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Pyroptosis-related noncoding RNAs and cancer involvement

Pyroptosis-related noncoding RNAs and cancer involvement IntroductionPyroptosis is a kind of cell programmed necrosis accompanied by a strong inflammatory response [1]. In 2015, scientists reported that Gasdermin D (GSDMD) which was the substrate of caspases, was essential for pyroptosis [2]. Now, pyroptosis is regarded as an important event in cancer [3] or inflammatory diseases, such as sepsis [4].Noncoding RNA (ncRNA) is a type of small regulatory RNA that affects the life processes of cells, resulting in cancer and inflammation. NcRNAs take part in the activation of inflammatory vesicles and have a key role in regulating pyroptosis [21]. Wang et al. showed that the m6A-inducible lncRNA FENDRR attenuated and promoted HPAEC cell scorching through regulation of DRP1 promoter methylation, thus providing a new potential target for hypoxic pulmonary hypertension (HPH) therapy [22]. Yang et al. identified NEAT1 as an important long-stranded non-coding RNA (lncRNA) for exercise-mediated amelioration of atherosclerosis. METTL14 is an m6A methylation-modifying enzyme that has a key role in exercise and endothelial cell scorching. m6A modification of NEAT1 was increased by METTL14, and NEAT1 expression was promoted by subsequent recognition of YTHDC1 to induce endothelial cell scorching. However, exercise can ameliorate the evolution of atherosclerosis by down-regulating METTL14 and weakening the action of NEAT1 [23]. Li et al. showed that lncRNA MALAT1 was involved in the scorching process of renal tubular epithelial cells in diabetic nephropathy, the increased expression of ELAVL1 promotes downstream production of NLRP3, Caspase-1, IL-1β and IL-1, which ultimately leads to renal inflammatory response and cell pyroptosis [24]. Yuan et al. identified a novel circRNA-DICAR as an endogenous protective factor against cardiomyocyte pyroptosis in diabetic cardiomyopathy. DICAR inhibited diabetes-induced cardiomyocyte pyroptosis by suppressing VCP protein-induced Med12 protein degradation through its specific junction site (DICAR-JP) [25]. Cancer has been an important human disease. Lung cancer now has the number one spot with 1.8 million deaths, accounting for 18 % of the world’s cancer deaths, far outstripping the cancers that rank behind it [26]. Here, we summarized the role of noncoding RNAs in regulating pyroptosis in cancer and other diseases.Pyroptosis and GasderminPyroptosis is induced by inflammatory cysteine aspartate protease (Caspase) [27]. Previous studies have shown that apoptotic caspase can actually participate in pyroptosis [28], activation of inflammatory caspases usually, but not always, completes pyroptosis [29]. GSDMD is essential for noncanonical inflammation signaling and pyroptosis as a response to cytosolic LPS (lipopolysaccharide, an important component of PAMP) [30, 31]. Kayagaki et al. showed that GSDMD was required for cytosolic LPS to trigger IL-1 production [32].Pyroptosis makes the surface of cells form membrane pores, then the membrane broken, and cell contents are freed. So it played a pivotal role in tumorigenesis [33].Pyroptosis is an essential immune response in the body and has a major role in the evolution and advancement of tumors [34], infectious diseases [29], metabolic diseases [35], neurologically related diseases [36] and atherosclerotic diseases [37]. The induction of pyroptosis in tumors can effectively regulate the tumor microenvironment, thereby enhancing the effectiveness of tumor immunotherapy. The latest research has revealed that after the pyroptosis 15 % of tumor cells, due to the release of some inflammatory factors, the anti-tumor immune response of the body can be stronger activated, resulting in the emergence of a large number of effective killer T cells in the tumor microenvironment to remove almost all of the tumor cells [38]. In addition to improving the effect of tumor immunotherapy, Zhang et al. have discovered that pyroptosis can convert “cold” tumors not recognized by the immune system into “hot” tumors that can be controlled by the immune system, thus further enhancing immune checkpoint inhibitor treatment for the purpose of inhibiting tumor growth [39].Shao et al. revealed that serine protease Granzyme A (a granular enzyme) released by lymphocytes such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells can enter tumor cells through perforin on the surface of tumor cells, thereby inducing tumor cell pyroptosis [40], and further activating