HaCaT cells, circ100284 was induced by p21 is a cell cycle suppressing protein, and overexpres- arsenite treatment and acted as a sponge for miR-217 to sion of p21 acts to suppress cell growth [88, 89]. up-regulate EZH2, which, in turn, increased the expression Circ-ITCH, the circularized product from several exons of cyclin D1 and CDK4, and thus lead to cell cycle acceler- of itchy E3 ubiquitin protein ligase homolog (ITCH), has ation and malignant transformation. In another study, been reported to be downregulated in bladder cancer Guan et al. [98] performed circRNA microarray analysis in (BCa)tissues and correlated with the histological grade HCC tissue and identified a highly expressed circRNA, and shortened survival of BCa patients [90]. It was also hsa_circ_0016788. Silencing of hsa_circ_0016788 inhibited downregulated in BCa cell lines, and the enforced expres- proliferation and promoted apoptosis of HCC cells through sion of circ-ITCH inhibited cell proliferation, migration, in- regulation of the miR-486/CDK4 axis. CircHIPK3 was vasion and metastasis. Mechanical assays demonstrated shown to be overexpressed in human gallbladder cancer that circ-ITCH could directly sponge miR-17 and miR-224 cells [99]. Silencing of circHIPK3 decreased the proliferative and lead to increased expression of their target genes, and survival capacities, induced apoptosis of gallbladder PTEN and p21. Another circRNA, circ-ZFR, was shown to cancer cells through sponging the tumor-suppressive be downregulated in gastric cancer (GC); circ-ZFR regu- miR-124, and increased expression of ROCK1 and CDK6, lated GC progression by directly binding with miR-130a/ which are miR-124 targets [100, 101]. miR-107, and further regulated the expression of PTEN, which is a target of these miRNAs [91]. In addition, Evading apoptosis CDR1as was overexpressed in GC tissues and correlated Apart from the rate of cell proliferation, the rate of cell with poor survival [92]. Ectopic expression of CDR1as in- attrition also determines the populations of cells [62]. creased expression of PTEN through sponging of miR-7 Apoptosis is the major mechanism leading to this attri- and subsequently activated the PTEN/PI3K/AKT pathway. tion. The other two pathways related to cell attrition are Liu and colleagues [93] identified circRNA-000425 as a autophagy and necrosis [85]. Cancer cells acquired the novel inhibitory target of Yes-associated protein 1 (YAP1), ability to evade these signals. an transcriptional coactivator factor that acts as an onco- It is well known that B-cell lymphoma-2 (Bcl-2) is an gene associated with cancer malignancy in several cancer important anti-apoptotic molecule that protects cells types [94, 95]. YAP1 could suppress the expression of from apoptosis, while BCL2-associated X protein (Bax) circRNA-000425 through binding to the promoter of is a proapoptotic gene [59, 102]. Thus, the ratio of Su et al. Molecular Cancer (2019) 18:90 Page 9 of 17 Bcl-2/Bax is a profound indicator of cell survival [103]. ends are critical for this finite replicative potential: they Hsa_circ_0007534 was significantly overexpressed in shorten after every cell division, and therefore, the number CRC tissues and related to tumor stage and lymph node of cell division cycles is dictated by the length of telomeres metastasis [104]. Silencing of hsa_circ_0007534 inhibited [111]. Approximately 85–90% of human cancers overex- proliferation while promoting the apoptosis of CRC cells. press telomerase, which adds telomeric repeats onto the Moreover, the Bcl-2/Bax ratio was decreased following ends of telomeric DNA, suggesting that limitless replica- hsa_circ_0007534 silencing, which demonstrated that tive potential is essential for the development of their ma- hsa_circ_0007534 inhibits CRC cell proliferation, at least lignant growth [112]. partially, by inducing apoptosis. However, how hsa_- Telomerase reverse transcriptase (TERT) is a catalytic circ_0007534 regulates the Bcl-2/Bax ratio is so far un- subunit of telomerase [113]. Zhang and colleagues [114] known and further studies will need to unravel the reported that hsa_circ_0020397, derived from the molecular mechanism. DOCK1 gene, was upregulated in CRC cells, promoted Zhang et al. [105] performed microarray experiments their viability, and inhibited apoptosis. By using a com- to examine the expression profiles of circRNAs in osteo- mon bioinformatic algorithm, the authors predict that sarcoma tissue and found that circUBAP2 was the most an important cancer suppressor, miR-138, possesses markedly increased circRNA. CircUBAP2 was also sig- multiple binding sites on hsa_circ_0020397. In addition, nificantly overexpressed in osteosarcoma cells. CircU- has_circ_0020397 was demonstrated to inhibit the activ- BAP2 knockdown inhibited cell proliferation and ity of miR-138, although it did not influence miR-138 promoted cell apoptosis. Mechanistically, circUBAP2 expression, and increase the expression of miR-138 tar- was found to directly bind to and inhibit the expression get genes including PD-L1 and TERT. of miR-143, thus enhancing the expression of the miR-143 target Bcl-2. Another study performed by Deng Sustained angiogenesis et al. [106] showed that hsa_circ_0009910 was upregu- Tumor size increases when cancer cells grow. However, lated in osteosarcoma cells. Circ_0009910 knockdown the size is limited to within 100–200 μm without angio- inhibited cell proliferation and induced cell cycle arrest genesis due to the limited natural diffusion capability of and apoptosis in osteosarcoma cells. Circ_0009910 was oxygen and nutrients [115]. Angiogenesis is the process found to directly bind to and function as a sponge of induced by tumor cells that forms new blood vessels in miR-449a, thereby regulating the target gene IL6R as order to supply the tumor with oxygen and nutrients well as the downstream Bcl-2 and Bax. and to dispose of tumor metabolic (toxic) wastes. In addition, there are several additional circRNAs in- Vascular endothelial growth factor (VEGF) is believed volved in apoptosis. For example, Hsa_circRNA_103809 to be the most potent mediator of crucial regulatory was downregulated in CRC and could promote apoptosis roles in angiogenesis [116, 117]. CircRNA-MYLK is through the miR-532-3p/FOXO4 axis [107]. CircNFIX spliced from MYLK gene, with the spliced mature se- was overexpressed in glioma and inhibited apoptosis quence length of 376 nt [118]. It was significantly over- through regulating NOTCH1 via binding to and spon- expressed in BC tissues and correlated with the clinical ging miR-34a-5p [108]. features of BC patients including the pathological stage, T Apart from apoptotic roles, there is also a circRNA in- and N classifications, and survival time. CircRNA-MYLK volved in autophagy. It has been reported that nuclear was also upregulated in BC cell lines. Moreover, translocation of p53 could induce cellular autophagy circRNA-MYLK promoted cell proliferation, migration, [109]. Circ-Dnmt1, generated from Exons 6 and 7 of the and the tube formation of HUVECs, which exhibits angio- mRNA NM_001130823.1, was found to be upregulated genic potential. Mechanistically, circRNA-MYLK could in tissues of BC as well as in eight BC cell lines [110]. directly bind to and sponge miR-29a, thus relieving sup- Overexpression of circ-Dnmt1 increased cell survival pression for target VEGFA and activating the VEGFA/ and proliferation of BC cells through stimulating cellular VEGFR2 signaling pathway. CircRNA-MYLK is not the autophagy. In addition, nuclear levels of circ-Dnmt1 only circRNA that plays a critical role in tumor angiogen- were increased in autophagy inducer-treated BC cells, esis: another circRNA, circHIPK3 [119], was shown to be indicating that autophagy could enhance the nuclear downregulated in Bca and suppress angiogenesis through translocation of circ-Dnmt1. Circ-Dnmt1 could directly the sponging of miR-558 and subsequent inhibition of bind with p53, promoting its nuclear translocation. HPSE, which could positively regulate the expression of VEGF [120, 121]. cZNF292 was also reported to be an Limitless replicative potential important circular oncogenic RNA taking part in the pro- Replicative potential is limited because of the appearance gression of tube formation in glioma [122]. The expression of two processes termed as senescence or crisis in normal of VEGF-A, EGF and active TGF-β1, as well as the levels cells [62]. The telomeres that locate at the chromosome of VEGFR-1/2, phosphorylated-VEGFR-1/2 and EGFR, Su et al. Molecular Cancer (2019) 18:90 Page 10 of 17 were significantly downregulated following the silencing addition, the expression of circSMAD2 was downregu- of cZNF292. Since the in-depth mechanism of cZNF292 lated in HCC tissues and correlated with the tumor dif- activity is unclear, more studies are necessary. ferentiation degree. Overexpression of circSMAD2 inhibited migration, invasion, and EMT in HCC cells Tissue invasion and metastasis through suppressing the expression of miR-629, which It is believed that 90% of human cancer deaths are could promote EMT in cancer cell lines. caused by metastases and not by the primary tumor FOXM1 has been shown to promote cell migration, [123]. During the development of most types of human invasion and EMT in a variety of tumors [138–140]. cancer, cancer cells can escape the primary tumor mass Chen et al. [141] reported that hsa_circ_0061140 was and initiate new colonies at distant sites. The process of overexpressed in ovarian cancerand could promote cell epithelial-mesenchymal transition (EMT) has been con- migration and invasion through regulation of the firmed to be essential in cell migration and tissue metas- miR-370/FOXM1 pathway-mediated EMT. Hsa_- tasis in cancer [124, 125]. It involves a cellular circ_0061140 silencing induced a decreased expression