T-cell immunity through inflammatory properties to enhance the anti-tumor immune response of the body [41]. In addition to immunotherapy, pyroptosis can also be used to relieve immunosuppression, promote systemic immune response and reduce the toxicity and side effects of chemotherapy drugs on normal tissues in the treatment of chemotherapy and radiotherapy for solid tumors [42, 43].The Gasdermin familyIn humans, Gasdermin family members have six members: GSDMA, GSDMB, GSDMC, GSDMD, GSDME and PJVK [40]. These members which have the function of punching holes in the cell membrane, are the performers of cell pyroptosis, and participate in cell growth regulation, inflammatory response and host defense [44].Gasdermin family members have three basic structures: N-terminal pore-forming domain (PFD), C-terminal repressor domain (RD), and linker [45]. Among them, PFD and RD are highly conserved, and the linking region is less conserved. Each member has its own relatively unique linking sequence. Usually, PFD and RD combine with each other and exist in the cell in a self-inhibiting form [46].When the body is infected by a pathogen, caspase cleaves Gasdermin, and PFD is released and to be integrated into the cell membrane, creating a diameter of 10–15 nm (or 21 nm). Besides, cellular osmolarity changes, increases in volume followed by swelling and release of cytokine interleukin-1β (interleukin-1β, IL-1β) and interleukin IL-18 (interleukin-18, IL-18), which can promote immune cell infiltration, helper T cell (helper T cell, Th) response, activate NF-κB (nuclear factor κB signaling, NF-κB) and other signaling pathways, triggering the inflammatory cascade [47].Pyroptosis pathwayPyroptosis will release a variety of cytokines, including IL-1β, IL-18, interleukin-6 (interleukin-6, IL-6), interleukin-12 (interleukin-12, IL-12), interleukin IL-17A (interleukin-17A, IL-17A), etc. Pro-inflammatory cytokines are the main mediators of the inflammatory response, and changes in these levels affect the process of inflammatory response.Pyroptosis falls into classical and non-classical pathways. When cells sense signals of microbial infection or other injury, they assemble to form a multi-protein complex, the inflammatory vesicle. The pyroptosis of extracellular is closely related to the inflammatory response signal pathway, especially the NF-κB signal pathway. There has been a detailed discussion of the NF-κB signaling pathway before, so it is omitted [48]. According to reports, TLR-4 recognition of LPS and activation of caspase-1 may be a key mechanism of the upstream pathway of extracellular pyroptosis. Activation of inflammatory vesicles such as NLRP3, NLRC4, AIM2, and Pyrin will activate and cleave Pro-Caspase-1 to form active Caspase-1. Activated Caspase-1 cleaves the GSDMD protein to form the active N-terminal and C-terminal ends, with the N-terminal end contributing to cell membrane perforation and cell death. Meanwhile, activated Caspase-1 cleaves GSDMD protein and processes IL-1β and IL-18 precursors into mature IL-1β and IL-18 and makes the cell pyroptosis osmotically release IL-1β and IL-18 to recruit more inflammatory cells to aggregate and amplify the inflammatory response. This extracellular pyroptosis dependent on inflammasomes is considered a classic form of pyroptosis.TLR-4 is not required for intracellular pyroptosis. Shao et al. used different methods to study and found that Caspase-4/5/11 can directly recognize LPS produced in the cell, and then cleave the GSDMD protein to cause pyroptosis [49–51]. This process is the non-classical pathway of pyroptosis. In the non-classical pyroptosis pathway, LPS can directly bind to Caspase-4/5/11. In one aspect, activated Caspase-4/5/11 can cleave the GSDMD protein, which can mediate both cell membrane lysis and cell scorch, and activate NLRP3 inflammatory vesicles to activate Caspase-1, which eventually produces IL-1β. In the other aspect, activated Caspase-4/5/11 activates the channel Pannexin-1, which releases ATP to open the cell membrane channel P2X7, causing the formation of small pores in the cell membrane to induce cell scorching, and the activated Pannexin-1 also activates NLRP3 inflammatory vesicles by exocytosis of K+, which eventually produces IL-1β and exocytosis. The classical and non-classical pathways of pyroptosis cross each other. Although Caspase-4/5/11 cannot directly process IL-1β and IL-18 precursors, potassium ions released from the ruptured cell membrane can induce the activation of Caspase-1. Indirectly contributes to the release of IL-1β