reprogramming process that drives epithelial cells into a of the EMT-related proteins, Snail and Vimentin, along mesenchymal-like phenotype, which is characterized by with an increased expression of E-cadherin. the loss of epithelial surface markers like E-cadherin and Circ_0067934 was shown to be upregulated in NSCLC the acquisition of the mesenchymal markers vimentin and capable of promoting cell EMT accompained with and N-cadherin. increased N-cadherin and vimentin expression and de- The Twist family is known as critical EMT-inducing creased E-cadherin expression [142]. CircRNA_0023642 transcription factor that increase expression of vimentin was upregulated in GC and acted as an oncogene by [126–128]. Meng et al. [129] demonstrated that twist1 regulating EMT [143]. CircRNA_0023642 was shown to bound to the promoter of Cul2 to activate its transcrip- suppress expression of E-cadherin and promote expres- tion and selectively induce expression of Cul2 circular sion of N-cadherin, vimentin, and snail in GC cells. RNA (circ-10,720) rather than mRNA. Circ-10,720 ex- Since the studies didn’t show the effector molecules of pression was high in metastatic HCC tissues and associ- circ_0067934 and circRNA_0023642, the exact mecha- ated with clinical stage, pathology grade, metastasis and nisms of the two circRNAs still need to be uncovered. survival of patients. Circ-10,720 played an oncogenic In addition to the circRNAs discussed above, it is role to promote the migration, invasion and EMT pro- likely that many more circRNAs could regulate the hall- gression of HCC cells. Furthermore, it was found that marks of cancer as a large number of studies have twist1 promoted vimentin through increasing levels of shown that circRNAs are involved in modulating prolif- circ-10,720, which could sponge miRNAs targeting eration, apoptosis and migration of cancer cells without Vimentin, including miR-1246, miR-578 and miR-490-5p. exploring the underling molecular mechanisms. Among them, miR-490-5p was considered to be the major miRNA regulating Vimentin in HCC due to its high ex- CircRNAs regulate stemness of cancer pression and stronger inhibitory effects to Vimentin Cancer stem cells (CSCs), a small proportion of cells 3′-UTR activities. that possess self-renewal and tumor-initiating capabil- TGF-β/Smad signaling has been proven to play a crucial ities, are considered to be responsible for metastatic dis- role in tumor metastasis and the EMT process in a variety semination and therapeutic failure [144–146]. Several of human cancers [130, 131]. CircPTK2 (hsa_- lines of evidence have suggested that circRNAs might circ_0008305) was found to be markedly downregulated contribute to the stemness of cancer (Table 2). in NSCLC cells during TGF-β-induced EMT [132]. Over- Yang and colleagues [147] performed high-throughput expression of circPTK2 arrested TGF-β-induced EMT and sequencing to screen the circRNA expression profiles of invasion of NSCLC cells. Mechanistically, circPTK2 func- breast CSCs (BCSCs) and matched non-BCSCs and tions as a sponge of miR-429/miR-200b-3p, which pro- found 27 aberrantly expressed circRNAs. Among these, motes EMT and cell invasion through targeting TIF1γ. circVRK1 was downregulated and was able to suppress TIF1γ is a TGF-β/Smad signaling regulator that could es- the expansion and self-renewal capacity of BCSCs, dis- calate TGF-β-induced EMT in cancer [133, 134]. In playing an inhibiting role in the stemness of BCSCs. BC addition, circPTK2 could also negatively regulate the ex- cells with circVRK1 knockdown exhibited an enhanced pression of Snail, an important downstream regulator of capacity to form mammospheres and colonies, and an TGF-β/Smad signaling [135]. increasing expression of stemness-related markers in- Compelling data revealed that SMAD2 potently con- cluding OCT4, SOX2 and NANOG, indicating that tributes to EMT [136]. Zhang et al. [137] reported that circVRK1 was involved in suppressing the stemness of circSMAD2 (hsa_circ_0000847), encoded by the SMAD2 BCSCs. In addition, it was speculated that circVRK1 was gene, was upregulated during TGF-β-induced EMT. In negatively correlated with stemness of BCSCs through Su et al. Molecular Cancer (2019) 18:90 Page 11 of 17 Table 2 CircRNAs involved in stemness and chemotherapy resistance of cancer Function CircRNA Cancer type expression Associated clinical features Associated cell process Targets Ref Regulating circVRK1 BC down – decrease proportion of BCSCs – [147] stemness with CD44 + CD24- phenotype, suppress BCSC’s expansion and self-renewal capacity hg19_circ_0005033 LSCC up – promote proliferation, migration, miR-4521 [150] invasion, and chemotherapy resistance of laryngeal cancer stem cells Regulating circPVT1 osteosarcoma up enneking stage, contributes to doxorubicin ABCB1 [154] chemotherapy chemoresistance, lung and cisplatinresistance resistance metastasis and survival circRNA-MTO1 BC up – inhibit cell viability and TRAF4/Eg5 [157] (hsa-circRNA- reverse monastrol resistance axis 007874) circBA9.3 CML up – promote resistance against c-ABL1 and [159] TKI therapy BCR-ABL1 the miR-153-5p/KLF5 axis, as miR-153-5p was one of the promote resistance to chemotherapy through pumping predicted miRNA targets of circVRK1 and was previously intracellular drugs outside of the cell [152, 153]. demonstrated to be involved in stemness maintenance of CircPVT1 (hsa_circ_0001821), originating from exon 3 BC via reducing the expression of KLF5 [148]. Further in- of the PVT1 gene, was significantly overexpressed in OS vestigations are necessary to support the hypothesis. tissues and associated with poor prognosis of OS pa- CD133 + CD44+ CSCs (TDP cells), isolated from la- tients [154]. It was also upregulated in chemoresistant ryngeal squamous cell carcinoma (LSCC) cells, have OS cell lines, and circPVT1 knockdown could weaken been shown to exhibit increased cell proliferation, mi- the doxorubicin and cisplatin resistance of OS cells via gration and colony-formation ability as well as resistance suppressing the expression of ABCB1. to chemo- and radiotherapy [149]. These TDP cells were Monastrol is a small molecule that selectively inhibits shown to highly express the stem-cell markers SOX2 Eg5, a microtubule-based motor protein that contributes and OCT4. In comparison with parental cells, TDP cells to the formation and maintenance of the bipolar mitotic exhibited 3684 circRNAs by RNA sequencing (q < 0.01 spindle [155, 156]. Liu et al. [157] performed a and log2FC (fold change) > 1) [150]. Hg19_circ_0005033 genome-wide circRNA microarray to search for dysregu- was one of the upregulated circRNAs in TDP cells, and it lated circRNAs in the monastrol-resistant BC cells and could promote the proliferation, migration, invasion, and re- identified circRNA-MTO1 (has-circRNA-007874) as an sistance to chemotherapy of TDP cells. Hg19_circ_0005033 upregulated circRNA in these cells. Upregulation of wasdemonstratedtobindtomiR-4521andcouldfunction circRNA-MTO1 promoted monastrol-induced cell cyto- as ceRNA to upregulate miR-4521 targeted mRNAs. In toxicity and reversed monastrol resistance. Mechanistic- addition, STAT5A, which was previously reported to induce ally, circRNA-MTO1 could suppress expression of Eg5 stem-like cell properties [151], was predicted as a target of through binding with TRAF4 and serve as a competing miR-4521. Thus, hg19_circ_0005033 was hypothesized to endogenous RNA (ceRNA) to repress TRAF4 from bind- support the stem cell characteristics of CD133 + CD44+ ing to the Eg5 gene. LSCC stem cells via the miR-4521/STAT5A axis, which Tyrosine kinase inhibitors (TKIs) are available for need further validation. managing chronic myelogenous leukaemia (CML) [158]. Pan and colleagues [159] identified an f-circRNA, cir- CircRNAs regulate chemotherapy resistance of cancer cBA9.3, generated from the BCR-ABL1 oncoprotein, Chemotherapy represents the primary treatment for that could contribute to the increased proliferation and both early and advanced tumors. However, acquired re- anti-apoptotic capacities of leukaemic cells [160]. Cir- sistance to chemotherapy is one of the major causes of cBA9.3 was upregulated in patients with TKI resistance therapeutic failure [130]. Recently, several circRNAs and could enhance the expression of BCR-ABL1, thus have been proven likely to play vital roles in the resist- contributing to resistance against TKI therapy. ance of cancer to chemotherapy (Table 2). It is well known that ATP-binding cassette B1 CircRNAs as biomarkers in Cancer (ABCB1) is a multidrug resistance-related protein that is The properties of circRNAs mentioned in previous sec- highly expressed in drug resistant cell lines and could tions (stability, conservatism, universality, and specificity) Su et al. Molecular Cancer (2019) 18:90 Page 12 of 17 indicate that circRNAs could be potentially valuable prog- plasma samples [163]. Its expression levels were signifi- nostic and diagnostic biomarkers for cancer. Recently, cantly associated with tumor size, distal metastasis, many studies have demonstrated circRNAs may be stably lymphatic metastasis, TNM stage and CA19–9 levels. The expressed and present in relatively high quantities in hu- area under curve (AUC) of hsa_circ_0000190 in tissues man body fluids, such as saliva, plasma, serum and exo- and plasma were 0.75 and 0.60, respectively; the AUC of somes, which also makes circRNAs ideal candidates as the combination was increased to 0.775, and the sensitiv- noninvasive liquid biopsy biomarkers for cancer [161]. ity and specificity of the combination were 0.712 and Circ-ZEB1.33 was shown to be overexpressed in human 0.750, respectively. In another study, hsa_circ_0000745 HCC tissues compared to non-tumorous tissues and in was shown to be lowly expressed in GC tissues and serum samples from HCC patients compared to healthy plasma samples [164]. The expression level of hsa_- controls, and its levels in HCC tissue and serum were cor- circ_0000745 in GC tissues was correlated with tumor dif- related with different TNM stages and overall survival in ferentiation, while the expression level in plasma was HCC patients, suggesting circ-ZEB1.33 may serve as a correlated with tumor-node metastasis stage. The AUC of valuable biomarker in HCC prognosis prediction [162]. hsa_circ_0000745 in plasma was 0.683, while combined Hsa_circ_0000190 was down-regulated in GC tissues and with carcinoembryogenic antigen (CEA) level, the AUC Table 3 CircRNAs as liquid biopsy biomarkers in cancer Source Cancer Cohort size CircRNA Expression Associated clinical features Ref type saliva OSCC 90 OSCC patients, 70 hsa_circ_0001874 up TNM stage, tumor grade [165] OLK subjects OSCC 90 OSCC patients, 70 hsa_circ_0001971 up TNM stage [165] OLK subjects plasma GC 104 GC patients, 104 Hsa_circ_0000190 down tumor diameter, lymphatic metastasis, distal [163] healthy individuals metastasis, TNM stage, CA19–9levels GC 20 GC patients, 20 hsa_circ_0006633 up distal metastasis, tissue carcinoembryonic antigen [167] healthy individuals level GC 45 GC patients, 17 hsa_circ_0000520 down CEA expression [168] healthy individuals GC 24 GC patients, 14 hsa_circ_0000673 down TNM stage [169] healthy individuals GC 121 GC patients, 121 hsa_circ_0001017, down OS, DFS [170] healthy individuals hsa_circ_0061276 ESCC 30 ESCC patients, 25 Circ-TTC17 up TNM stage, lymphatic metastasis, OS [171] healthy individuals PC 31 PC patients, 31 circ-LDLRAD3 up CA19–9, N classification, venous invasion, [172] healthy individuals lymphatic invasion BC 57 BC patients, 17 hsa_circ_0001785 down histological grade, TNM stage, distant metastasis [173] healthy individuals HCC 104 HCC patients, 52 hsa_circ_0001445 down AFP level [174] healthy individuals GC 102 GC patients, 105 Hsa_circ_0000181 down tumor differentiation, carcinoembryonic antigen [175] healthy individuals LAC 30 LAC patients, 30 hsa_circ_0013958 up TNM stage, lymphatic metastasis [176] healthy individuals serum HCC 64 HCC patients, 30 circ-ZEB1.33 up TMN stages, OS [162] healthy individuals BCa 197 BCa patients, 97 hsa_circ_0000285 down tumor size, differentiation, lymph node metastasis, [177] healthy individuals distant metastasis, TNM stage, OS NPC 150 NPC patients, 100 circRNA_0000285 up tumor size, differentiation, lymph node metastasis, [178] healthy individuals distant metastasis, TNM stage. exosome UCB 71 UCB patients, 36 circPRMT5 up lymph node metastasis, T and N status, DFS [166] (serum and urine) healthy individuals UCB 18 UCB patients, 14 circPRMT5 up lymph node metastasis, T and N status, DFS [166] healthy individuals Su et al. Molecular Cancer (2019) 18:90 Page 13 of 17 increased to 0.775, suggesting good diagnostic value of and their important roles in organisms, especially in can- hsa_circ_0000745 in plasma in combination with CEA cer. The stability, conservatism, universality, and specifi- level in GC. Zhao and colleagues [165] performed micro- city of circRNAs make it to be a potential valuable array screening of circRNA in saliva from oral squamous prognostic and diagnostic biomarker for cancer, and the cell carcinoma patients compared with healthy controls functions and regulatory roles that circRNAs play in and identified 20 downregulated and 12 upregulated cir- tumor cells make it possible to be a target for the treat- cRNAs in oral squamous cell carcinoma saliva. Among ment of cancer. However, the study of circRNAs in can- these, two upregulated circRNAs, hsa_circ_0001874 and cer remains in its infancy. CircRNAs are far from being hsa_circ_0001971, showed a AUC of 0.863 and 0.845, re- able to be incorporated into clinical practice, and there spectively. The combination of these two circRNAs are still fundamental problems necessitating further in- showed a AUC of 0.922. Furthermore, the risk score based vestigation in this field. For example, there is an urgent on hsa_circ_0001874 and hsa_circ_0001971 could dis- need to develop a common standardized naming system criminate patients with OSCC from patients with oral for circRNA research. In addition, further investigation leukoplakia with AUC for risk score 0.863, suggesting po- is needed regarding the precise mechanisms, other than tential of salivary hsa_circ_0001874 and hsa_circ_0001971 those of miRNA sponge activity, of circRNAs underlying as OSCC diagnostic biomarker. Moreover, recently studies the initiation and progression of cancer. Furthermore, have found that circRNAs were enriched and stable in more controlled and large-scale clinical studies are re- exosomes, which are small membrane vesicles secreted by quired before cancer-specific circRNAs can be recom- tumor cells into the extracellular fluids. Chen and col- mended for diagnosis and treatment. An advanced leagues [166] revealed that circPRMT5 was enriched in understanding of circRNA will provide beneficial insights both serum and urine exosomes from urothelial carcin- and generate new hypotheses regarding cancer pathogen- oma patients compared to healthy donors. The high levels esis. We hope that the appropriate and precise use of cir- of circPRMT5 in serum and urinary exosomes were cRNAs in clinical applications might eventually create positively associated with lymph node metastasis and ad- breakthroughs for cancer therapy in the near future. vanced tumor progression, suggesting that circPRMT5 Abbreviations might be a prognostic biomarker in urothelial carcinoma. 3′-UTR: 3′-untranslated region; ABCB1: ATP-binding cassette B1; AKT: Protein In addition, it was found that other circRNAs, such as kinase B; As-HaCaT: Arsenite-treated HaCaT; AUC: Area under curve; BAX: BCL2-associated X Protein; BC: Breast cancer; Bca: Bladder cancer; bcl- hsa_circ_0006633 [167], hsa_circ_0000520 [168], hsa_- 2: B-cell lymphoma-2; BCSCs: Breast CSCs; CCNE1: Cyclin E1; CDK: Cyclin- circ_0000673 [169], hsa_circ_0001017 [170], hsa_- dependent kinase; CDR1as: Cerebellar degeneration-related protein 1 anti- circ_0061276 [170], circ-TTC17 [171], circ-LDLRAD3 sense RNA; ceRNA: Competing endogenous RNA; circ-Amotl1: CircRNA derived from angiomotin-like1; CircRNAs: Circular RNAs; ciRNA: Circular [172], hsa_circ_0001785 [173], hsa_circ_0001445 [174], intronic RNA; CML: Chronic myelogenous leukaemia; CRC: Colorectal cancer; hsa_circ_0000181 [175], hsa_circ_0013958 [176] and hsa_- CSCs: Cancer stem cells; DNMT1: DNA methyltransferase 1; DOCK1: Dedicator circ_0000285 [177, 178], were also detectable in plasma, of cytokinesis 1; ecircRNA: Exonic circRNA; ECM: Extracellular matrix; EGFR: Epidermal growth factor receptor; EIciRNA: Exon-intron circRNA; serum or exosomes and could distinguish patients with EIF3J: Eukaryotic translation initiation factor 3 subunit J; EMT: Epithelial- cancer from healthy controls and were potential valuable mesenchymal transition; EZH2: Enhancer of zeste homolog 2; FLI1: Friend biomarkers in cancer (Table 3). leukemia virus integration 1; Foxo4: Forkhead Box O 4; GC: Gastric cancer; HPSE: Heparanase; HuR: Human antigen R/ELAV-like protein 1; IGF1R: Insulin- like growth factor I receptor; IRES: Internal ribosome entry site; ITGB8: Integrin subunit beta 8; LSCC: Laryngeal squamous cell carcinoma; Conclusions MREs: miRNA response elements; MYLK: Myosin Light Chain Kinase; NSCLC: Non-small cell lung cancer; nt: Nucleotide; ORF: Open reading frame; CircRNAs were previously thought to represent errors OS: Osteosarcoma; PAIP2: Polyadenylate-binding protein-interacting protein during the process of RNA splicing. Fortunately, in the 2; PD-L1: Programmed death-ligand 1; PIK3CD: Phosphatidylinositol-4,5- past few years, accumulating evidence has illustrated the bisphosphonate 3-kinase, catalytic subunit delta gene; PRC2: Polycomb- repressive complex 2; PTEN: Phosphatase and tensin homolog deleted on significant regulatory effects of circRNAs on pathophysi- chromosome ten; ROCK1: Rho-associated protein kinase 1; Smad: Mothers ologic processes, including tumorigenesis. CircRNAs are against decapentaplegic; snRNPs: Small nuclear ribonucleic proteins; TDP now regarded as a class of abundant, stable, diverse and cells: CD133 + CD44+ CSCs; TERT: Telomerase reverse transcriptase; TGF- β: Transforming growth factor-β; TIF1γ: Transcriptional intermediary factor 1 conserved RNA molecules with a range of activities, in- γ; TKI: Tyrosine kinase inhibitor; VEGF: Vascular endothelial growth factor; cluding sponge, translation, splicing and regulation. The VEGFR: Vascular endothelial growth factor receptor; YAP1: Yes-associated functions of circRNAs in cancer are gaining considerable protein 1; YY1: Yin Yang-1 interest and have become a focus of cancer research. In Acknowledgements this review, we briefly summarized the recent advances We thank Dr. Kunjian Peng for the helpful discussion. regarding circRNAs in the hallmarks, stemness, resistance Funding to therapy, and the possibility as biomarkers for cancer. This work is supported by grants from the National Natural Scientific These research endeavors into circRNAs expand our Foundation of China (81802947), the Natural Science Foundation of Hunan understanding of eukaryotic transcription participants Province (2019JJ50968, 2019JJ50358, 2017JJ2173, 2018JJ3314), Health and Su et al. Molecular Cancer (2019) 18:90 Page 14 of 17 Family Planning Commission of Hunan Province (B20180545, C2019074), modulates ribosomal RNA maturation and atherosclerosis in humans. 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Circular RNAs in Cancer: emerging functions in hallmarks, stemness, resistance and roles as potential biomarkers

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Springer Journals
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Copyright © 2019 by The Author(s).