and IL-18.In addition to the above two cellular pyroptosis pathways, it was found that in macrophages lacking Caspase-1/11, the inflammatory vesicle NLRP3 activates Caspase-3/8, which in turn cleaves GSDME, triggering a form of incomplete pyroptosis. It is incomplete because the process does not involve the release of IL-1β, a key factor in pyroptosis, but the secretion of IL-1α instead. Shao et al. revealed for the first time that cytotoxic lymphocytes secreted Granzyme A (GZMA), and GZMA releases GSDMB-N fragments by cleaving GSDMB, causing cell perforation to induce cell focal death [52] (Figure 1).Figure 1:Pyroptosis signaling.Pyroptosis in tumorgenesisUntil now, the majority of studies have focused on the GSDM family in pyroptosis in cancer. The N-terminal domains of Gsdma3 and DFNA5 can form transmembrane pores on liposomes [53]. A conserved autoinhibitory mechanism was seen in GSDM family [54]. The oligomerization and pore form of the NTD was inhibited by the CTD when the lipid-binding surface was blocked [54]. GSDMA has proapoptotic activity downstream of the transforming growth factor-beta (TGF-beta)-dependent which suppressed tumorigenesis in gastric tissue [55].GSDMB acted as an oncogene, it was much higher expression in uterine cervical cancer [56] and breast cancer [57]. GSDMB promoted cell motility and invasion in breast carcinoma cell line – MCF7 [58], and increased the proliferation of HeLa cancer cells and hepatocarcinoma cancer HepG2 cells [59]. In breast cancer, GSDMB antibody reduced invasive nature of HER2-positive breast cancer [60].GSDMC increased the proliferation of colorectal cancer (CRC) cell lines, and inhibition of GSDMC reduced carcinogenesis [61]. GSDMC promotes CRC cell proliferation in colorectal carcinogenesis. GSDMC expression was also increased in metastatic melanoma [62], while decreased in esophageal and gastric cancer cells [63].GSDMD could have different role in cancers. GSDMD inhibited the growth of gastric cancer cell lines [64], whereas GSDMD promoted cell proliferation in non-small cell lung cancer [65].Noncoding RNA and pyroptosisNcRNA is a type of single-stranded nucleic acid molecule that does not code for protein. It is widely present in the human genome [66]. It can finely regulate the life activities in the protein level and chromatin level. It mainly includes microRNA (miRNA), long noncoding RNA (LncRNA) and circular RNA (CircRNA) [67].As the course of the disease changes, patients will develop a pro-inflammatory state and an immunosuppressive state. NcRNA may play an important role in the transition between these two states. Compared with healthy individuals, ncRNA levels in patients have obvious changes which are related to the inflammatory response of cells.MicroRNA and pyroptosisMiRNA can regulate the inflammatory response of sepsis by regulating the levels of pro-inflammatory cytokines, and this process involves pyroptosis. MiR-27 can promote sepsis by up-regulating the level of TNF-α [68]; down-regulation of miR-223-3p in septic innate immunity induces the expression of IL-6, IL-1β and TNF-α [69]; In the toxicosis model, miR-146a and miR-146b can inhibit the expression of IL-6 and IL-8 [70]; the use of miR-155 inhibitors will reduce the levels of TNF-α and IL-6 [71]. At present, research groups have identified the pyroptosis executive molecule GSDMD is a target gene of miR-193a-5p (Table 1).Table 1:Confirmed microRNAs in pyroptosis.MiRNAExpression levelTargetDamageReferencesmiR-204DownGSDMDSynovial tissue[5]miRNA-22DownGSDMDSpinal cord injury[6]miR-223-3pDownGSDMDPeriodontitis[7]miR-182-5pDownGSDMDMyocardial[8]miR-133aDownGSDMDAcute aortic dissection[9]miR-379-5pDownGSDMDLiver[10]MiR-326UpTLR4Lung[11]MiR-128-3pDownTGFBR2Kidney[12]LncRNA and pyroptosisWhen adding plasma obtained from patients with sepsis, cardiomyocytes and monocytes will have differential expression of LncRNA. The LncRNA gene chip analysis of the stimulated human monocytes found that the expression of 443 LncRNAs increased by two times, and the expression of 718 LncRNAs decreased to half of the original. Among them, the most up-regulated were the inflammation-related molecules mainly in the nucleus of human leukocytes. Interleukin 7 receptor (Lnc IL7R) [72], Considering the important role of IL7R in the NF-κB signaling pathway, the up-regulation of LncIL7R suggests the potential for LncRNA to regulate cell pyroptosis. In fact, due to the sponge adsorption effect of LncRNA on MiRNA, LncRNA in sepsis often forms a signal axis with MiRNA to participate in the NF-κB signaling pathway