Subject
Biomedicine; Cancer Research; Oncology
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1476-4598
DOI
10.1186/s12943-019-1002-6
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Abstract

Circular RNAs (circRNAs) are a class of RNA molecules with closed loops and high stability. CircRNAs are abundantly expressed in eukaryotic organisms and exhibit both location- and step-specificity. In recent years, circRNAs are attracting considerable research attention attributed to their possible contributions to gene regulation through a variety of actions, including sponging microRNAs, interacting with RNA-binding proteins, regulating transcription and splicing, and protein translation. Growing evidence has revealed that circRNAs play critical roles in the development and progression of diseases, especially in cancers. Without doubt, expanding our understanding of circRNAs will enrich knowledge of cancer and provide new opportunities for cancer therapy. In this review, we provide an overview of the characteristics, functions and functional mechanisms of circRNAs. In particular, we summarize current knowledge regarding the functions of circRNAs in the hallmarks, stemness, resistance of cancer, as well as the possibility of circRNAs as biomarkers in cancer. Keywords: CircRNAs, Cancer, Function, Hallmarks, Stemness, Resistance, Biomarker Introduction revealed that more than 10% of expressed genes are able CircRNAs are a class of single-stranded closed circular to produce circRNAs. In 2013, Hansen et al. [6] and RNA molecules that lack 5′-3′ ends and poly (A) tails Memczak et al. [7] reported that circular transcripts of [1]. Four decades have elapsed since circular RNAs (cir- cerebellar degeneration-related protein 1 antisense RNA cRNAs) were first found in plant-based viruses in 1976 (CDR1as, also known as ciRS-7) can serve as miRNA [2]. CircRNAs were later found in eukaryotes as an en- sponges for miR-7. These works transformed circRNAs dogenous RNA splicing product in 1979 and in humans into a focal point of scientific research and rising stars in following hepatitis delta virus infection in 1986 [3, 4]. the noncoding RNA field. However, circRNAs were initially considered as func- In recent years, following the development and appli- tionless byproducts of aberrant RNA splicing and thus cation of high-throughput deep RNA sequencing and have not garnered sufficient scientific attention. In 2012, bioinformatics technology, circRNAs have been found to Salzman et al. [5] identified the abundance of circRNA be widespread in eukaryotic cells and dynamically species in both normal and mammalian cells and expressed in various developmental stages and physio- logical conditions [8, 9]. A large number of researchers have demonstrated that circRNAs are correlated with * Correspondence: hnchw11@163.com; liaoqianjin@hnszlyy.com the pathogenesis of various human diseases, including Min Su and Yuhang Xiao contributed equally to this work. nervous system disorders [10], cardiovascular disorders Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, [11], Alzheimer’s disease [12], osteoarthritis [13], dia- Central South University, Changsha, China betes [14], silicosis [15] and cancer [16, 17]. In particular, Department of the 2nd Department of Thoracic Surgery, Hunan Cancer circRNAs have been reported to play critical roles in Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, People’s Republic of cancer growth, metastasis, stemness and resistance to China therapy [18, 19]. Natural circRNA, which plays an Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Su et al. Molecular Cancer (2019) 18:90 Page 2 of 17 important role in the RNA interaction network, was stretches initially characterized by the action of the proven to be extremely abundant, relatively stable, di- Arthrobacterluteus restriction endonuclease) across verse and conserved [8]. Emerging evidence suggests exon-flanking introns. Intron paring place the splice sites that circRNAs are responsible for complicated functions close to each other, followed by back-splicing of pre- such as serving as endogenous RNAs to sponge miRNAs, mRNAs and exon circularization. Unlike ecircRNAs, regulating expression of parental genes, modulating alter- EIciRNAs retain the introns that are not spliced out com- native splicing, regulating RNA–protein interactions, and pletely [29]. Pre-mRNAs that contain flanking Alu com- acting as scaffolds in the assembly of protein complexes plementary pairs or flanking complementary sequence [20, 21]. In this review, we describe the characteristics, pairs other than Alu could facilitate the production of functions and functional mechanisms of circRNA. Specif- EIciRNAs [29]. In addition, ciRNAs are derived from in- ically, we discuss the role of circRNA in the hallmarks, tron lariats that escape the normal intron debranching stemness, resistance of cancer, as well as the possibility of and degradation [30]. The formation of ciRNAs are circRNAs as biomarkers in cancer. dependent on the presence of a 7 nt GU-rich sequence near the 5′ splicing site and a 11 nt C-rich motifs near the Characteristics and biogenesis of circRNAs 3′ branch point site. Up to today, several sequence fea- According to recent research, circRNAs are typically tures have been indicated to influence the biosynthesis of generated from one to five exons with length between a circRNA, such as length of intron and exon, repetitive se- few hundred to thousands of nucleotides (nt) [22, 23]. quences and RNA-binding proteins (RBPs) [31, 32]. The There are several important properties of circRNAs gen- RBPs that include muscleblind (MBL), quaking (QKI), SR erated by back-splicing: (1) circRNAs have a closed ring protein, adenosine deaminases that act on RNA (ADAR1), structure—without either 5′–3′ polarity or a polyadeny- fused in sarcoma (FUS), heterogeneous nuclear ribonu- lated tail—and are thus insusceptible to degradation by cleoprotein (hnRNP), NF90/NF110, heterogeneous nucle- exonucleases and much more stable than linear RNA arribonucleoprotein L (HNRNPL) and muscleblind [24]; (2) circRNAs are widely expressed in eukaryotic (MBL), could positively or negatively regulate the forma- cells, and more than one million circRNAs exist in hu- tion of circRNAs [32–35](Fig. 1). man tissues as detected by high-throughput sequencing [25]; (3) circRNAs primarily reside in the cytoplasm, Functional mechanisms of circRNAs whereas a small number of circRNAs are located in the Act as miRNA sponges nucleus [7]; (4) most circRNAs have highly conserved se- Multiple lines of evidence have proven that some cir- quences between different species [26]; (5) circRNAs exhibit cRNAs are rich in miRNA response elements (MREs) tissue-specific and dynamic developmental stage-expression and may serve as miRNA sponges. MiRNAs are small, patterns [9]; (6)circRNAsplayaregulatoryrole atthe level noncoding RNAs with approximately 22 nt lengths that of transcription or posttranscription [7]. play an important role in posttranscriptional gene ex- Both circRNAs and linear RNAs are originated from pression through binding to specific target sites within precursor mRNAs (pre-mRNAs), but in contrast to linear the mRNA 3′-untranslated region (3′-UTR), leading to RNAs that are generated by classical splicing, circRNAs decreased mRNA stability and suppression of translation are usually formed by back-splicing [8]. CircRNAs can be [36, 37]. CircRNAs may regulate gene expression derived from all regions of the genome, including inter- through binding to and releasing miRNAs from their genic, intronic, antisense and untranslational regions [7]. downstream target genes [38, 39]. In comparison with There are three major categories of circRNAs base on other miRNA sponges, some circRNAs exhibit a super- their origin: exonic circRNAs (ecircRNAs), exon-intron ior ability to bind with miRNAs and have been referred circRNAs (EIciRNAs), and circular intronic RNAs (ciR- to as “super sponge” [21]. The best example is CDR1as, NAs) [27]. EcircRNAs are derived from exons and ac- which harbors more than 70 selectively conserved miR-7 count for the main part of identified circRNAs [28]. Two binding sites [40]. In addition, there are a large number of models of ecircRNA formation have been proposed [8]. examples of circRNAs able to act as miRNA sponges, includ- (1) Iariat-driven circularization model: the introns in a lar- ing circRNA ZNF609 [41], circ-SRY [42], mm9_circ_012559 iat intermediate that consists several exons and introns [43], circDOCK1 [44], and many others. are removed, followed by the connection between the 3′ splice site of an upstream exon (splice acceptor) and the Interact with RNA binding proteins 5′ splice site of a downstream of exon (splice donor), In addition to acting as miRNA sponges, some circRNAs resulting in the formation of ecircRNAs. (2) Intron that harbor binding sites for RNA-binding proteins may pairing-driven circularizing model: a circular structure is serve as protein sponges or decoys and thus regulate formed by base-paring between reverse complementary gene expression. For instance, the circRNA originating sequences (such as Alu repeats, which are short DNA from the PABPN1 locus (circ-PABPN1) binds to human Su et al. Molecular Cancer (2019) 18:90 Page 3 of 17 Fig. 1 Formation of three types of circRNAs. a Exonic circular RNA (ecircRNA) is formed through back-splicing of the 5’splice site (splice donor site) to a 3’splice site (splice acceptor site); (b) The intron 1 is removed and bring the 5′ splice site of Exon 2 close to 3′ splice site of Exon 1, to form a ecircRNA that contains multiple exons. Exons can also skip splicing, exon 1 can also link with exon 3; (c) Circular intronic RNA (ciRNA) are derived from intron lariats that escape the normal intron debranching and degradation. Reverse complementary sequences of lariat intron excised from pre-mRNA can pair to produce close loop structure termed as ciRNA; (d) Exon–intron circRNAs (EIciRNAs) are circularized with introns‘retained’between the exons. Intron 3 retaines with Exon 3 and Exon 4 to form an EIciRNAs antigen R/ELAV-like protein 1 (HuR) and prevents HuR shown that some circRNAs possess translational ability. from binding to PABPN1 mRNA, subsequently sup- To this point, at least four circRNA molecules have been pressing PABPN1 translation [45]. The other examples, proven to be translatable. Legnini I. et al. [50] revealed including circ-Foxo3 [46] and circ-Mbl [31], primarily that circ-ZNF609 contains an open reading frame (ORF) interact with RNA binding proteins. and could be translated into a protein in murine myo- blasts when driven by IRES. Additionally, circ-SHPRH Regulate transcription or splicing [51] and circ-FBXW7 [52], as well as proteins encoded Some circRNAs have been demonstrated to regulate gene by them, are found to be abundantly expressed in nor- transcription through combining with RNA polymerase II mal human brains but downregulated in glioma. Both of complex and translating related proteins [47]. For example, the circRNAs have an ORF driven by the IRES to trans- circ-EIF3J and circ-PAIP2 were found to interact with the late a functional protein. Analogously, Pamudurti N. R. U1 snRNPs and RNA polymerase II in the promoter region et al. [53] found that circMbl can also translate protein of the host gene to realize enhanced transcription of their in a cap-independent manner. parental genes, such as PAIP2 and EIF3J [29]. Studies have also suggested that circRNAs can contrib- Regulate epigenetic alterations ute to the regulation of selective splicing. A study by Aberrant DNA methylation and histone modifications Ashwal-Fluss et al. [31] showed that circMbl is derived that associated with epigenetic gene expression are fre- from the circularization of the second exon of the spli- quently found in cancer [54, 55]. Some circRNAs have cing factor muscleblind (MBL) and could compete with been found to regulate these epigenetic alterations. Chen linear MBL mRNA for selective splicing. Notably, due to et al. [56] reported that circFECR1 induced extensive the presence of functional circMbl binding sites in the CpG DNA demethylation in the promoter of FLI1 and MBL protein, MBL could interact with circMbl and pro- thus epigenetically activated FLI1. CircFECR1 was dem- mote circMbl production. Thus, circMbl negatively af- onstrated to downregulate the transcription of DNMT1, fects canonical splicing and decreases the production of a critical methyltransferase required for the maintenance the parental mRNA. of DNA methylation, through binding to the DNMT1 promoter. In addition, circFECR1 could recruit TET1 Translate proteins DNA demethylase to the FLI1 promoter and induce Because of lacking 5′-3′ polarity and polyadenylated DNA demethylation. Enhancer of zeste homolog 2 tails, as well as internal ribosome entry sites (IRES), cir- (EZH2) is a subunit of polycomb-repressive complex 2 cRNAs were initially defined as a distinct class of en- (PRC2), which functions as a H3K27 methyltransferase dogenous noncoding RNA that could not translate and regulates histone methylation [57, 58]. Several cir- proteins [48, 49]. However, convincing evidence has cRNAs have been reported to regulate EZH2 expression Su et al. Molecular Cancer (2019) 18:90 Page 4 of 17 through acting as miRNA sponges, subsequently regulate factors and regulate cell growth [63, 64]. A variety of studies histone methylation indirectly. For example, circBCRC4 is have shown that EGFR is a target of miR-7, which is a tumor able to promote the expression of EZH2 by binding with suppressor regulating various biological processes [65, 66]. miR-101 [59], hsa_circ_0020123 is able to upregulate EZH2 One of the most well-known circRNAs, CDR1as, harbors and ZEB1 through sponging miR-144 [60], hsa_circ_0071589 more than 70 selectively conserved miR-7 target sites, thus can regulate the miR-600/EZH2 signaling [61](Fig. 2). acting as a sponge of miR-7 [6, 7]. CDR1as, predominantly found in human brain, is approximately 1500 nt in length CircRNAs regulate the hallmarks of cancer [67]. CDR1as has been reported to be involved in pulmonary In 2000, Hanahan and Weinberg proposed six hallmarks fibrosis, myocardial infarction, insulin secretion, neuropsychi- of cancer that result in the progressive conversion of atric disorders, and cancer [68–71]. Zhang et al. [72]re- normal cells into cancerous cells [62]. Most and perhaps ported that CDR1as was highly expressed in non-small cell all types of human cancer shared these acquired capabil- lung cancer (NSCLC) tissues, correlated with TNM stage, ities, including self-sufficiency in growth signals, evasion lymph node metastasis and survival time, and acted as an in- of antigrowth signals, resistance to cell death, limitless dependent prognostic factor for the NSCLC patients. Knock- replicative potential, sustained angiogenesis, tissue inva- down of CDR1as promotes cell vitality and growth through sion and metastasis. In recent years, some circRNAs induction of cell apoptosis and cell cycle arrest in G1/S have been shown to be involved in these properties of phase. Mechanical assays revealed that CDR1as functioned cancer (Fig. 3 and Table 1). as a miR-7 sponge to increase the expression levels of miR-7 targeting proto-oncogenes (EGFR, CCNE1 and PIK3CD). In Self-sufficiency in growth signals addition, CDR1as was also markedly overexpressed in colo- Normal cells acquire self-sufficiency in growth signals to rectal cancer (CRC) tissues and correlated with advanced change into an active proliferative state [62]. The mito- tumor stage, lymph node involvement, distant metastasis genic growth signals are transmitted into the cell interior and poor patient survival of CRC patients [73]. Overexpres- by binding to the transmembrane receptors. Cancer cells sion of CDR1as led to blocking of the tumor suppressive ef- could produce dysregulated growth factors and/or the fects of miR-7 and resulted in a more aggressive oncogenic corresponding receptor molecules themselves to lead to phenotype. Overexpression of CDR1as induced inhibition of an autocrine stimulation. miR-7 and subsequent activation of miR-7 target oncogenes Epidermal growth factor receptor (EGFR), highly expressed EGFR and RAF1. However, in another study, CDR1as ex- in a variety of solid tumors, is a critical molecular signal that pression was shown to be downregulated in hepatocellular can trigger an intracellular transduction cascade of growth carcinoma (HCC) tissues and cell lines [74]. The expression Fig. 2 The functional mechanisms of CircRNAs. a Acting as miRNA sponge; (b) Binding with RNA binding protein (RBP); (c) Regulating transcription; (d) Regulating splicing; (e) Translated into Protein; (f) Regulating epigenetic alterations Su et al. Molecular Cancer (2019) 18:90 Page 5 of 17 Fig. 3 CircRNAs involved in the hallmarks of cancer. a CDR1as and circHIPK3 active cell proliferative through regulating EGFR; (b) Circ-ITCH et al. promote cancer cells evading antigrowth signals by preventing expression or activation of tumor suppressors,suchasPTEN andCDK;(c) Hsa_circ_0007534 et al. promote cancer cells evading cell death via regulating cellular apoptosis or autophagy; (d) Has-circ-0020397 limits replicative potential of cancer cell trough regulating TERT; (e) CircRNA-MYLK et al. sustain angiogenesis trough regulating VEGF; (f) Dirc-10,720 et al. regulate the process of EMT and thus tissue invasion and metastasis of cancer profiles differ between NSCLC, CRC and HCC, possibly due migration of cells. Following binding to specific moieties to the tissue-specificity of circRNAs. Ectopic expression of of the ECM, the integrin receptors are able to transduce CDR1as could increase cell growth and adhesion while inhi- signals into the cell that mediate cell behavior. Integrin biting the migration of HCC cells. CDR1as exhibited these subunit beta 8 (ITGB8) is an important member of the functions through regulating the expression of EGFR. An- integrin family [79]. A recently study showed that hsa_- other circRNA that regulates EGFR is circHIPK3 (hsa_- circ_0046701, which was highly expressed in glioma tis- circ_0000284), which originates from the HIPK3 gene exon sues and cell lines, was able to promote cell proliferation 2, with the length of 1099 nt [75, 76]. CircHIPK3 is a particu- and invasion through regulating ITGB8 expression by larly abundant circRNA that has been proposed to be in- sponging miR-142-3p [80]. volved in tumorigenesis [76, 77]. It was shown to be C-myc, an important transcription factor, acts as an markedly overexpressed in CRC tissues and cell lines and oncogene to regulate various cellular processes including positively associated with advanced clinical stage and poor cell proliferation, differentiation, and apoptosis [81, 82]. survival of CRC patients [75]. CircHIPK3 knockdown signifi- It has been reported that c-myc can regulate up to 15% cantly inhibited CRC cell proliferation while inducing cell of gene expression [83]. Yang and coworkers [52]conducted apoptosis. Interestingly, miR-7 was identified and confirmed the RNA-expression profiling from glioblastoma and to be the only miRNA that directly interacts with circHIPK3 matched noncancerous tissues and characterized the circular [75]. Furthermore, overexpression of circHIPK3 effectively form of the FBXW7 gene, circ-FBXW7. Circ-FBXW7 was reversed miR-7-induced attenuation of CRC cell progression downregulated in glioblastoma tissues and correlated with through upregulating the expression of several key miR-7 tar- overall survival of glioblastoma patients. The spanning junc- get genes, including EGFR, IGF1R, FAK and YY1. tion open reading frame in circ-FBXW7 driven by internal However, EGFR is not the only growth signal regulated ribosome entry site encoded a novel 185-amino acid protein, by circRNAs. Integrins are transmembrane receptors which was termed as FBXW7-185aa. FBXW7-185aa, but not and mediators of the interactions between cells and the circ-FBXW7, could function as a tumor suppressor to induce extracellular matrix (ECM) [78]. Integrin-mediated inter- cell cycle arrest and inhibit proliferation in glioma cells actions are required for the cytoskeletal organization, at- through reducing the half-life of c-myc. FBXW7-185aa was tachment, survival, proliferation, differentiation and shown to directly interact with de-ubiquitinating enzyme Su et al. Molecular Cancer (2019) 18:90 Page 6 of 17 Table 1 CircRNAs involved in the hallmarks of cancer Function CircRNA Cancer type expression Associated clinical features Associated cell process Targets Ref. Sustaining growth CDR1as NSCLC up TNM stage, lymph nodes metastasis promote cell vitalities and growth, inhibit miR-7/EGFR, CCNE1, [72] signaling and survival time apoptosis and cell cycle arrest PIK3CD. CDR1as CRC up advanced tumor stage, tumor depth, – miR-7/EGFR, RAF1 [73] and survival time CDR1as HCC down – promote cell growth, adhesion, and inhibit miR-7/EGFR [74] migration circHIPK3 CRC up metastasis, clinical stage and survival inhibite cell proliferation, migration, invasion, and miR-7/EGFR, FAK, IGF1R, [75] time induce apoptosis YY1 hsa_circ_0046701 glioma up – promote cell proliferation and invasion miR-142-3p/ITGB8 [80] circ-FBXW7 glioblastoma down survival time inhibit cell proliferation and cell cycle acceleration FBXW7-185aa/c-Myc [52] Circ-Amotl1 – up – promote cell proliferation c-myc [84] Evading growth circ-ITCH Bca down histological grade and survival time inhibite cell proliferation, migration, invasio, induce miR-17, miR-224/p21, [90] inhibitors G1/S cell cycle arrest and apoptosis PTEN axis circ-ZFR GC down – inhibit cell propagation, cell cycle and promote miR-130a, miR-107/PTEN [91] apoptosis CDR1as GC up lymph nodes metastasis and survival promote cell proliferation, migration and inhibit miR-7/PTEN/PI3K/AKT [92] time apoptosis circRNA-000425 GC down – inhibit cell growth miR-17,miR-106/p21, BIM [93] Circ100284 – up – promote cell cycle acceleration miR-217/EZH2/cyclin D1, [97] CDK4 hsa_circ_0016788 HCC up – promote cell proliferation, invasion and inhibit miR-486/CDK4 axis [98] apoptosis circHIPK3 gallbladder up – promote cell survival and proliferation, inhibit cell miR-124/ROCK1, CDK6 [99] cancer apoptosis Resisting apoptosis hsa_circ_0007534 CRC up tumor stage and lymph node ptomote cell proliferation and inhibit apoptosis Bcl-2, Bax [104] metastasis circUBAP2 osteosarcoma up tumor progression and prognosis promote cell growth and inhibit apoptosis miR-143/Bcl-2 [105] hsa_circ_0009910 osteosarcoma up – promote cell proliferation inhibition, inhibit cell miR-449a/IL6R/Bcl-2/Bax [106] cycle arrest, and inhibit apoptosis hsa_circRNA_103809 CRC down – promote apoptosis miR-532-3p/FOXO4 axis [107] circNFIX glima up – promote cell propagation, migration and inhibit miR-34a-5p/NOTCH1 [108] apoptosis circ-DNMT1 BC up – inhibit autophagy, promote cell proliferation and p53, AUF1 [110] survival Uncontrolled has-circ-0020397 CRC up – promote cell viability and inhibit apoptosis mir-138/TERT, PD-L1 [114] replicative immortality Promoting circRNA-MYLK Bca up pathological stage, T and N promote cell growth, angiogenesis and metastasis miR-29a/VEGFA/VEGFR2 [118] angiogenesis classifications and survival time Su et al. Molecular Cancer (2019) 18:90 Page 7 of 17 Table 1 CircRNAs involved in the hallmarks of cancer (Continued) Function CircRNA Cancer type expression Associated clinical features Associated cell process Targets Ref. cZNF292 Glima up – promote cell proliferation, tube formation and VEGF-A, EGF, TGF-β1[122] angiogenic potential circHIPK3 Bca down tumor grade, invasion, lymph node inhibit migration, invasion, and angiogenesis miR-558/HPSE/VEGF [119] metastasis Activating invasion circ-10,720 HCC up Tumor metastasis and survival time promote cell proliferation, migration, invasion and Vimentin [129] and metastasis EMT circPTK2 NSCLC down – inhibit cell invasion and EMT miR-429, miR-200b-3p/ [132] TIF1y circSMAD2 HCC down – inhibit cell migration, invasion, and EMT miR-629 [137] hsa_circ_0061140 ovarian up – promote cell proliferation, migration, invasion and miR-370/FOXM1 [141] cancer EMT circ_0067934 NSCLC up TNM stage, lymph node statu, distant promote cell proliferation, migration, invasion and N-cadherin, vimentin [142] metastasis and survival time EMT snail, and E-cadherin circRNA_0023642 GC up – pormote cell proliferation, migration, invasion and N-cadherin, vimentin [143]` EMT snail, and E-cadherin Su et al. Molecular Cancer (2019) 18:90 Page 8 of 17 USP28, and thus antagonize the USP28-induced de-ubiquiti- HNRNPH1, which codes for circRNA-000425. nation of c-Myc and increase c-Myc ubiquitination. Another CircRNA-000425 was identified as a sponge of miR-17/ circRNA that could regulate c-myc is circRNA derived from miR-106b and indirectly modulated their targets, such as angiomotin-like1 (circ-Amotl1) [84]. Circ-Amotl1 was highly p21 and BIM, thus suppressing GC cell growth. expressed in breast cancer (BC) tissues and cell lines. Knock- In addition to these well-known tumor suppressors, down of circ-Amotl1 promoted cell proliferation and inhib- some circRNAs could also regulate tumor growth by ited apoptosis of BC cells. In addition, circ-Amotl1 was regulating cell cycle mediators, such as Cyclin D1, a demonstrated to bind to c-myc, translocate into nucleus and well-known regulator of the cell cycle that promotes the prevented degradation of c-myc. Ectopic expression of transition from G1 to S phase by activating CDK4 or circ-Amotl1 enhanced the binding affinity of c-myc to the CDK6 [96]. Xue and coworkers [97] performed a cir- promoters of a number of its targets, including HIF-1α, cRNA microarray to analyze the variability of circRNAs Cdc25a, ELK-1, and JUN. However, how circ-Amotl1 pre- in arsenite-treated HaCaT (As-HaCaT) cells and in vents c-myc degradation is not clear and awaits further arsenite-transformed cells compared to normal HaCaT cells investigation. and identify cirRNAs that involved in arsenite-induced ac- celeration of the cell cycle. Circ100284 was greatest Insensitivity antigrowth signals up-regulated in As-HaCaT cells and showed the most There are multiple antiproliferative signals in normal change following arsenite treatment. Knockdown of cells that operate to maintain cells in a quiescent state circ100284 inhibited G1/S transition in As-HaCaT cells. [62]. These signals can block cell proliferation through Circ100284 was demonstrated to be involved in the arresting the cell cycle [85]. However, cancer cells can arsenite-promoted cell cycle through regulation of EZH2 evade antigrowth signals by preventing expression or ac- via sponging miR-217. EZH2 subsequently bind to the pro- tivation of tumor suppressors. moter of CCND1, the host gene of cyclin D1. Knockdown Phosphatase and tensin homolog (PTEN), deleted of EZH2 suppressed the expression of cyclin D1 and from chromosome ten and mutated at high frequency in CDK4. Although EZH2 frequently acts through methyla- a variety of cancers, can contribute to the G0-G1 cell tion of H3K27 as discussed above, here, it functions cycle regulation and additional cellular functional activ- through the methylase-independent pathway. These results ities [86, 87]. Cyclin-dependent kinase (CDK) inhibitor suggested that, in HaCaT cells, circ100284 was induced by p21 is a cell cycle suppressing protein, and overexpres- arsenite treatment and acted as a sponge for miR-217 to sion of p21 acts to suppress cell growth [88, 89]. up-regulate EZH2, which, in turn, increased the expression Circ-ITCH, the circularized product from several exons of cyclin D1 and CDK4, and thus lead to cell cycle acceler- of itchy E3 ubiquitin protein ligase homolog (ITCH), has ation and malignant transformation. In another study, been reported to be downregulated in bladder cancer Guan et al. [98] performed circRNA microarray analysis in (BCa)tissues and correlated with the histological grade HCC tissue and identified a highly expressed circRNA, and shortened survival of BCa patients [90]. It was also hsa_circ_0016788. Silencing of hsa_circ_0016788 inhibited downregulated in BCa cell lines, and the enforced expres- proliferation and promoted apoptosis of HCC cells through sion of circ-ITCH inhibited cell proliferation, migration, in- regulation of the miR-486/CDK4 axis. CircHIPK3 was vasion and metastasis. Mechanical assays demonstrated shown to be overexpressed in human gallbladder cancer that circ-ITCH could directly sponge miR-17 and miR-224 cells [99]. Silencing of circHIPK3 decreased the proliferative and lead to increased expression of their target genes, and survival capacities, induced apoptosis of gallbladder PTEN and p21. Another circRNA, circ-ZFR, was shown to cancer cells through sponging the tumor-suppressive be downregulated in gastric cancer (GC); circ-ZFR regu- miR-124, and increased expression of ROCK1 and CDK6, lated GC progression by directly binding with miR-130a/ which are miR-124 targets [100, 101]. miR-107, and further regulated the expression of PTEN, which is a target of these miRNAs [91]. In addition, Evading apoptosis CDR1as was overexpressed in GC tissues and correlated Apart from the rate of cell proliferation, the rate of cell with poor survival [92]. Ectopic expression of CDR1as in- attrition also determines the populations of cells [62]. creased expression of PTEN through sponging of miR-7 Apoptosis is the major mechanism leading to this attri- and subsequently activated the PTEN/PI3K/AKT pathway. tion. The other two pathways related to cell attrition are Liu and colleagues [93] identified circRNA-000425 as a autophagy and necrosis [85]. Cancer cells acquired the novel inhibitory target of Yes-associated protein 1 (YAP1), ability to evade these signals. an transcriptional coactivator factor that acts as an onco- It is well known that B-cell lymphoma-2 (Bcl-2) is an gene associated with cancer malignancy in several cancer important anti-apoptotic molecule that protects cells types [94, 95]. YAP1 could suppress the expression of from apoptosis, while BCL2-associated X protein (Bax) circRNA-000425 through binding to the promoter of is a proapoptotic gene [59, 102]. Thus, the ratio of Su et al. Molecular Cancer (2019) 18:90 Page 9 of 17 Bcl-2/Bax is a profound indicator of cell survival [103]. ends are critical for this finite replicative potential: they Hsa_circ_0007534 was significantly overexpressed in shorten after every cell division, and therefore, the number CRC tissues and related to tumor stage and lymph node of cell division cycles is dictated by the length of telomeres metastasis [104]. Silencing of hsa_circ_0007534 inhibited [111]. Approximately 85–90% of human cancers overex- proliferation while promoting the apoptosis of CRC cells. press telomerase, which adds telomeric repeats onto the Moreover, the Bcl-2/Bax ratio was decreased following ends of telomeric DNA, suggesting that limitless replica- hsa_circ_0007534 silencing, which demonstrated that tive potential is essential for the development of their ma- hsa_circ_0007534 inhibits CRC cell proliferation, at least lignant growth [112]. partially, by inducing apoptosis. However, how hsa_- Telomerase reverse transcriptase (TERT) is a catalytic circ_0007534 regulates the Bcl-2/Bax ratio is so far un- subunit of telomerase [113]. Zhang and colleagues [114] known and further studies will need to unravel the reported that hsa_circ_0020397, derived from the molecular mechanism. DOCK1 gene, was upregulated in CRC cells, promoted Zhang et al. [105] performed microarray experiments their viability, and inhibited apoptosis. By using a com- to examine the expression profiles of circRNAs in osteo- mon bioinformatic algorithm, the authors predict that sarcoma tissue and found that circUBAP2 was the most an important cancer suppressor, miR-138, possesses markedly increased circRNA. CircUBAP2 was also sig- multiple binding sites on hsa_circ_0020397. In addition, nificantly overexpressed in osteosarcoma cells. CircU- has_circ_0020397 was demonstrated to inhibit the activ- BAP2 knockdown inhibited cell proliferation and ity of miR-138, although it did not influence miR-138 promoted cell apoptosis. Mechanistically, circUBAP2 expression, and increase the expression of miR-138 tar- was found to directly bind to and inhibit the expression get genes including PD-L1 and TERT. of miR-143, thus enhancing the expression of the miR-143 target Bcl-2. Another study performed by Deng Sustained angiogenesis et al. [106] showed that hsa_circ_0009910 was upregu- Tumor size increases when cancer cells grow. However, lated in osteosarcoma cells. Circ_0009910 knockdown the size is limited to within 100–200 μm without angio- inhibited cell proliferation and induced cell cycle arrest genesis due to the limited natural diffusion capability of and apoptosis in osteosarcoma cells. Circ_0009910 was oxygen and nutrients [115]. Angiogenesis is the process found to directly bind to and function as a sponge of induced by tumor cells that forms new blood vessels in miR-449a, thereby regulating the target gene IL6R as order to supply the tumor with oxygen and nutrients well as the downstream Bcl-2 and Bax. and to dispose of tumor metabolic (toxic) wastes. In addition, there are several additional circRNAs in- Vascular endothelial growth factor (VEGF) is believed volved in apoptosis. For example, Hsa_circRNA_103809 to be the most potent mediator of crucial regulatory was downregulated in CRC and could promote apoptosis roles in angiogenesis [116, 117]. CircRNA-MYLK is through the miR-532-3p/FOXO4 axis [107]. CircNFIX spliced from MYLK gene, with the spliced mature se- was overexpressed in glioma and inhibited apoptosis quence length of 376 nt [118]. It was significantly over- through regulating NOTCH1 via binding to and spon- expressed in BC tissues and correlated with the clinical ging miR-34a-5p [108]. features of BC patients including the pathological stage, T Apart from apoptotic roles, there is also a circRNA in- and N classifications, and survival time. CircRNA-MYLK volved in autophagy. It has been reported that nuclear was also upregulated in BC cell lines. Moreover, translocation of p53 could induce cellular autophagy circRNA-MYLK promoted cell proliferation, migration, [109]. Circ-Dnmt1, generated from Exons 6 and 7 of the and the tube formation of HUVECs, which exhibits angio- mRNA NM_001130823.1, was found to be upregulated genic potential. Mechanistically, circRNA-MYLK could in tissues of BC as well as in eight BC cell lines [110]. directly bind to and sponge miR-29a, thus relieving sup- Overexpression of circ-Dnmt1 increased cell survival pression for target VEGFA and activating the VEGFA/ and proliferation of BC cells through stimulating cellular VEGFR2 signaling pathway. CircRNA-MYLK is not the autophagy. In addition, nuclear levels of circ-Dnmt1 only circRNA that plays a critical role in tumor angiogen- were increased in autophagy inducer-treated BC cells, esis: another circRNA, circHIPK3 [119], was shown to be indicating that autophagy could enhance the nuclear downregulated in Bca and suppress angiogenesis through translocation of circ-Dnmt1. Circ-Dnmt1 could directly the sponging of miR-558 and subsequent inhibition of bind with p53, promoting its nuclear translocation. HPSE, which could positively regulate the expression of VEGF [120, 121]. cZNF292 was also reported to be an Limitless replicative potential important circular oncogenic RNA taking part in the pro- Replicative potential is limited because of the appearance gression of tube formation in glioma [122]. The expression of two processes termed as senescence or crisis in normal of VEGF-A, EGF and active TGF-β1, as well as the levels cells [62]. The telomeres that locate at the chromosome of VEGFR-1/2, phosphorylated-VEGFR-1/2 and EGFR, Su et al. Molecular Cancer (2019) 18:90 Page 10 of 17 were significantly downregulated following the silencing addition, the expression of circSMAD2 was downregu- of cZNF292. Since the in-depth mechanism of cZNF292 lated in HCC tissues and correlated with the tumor dif- activity is unclear, more studies are necessary. ferentiation degree. Overexpression of circSMAD2 inhibited migration, invasion, and EMT in HCC cells Tissue invasion and metastasis through suppressing the expression of miR-629, which It is believed that 90% of human cancer deaths are could promote EMT in cancer cell lines. caused by metastases and not by the primary tumor FOXM1 has been shown to promote cell migration, [123]. During the development of most types of human invasion and EMT in a variety of tumors [138–140]. cancer, cancer cells can escape the primary tumor mass Chen et al. [141] reported that hsa_circ_0061140 was and initiate new colonies at distant sites. The process of overexpressed in ovarian cancerand could promote cell epithelial-mesenchymal transition (EMT) has been con- migration and invasion through regulation of the firmed to be essential in cell migration and tissue metas- miR-370/FOXM1 pathway-mediated EMT. Hsa_- tasis in cancer [124, 125]. It involves a cellular circ_0061140 silencing induced a decreased expression reprogramming process that drives epithelial cells into a of the EMT-related proteins, Snail and Vimentin, along mesenchymal-like phenotype, which is characterized by with an increased expression of E-cadherin. the loss of epithelial surface markers like E-cadherin and Circ_0067934 was shown to be upregulated in NSCLC the acquisition of the mesenchymal markers vimentin and capable of promoting cell EMT accompained with and N-cadherin. increased N-cadherin and vimentin expression and de- The Twist family is known as critical EMT-inducing creased E-cadherin expression [142]. CircRNA_0023642 transcription factor that increase expression of vimentin was upregulated in GC and acted as an oncogene by [126–128]. Meng et al. [129] demonstrated that twist1 regulating EMT [143]. CircRNA_0023642 was shown to bound to the promoter of Cul2 to activate its transcrip- suppress expression of E-cadherin and promote expres- tion and selectively induce expression of Cul2 circular sion of N-cadherin, vimentin, and snail in GC cells. RNA (circ-10,720) rather than mRNA. Circ-10,720 ex- Since the studies didn’t show the effector molecules of pression was high in metastatic HCC tissues and associ- circ_0067934 and circRNA_0023642, the exact mecha- ated with clinical stage, pathology grade, metastasis and nisms of the two circRNAs still need to be uncovered. survival of patients. Circ-10,720 played an oncogenic In addition to the circRNAs discussed above, it is role to promote the migration, invasion and EMT pro- likely that many more circRNAs could regulate the hall- gression of HCC cells. Furthermore, it was found that marks of cancer as a large number of studies have twist1 promoted vimentin through increasing levels of shown that circRNAs are involved in modulating prolif- circ-10,720, which could sponge miRNAs targeting eration, apoptosis and migration of cancer cells without Vimentin, including miR-1246, miR-578 and miR-490-5p. exploring the underling molecular mechanisms. Among them, miR-490-5p was considered to be the major miRNA regulating Vimentin in HCC due to its high ex- CircRNAs regulate stemness of cancer pression and stronger inhibitory effects to Vimentin Cancer stem cells (CSCs), a small proportion of cells 3′-UTR activities. that possess self-renewal and tumor-initiating capabil- TGF-β/Smad signaling has been proven to play a crucial ities, are considered to be responsible for metastatic dis- role in tumor metastasis and the EMT process in a variety semination and therapeutic failure [144–146]. Several of human cancers [130, 131]. CircPTK2 (hsa_- lines of evidence have suggested that circRNAs might circ_0008305) was found to be markedly downregulated contribute to the stemness of cancer (Table 2). in NSCLC cells during TGF-β-induced EMT [132]. Over- Yang and colleagues [147] performed high-throughput expression of circPTK2 arrested TGF-β-induced EMT and sequencing to screen the circRNA expression profiles of invasion of NSCLC cells. Mechanistically, circPTK2 func- breast CSCs (BCSCs) and matched non-BCSCs and tions as a sponge of miR-429/miR-200b-3p, which pro- found 27 aberrantly expressed circRNAs. Among these, motes EMT and cell invasion through targeting TIF1γ. circVRK1 was downregulated and was able to suppress TIF1γ is a TGF-β/Smad signaling regulator that could es- the expansion and self-renewal capacity of BCSCs, dis- calate TGF-β-induced EMT in cancer [133, 134]. In playing an inhibiting role in the stemness of BCSCs. BC addition, circPTK2 could also negatively regulate the ex- cells with circVRK1 knockdown exhibited an enhanced pression of Snail, an important downstream regulator of capacity to form mammospheres and colonies, and an TGF-β/Smad signaling [135]. increasing expression of stemness-related markers in- Compelling data revealed that SMAD2 potently con- cluding OCT4, SOX2 and NANOG, indicating that tributes to EMT [136]. Zhang et al. [137] reported that circVRK1 was involved in suppressing the stemness of circSMAD2 (hsa_circ_0000847), encoded by the SMAD2 BCSCs. In addition, it was speculated that circVRK1 was gene, was upregulated during TGF-β-induced EMT. In negatively correlated with stemness of BCSCs through Su et al. Molecular Cancer (2019) 18:90 Page 11 of 17 Table 2 CircRNAs involved in stemness and chemotherapy resistance of cancer Function CircRNA Cancer type expression Associated clinical features Associated cell process Targets Ref Regulating circVRK1 BC down – decrease proportion of BCSCs – [147] stemness with CD44 + CD24- phenotype, suppress BCSC’s expansion and self-renewal capacity hg19_circ_0005033 LSCC up – promote proliferation, migration, miR-4521 [150] invasion, and chemotherapy resistance of laryngeal cancer stem cells Regulating circPVT1 osteosarcoma up enneking stage, contributes to doxorubicin ABCB1 [154] chemotherapy chemoresistance, lung and cisplatinresistance resistance metastasis and survival circRNA-MTO1 BC up – inhibit cell viability and TRAF4/Eg5 [157] (hsa-circRNA- reverse monastrol resistance axis 007874) circBA9.3 CML up – promote resistance against c-ABL1 and [159] TKI therapy BCR-ABL1 the miR-153-5p/KLF5 axis, as miR-153-5p was one of the promote resistance to chemotherapy through pumping predicted miRNA targets of circVRK1 and was previously intracellular drugs outside of the cell [152, 153]. demonstrated to be involved in stemness maintenance of CircPVT1 (hsa_circ_0001821), originating from exon 3 BC via reducing the expression of KLF5 [148]. Further in- of the PVT1 gene, was significantly overexpressed in OS vestigations are necessary to support the hypothesis. tissues and associated with poor prognosis of OS pa- CD133 + CD44+ CSCs (TDP cells), isolated from la- tients [154]. It was also upregulated in chemoresistant ryngeal squamous cell carcinoma (LSCC) cells, have OS cell lines, and circPVT1 knockdown could weaken been shown to exhibit increased cell proliferation, mi- the doxorubicin and cisplatin resistance of OS cells via gration and colony-formation ability as well as resistance suppressing the expression of ABCB1. to chemo- and radiotherapy [149]. These TDP cells were Monastrol is a small molecule that selectively inhibits shown to highly express the stem-cell markers SOX2 Eg5, a microtubule-based motor protein that contributes and OCT4. In comparison with parental cells, TDP cells to the formation and maintenance of the bipolar mitotic exhibited 3684 circRNAs by RNA sequencing (q < 0.01 spindle [155, 156]. Liu et al. [157] performed a and log2FC (fold change) > 1) [150]. Hg19_circ_0005033 genome-wide circRNA microarray to search for dysregu- was one of the upregulated circRNAs in TDP cells, and it lated circRNAs in the monastrol-resistant BC cells and could promote the proliferation, migration, invasion, and re- identified circRNA-MTO1 (has-circRNA-007874) as an sistance to chemotherapy of TDP cells. Hg19_circ_0005033 upregulated circRNA in these cells. Upregulation of wasdemonstratedtobindtomiR-4521andcouldfunction circRNA-MTO1 promoted monastrol-induced cell cyto- as ceRNA to upregulate miR-4521 targeted mRNAs. In toxicity and reversed monastrol resistance. Mechanistic- addition, STAT5A, which was previously reported to induce ally, circRNA-MTO1 could suppress expression of Eg5 stem-like cell properties [151], was predicted as a target of through binding with TRAF4 and serve as a competing miR-4521. Thus, hg19_circ_0005033 was hypothesized to endogenous RNA (ceRNA) to repress TRAF4 from bind- support the stem cell characteristics of CD133 + CD44+ ing to the Eg5 gene. LSCC stem cells via the miR-4521/STAT5A axis, which Tyrosine kinase inhibitors (TKIs) are available for need further validation. managing chronic myelogenous leukaemia (CML) [158]. Pan and colleagues [159] identified an f-circRNA, cir- CircRNAs regulate chemotherapy resistance of cancer cBA9.3, generated from the BCR-ABL1 oncoprotein, Chemotherapy represents the primary treatment for that could contribute to the increased proliferation and both early and advanced tumors. However, acquired re- anti-apoptotic capacities of leukaemic cells [160]. Cir- sistance to chemotherapy is one of the major causes of cBA9.3 was upregulated in patients with TKI resistance therapeutic failure [130]. Recently, several circRNAs and could enhance the expression of BCR-ABL1, thus have been proven likely to play vital roles in the resist- contributing to resistance against TKI therapy. ance of cancer to chemotherapy (Table 2). It is well known that ATP-binding cassette B1 CircRNAs as biomarkers in Cancer (ABCB1) is a multidrug resistance-related protein that is The properties of circRNAs mentioned in previous sec- highly expressed in drug resistant cell lines and could tions (stability, conservatism, universality, and specificity) Su et al. Molecular Cancer (2019) 18:90 Page 12 of 17 indicate that circRNAs could be potentially valuable prog- plasma samples [163]. Its expression levels were signifi- nostic and diagnostic biomarkers for cancer. Recently, cantly associated with tumor size, distal metastasis, many studies have demonstrated circRNAs may be stably lymphatic metastasis, TNM stage and CA19–9 levels. The expressed and present in relatively high quantities in hu- area under curve (AUC) of hsa_circ_0000190 in tissues man body fluids, such as saliva, plasma, serum and exo- and plasma were 0.75 and 0.60, respectively; the AUC of somes, which also makes circRNAs ideal candidates as the combination was increased to 0.775, and the sensitiv- noninvasive liquid biopsy biomarkers for cancer [161]. ity and specificity of the combination were 0.712 and Circ-ZEB1.33 was shown to be overexpressed in human 0.750, respectively. In another study, hsa_circ_0000745 HCC tissues compared to non-tumorous tissues and in was shown to be lowly expressed in GC tissues and serum samples from HCC patients compared to healthy plasma samples [164]. The expression level of hsa_- controls, and its levels in HCC tissue and serum were cor- circ_0000745 in GC tissues was correlated with tumor dif- related with different TNM stages and overall survival in ferentiation, while the expression level in plasma was HCC patients, suggesting circ-ZEB1.33 may serve as a correlated with tumor-node metastasis stage. The AUC of valuable biomarker in HCC prognosis prediction [162]. hsa_circ_0000745 in plasma was 0.683, while combined Hsa_circ_0000190 was down-regulated in GC tissues and with carcinoembryogenic antigen (CEA) level, the AUC Table 3 CircRNAs as liquid biopsy biomarkers in cancer Source Cancer Cohort size CircRNA Expression Associated clinical features Ref type saliva OSCC 90 OSCC patients, 70 hsa_circ_0001874 up TNM stage, tumor grade [165] OLK subjects OSCC 90 OSCC patients, 70 hsa_circ_0001971 up TNM stage [165] OLK subjects plasma GC 104 GC patients, 104 Hsa_circ_0000190 down tumor diameter, lymphatic metastasis, distal [163] healthy individuals metastasis, TNM stage, CA19–9levels GC 20 GC patients, 20 hsa_circ_0006633 up distal metastasis, tissue carcinoembryonic antigen [167] healthy individuals level GC 45 GC patients, 17 hsa_circ_0000520 down CEA expression [168] healthy individuals GC 24 GC patients, 14 hsa_circ_0000673 down TNM stage [169] healthy individuals GC 121 GC patients, 121 hsa_circ_0001017, down OS, DFS [170] healthy individuals hsa_circ_0061276 ESCC 30 ESCC patients, 25 Circ-TTC17 up TNM stage, lymphatic metastasis, OS [171] healthy individuals PC 31 PC patients, 31 circ-LDLRAD3 up CA19–9, N classification, venous invasion, [172] healthy individuals lymphatic invasion BC 57 BC patients, 17 hsa_circ_0001785 down histological grade, TNM stage, distant metastasis [173] healthy individuals HCC 104 HCC patients, 52 hsa_circ_0001445 down AFP level [174] healthy individuals GC 102 GC patients, 105 Hsa_circ_0000181 down tumor differentiation, carcinoembryonic antigen [175] healthy individuals LAC 30 LAC patients, 30 hsa_circ_0013958 up TNM stage, lymphatic metastasis [176] healthy individuals serum HCC 64 HCC patients, 30 circ-ZEB1.33 up TMN stages, OS [162] healthy individuals BCa 197 BCa patients, 97 hsa_circ_0000285 down tumor size, differentiation, lymph node metastasis, [177] healthy individuals distant metastasis, TNM stage, OS NPC 150 NPC patients, 100 circRNA_0000285 up tumor size, differentiation, lymph node metastasis, [178] healthy individuals distant metastasis, TNM stage. exosome UCB 71 UCB patients, 36 circPRMT5 up lymph node metastasis, T and N status, DFS [166] (serum and urine) healthy individuals UCB 18 UCB patients, 14 circPRMT5 up lymph node metastasis, T and N status, DFS [166] healthy individuals Su et al. Molecular Cancer (2019) 18:90 Page 13 of 17 increased to 0.775, suggesting good diagnostic value of and their important roles in organisms, especially in can- hsa_circ_0000745 in plasma in combination with CEA cer. The stability, conservatism, universality, and specifi- level in GC. Zhao and colleagues [165] performed micro- city of circRNAs make it to be a potential valuable array screening of circRNA in saliva from oral squamous prognostic and diagnostic biomarker for cancer, and the cell carcinoma patients compared with healthy controls functions and regulatory roles that circRNAs play in and identified 20 downregulated and 12 upregulated cir- tumor cells make it possible to be a target for the treat- cRNAs in oral squamous cell carcinoma saliva. Among ment of cancer. However, the study of circRNAs in can- these, two upregulated circRNAs, hsa_circ_0001874 and cer remains in its infancy. CircRNAs are far from being hsa_circ_0001971, showed a AUC of 0.863 and 0.845, re- able to be incorporated into clinical practice, and there spectively. The combination of these two circRNAs are still fundamental problems necessitating further in- showed a AUC of 0.922. Furthermore, the risk score based vestigation in this field. For example, there is an urgent on hsa_circ_0001874 and hsa_circ_0001971 could dis- need to develop a common standardized naming system criminate patients with OSCC from patients with oral for circRNA research. In addition, further investigation leukoplakia with AUC for risk score 0.863, suggesting po- is needed regarding the precise mechanisms, other than tential of salivary hsa_circ_0001874 and hsa_circ_0001971 those of miRNA sponge activity, of circRNAs underlying as OSCC diagnostic biomarker. Moreover, recently studies the initiation and progression of cancer. Furthermore, have found that circRNAs were enriched and stable in more controlled and large-scale clinical studies are re- exosomes, which are small membrane vesicles secreted by quired before cancer-specific circRNAs can be recom- tumor cells into the extracellular fluids. Chen and col- mended for diagnosis and treatment. An advanced leagues [166] revealed that circPRMT5 was enriched in understanding of circRNA will provide beneficial insights both serum and urine exosomes from urothelial carcin- and generate new hypotheses regarding cancer pathogen- oma patients compared to healthy donors. The high levels esis. We hope that the appropriate and precise use of cir- of circPRMT5 in serum and urinary exosomes were cRNAs in clinical applications might eventually create positively associated with lymph node metastasis and ad- breakthroughs for cancer therapy in the near future. vanced tumor progression, suggesting that circPRMT5 Abbreviations might be a prognostic biomarker in urothelial carcinoma. 3′-UTR: 3′-untranslated region; ABCB1: ATP-binding cassette B1; AKT: Protein In addition, it was found that other circRNAs, such as kinase B; As-HaCaT: Arsenite-treated HaCaT; AUC: Area under curve; BAX: BCL2-associated X Protein; BC: Breast cancer; Bca: Bladder cancer; bcl- hsa_circ_0006633 [167], hsa_circ_0000520 [168], hsa_- 2: B-cell lymphoma-2; BCSCs: Breast CSCs; CCNE1: Cyclin E1; CDK: Cyclin- circ_0000673 [169], hsa_circ_0001017 [170], hsa_- dependent kinase; CDR1as: Cerebellar degeneration-related protein 1 anti- circ_0061276 [170], circ-TTC17 [171], circ-LDLRAD3 sense RNA; ceRNA: Competing endogenous RNA; circ-Amotl1: CircRNA derived from angiomotin-like1; CircRNAs: Circular RNAs; ciRNA: Circular [172], hsa_circ_0001785 [173], hsa_circ_0001445 [174], intronic RNA; CML: Chronic myelogenous leukaemia; CRC: Colorectal cancer; hsa_circ_0000181 [175], hsa_circ_0013958 [176] and hsa_- CSCs: Cancer stem cells; DNMT1: DNA methyltransferase 1; DOCK1: Dedicator circ_0000285 [177, 178], were also detectable in plasma, of cytokinesis 1; ecircRNA: Exonic circRNA; ECM: Extracellular matrix; EGFR: Epidermal growth factor receptor; EIciRNA: Exon-intron circRNA; serum or exosomes and could distinguish patients with EIF3J: Eukaryotic translation initiation factor 3 subunit J; EMT: Epithelial- cancer from healthy controls and were potential valuable mesenchymal transition; EZH2: Enhancer of zeste homolog 2; FLI1: Friend biomarkers in cancer (Table 3). leukemia virus integration 1; Foxo4: Forkhead Box O 4; GC: Gastric cancer; HPSE: Heparanase; HuR: Human antigen R/ELAV-like protein 1; IGF1R: Insulin- like growth factor I receptor; IRES: Internal ribosome entry site; ITGB8: Integrin subunit beta 8; LSCC: Laryngeal squamous cell carcinoma; Conclusions MREs: miRNA response elements; MYLK: Myosin Light Chain Kinase; NSCLC: Non-small cell lung cancer; nt: Nucleotide; ORF: Open reading frame; CircRNAs were previously thought to represent errors OS: Osteosarcoma; PAIP2: Polyadenylate-binding protein-interacting protein during the process of RNA splicing. Fortunately, in the 2; PD-L1: Programmed death-ligand 1; PIK3CD: Phosphatidylinositol-4,5- past few years, accumulating evidence has illustrated the bisphosphonate 3-kinase, catalytic subunit delta gene; PRC2: Polycomb- repressive complex 2; PTEN: Phosphatase and tensin homolog deleted on significant regulatory effects of circRNAs on pathophysi- chromosome ten; ROCK1: Rho-associated protein kinase 1; Smad: Mothers ologic processes, including tumorigenesis. CircRNAs are against decapentaplegic; snRNPs: Small nuclear ribonucleic proteins; TDP now regarded as a class of abundant, stable, diverse and cells: CD133 + CD44+ CSCs; TERT: Telomerase reverse transcriptase; TGF- β: Transforming growth factor-β; TIF1γ: Transcriptional intermediary factor 1 conserved RNA molecules with a range of activities, in- γ; TKI: Tyrosine kinase inhibitor; VEGF: Vascular endothelial growth factor; cluding sponge, translation, splicing and regulation. The VEGFR: Vascular endothelial growth factor receptor; YAP1: Yes-associated functions of circRNAs in cancer are gaining considerable protein 1; YY1: Yin Yang-1 interest and have become a focus of cancer research. In Acknowledgements this review, we briefly summarized the recent advances We thank Dr. Kunjian Peng for the helpful discussion. regarding circRNAs in the hallmarks, stemness, resistance Funding to therapy, and the possibility as biomarkers for cancer. This work is supported by grants from the National Natural Scientific These research endeavors into circRNAs expand our Foundation of China (81802947), the Natural Science Foundation of Hunan understanding of eukaryotic transcription participants Province (2019JJ50968, 2019JJ50358, 2017JJ2173, 2018JJ3314), Health and Su et al. Molecular Cancer (2019) 18:90 Page 14 of 17 Family Planning Commission of Hunan Province (B20180545, C2019074), modulates ribosomal RNA maturation and atherosclerosis in humans. 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Molecular CancerSpringer Journals

Published: Apr 18, 2019

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