to mediate pyroptosis and jointly regulate the disease process. For illustration, the level of LncTapSAKI targeting MiR-22 was elevated in kidney injury, which can mediate the TapSAKI/miR-22/TLR4/NF-κB pathway and reduce the levels of TNF-α and IL-6 [73]; The LncMEG3-4 of miR-138 can increase the activity of IL-1β, thereby negatively feeding back the NF-κB signaling pathway [74]; LncANRIL targeting miR-125a can be used as a biomarker to predict the severity of sepsis [75]. LncNEAT1 negatively regulates miR-204, which can target the inflammasome receptor IL-6R, leading to inactivation of the NF-κB signaling pathway. Inhibiting LncNEAT1 can overexpression of miR-204, thereby reducing LPS-induced kidney damage [76]. The following year, it was reported that the long-chain non-coding RNA Lnc NEAT1 in macrophages could increase the stability of the inflammatory complex and Caspase-1 enzyme activity, up-regulate the levels of IL-1β and IL-18, and increase the pyroptosis (Table 2).Table 2:Confirmed LncRNAs in pyroptosis.LncRNAExpression levelDamageNetworkReferencesLncRNA THRILUpLung, epithelial cellmiR-19a, miR-34a, miR-424[13–15]LncRNA TapSAKIUpEpithelial cell, Kidney tubulesmiR-22[16]LncRNA MIATUpHeartmiR-330-5p[17]LncRNA H19DownCardiac musclemiR-93-5p[18]LncRNA RMRPUpCardiac musclemiR-1-5p[19]LncRNA SNHG16UpLungmiR-146a-5p[20]CircRNA and pyroptosisCircRNA is a new emerging non-coding RNA molecule, which forms a covalent closed cyclic structure after back-splicing [77]. CircUBE2G1 regulates LPS-induced osteoarthritis through the miR-373/HIF-1α axis [78]. CircPWWP2A affects LPS-induced liver fibrosis through sponge adsorption of miR-203 and miR-223 [79]; Circ_102685 and CircRSF1 can adjust miR-146a expression, thereby inhibiting pus Toxic process [69]. CircRNA plays a significant part in cell pyroptosis process. The N6-methyladenosine (m6A) modification of Circ_0029589 can induce macrophage pyroptosis and inflammation in patients with coronary artery disease [80]. Circ_4099 was induced by the inflammatory mediator TNF-α, which in turn regulates the NF-κB signaling pathway [69] (Figure 2).Figure 2:The regulation of ncRNAs in pyroptosis.Conclusions and discussionsConclusionsPyroptosis is an essential natural immune response that plays an instrumental role in opposing infections and internal danger signs. It is extensively engaged in the progression of infectious diseases, neurological disorders and atherosclerotic diseases, among others. An intensive study of pyroptosis will lead to an understanding of its contribution in the evolution and regression of these illnesses and offer new insights for clinical therapies. Research has revealed that hyperglycemia can cause increased production of reactive oxygen species, which in turn upregulates NF-κB and TXNIP, which in turn upregulates the expression of NLRP3, IL-1β precursor and IL-18 precursor; TXNIP activates Caspase-1 by altering the structure of NLRP3, and the activated Caspase-1 cleaves GSDMD on the one hand. forming a peptide containing the nitrogen-terminal active domain of GSDMD, inducing perforation and rupture of the cardiomyocyte membrane, releasing the contents and causing an inflammatory response; on the other hand, activated Caspase-1 cleaves the precursors of IL-1β and IL-18, forming active IL-1β and IL-18 and releasing them to the extracellular space, recruiting inflammatory cells to aggregate and enlarge the inflammatory response [81]. Now, great progress has been made by pyroptosis, and pyroptosis has been shown to be closely related to the development of many inflammation-related diseases, including tumors, and has shown great potential in tumor therapy. Tumors are in a complex immune microenvironment [82], and pyroptosis is a form of immune cell death. Researchers have identified pyroptosis related with the development and treatment of all kinds of tumors, and some of the mechanisms have been elucidated [57, 83, 84]. For instance, Gasdermin-B can directly cleave GSDME and induce cancer cells to undergo pyroptosis, which to increase stimulating anti-tumor immune response and suppresses tumor development [85]. GSDMs play a key role in oncogenesis, acting as both promoters and suppressors of tumors. The basic mechanisms remain to be further explored, which will provide insight into the development of potent cancer immunotherapies.NcRNA is widely present in serum, plasma, urine or other body fluids. It may have a key role in tumors and can be regarded as a biomarker or potential therapeutic target. On the one hand, ncRNA was reported to participate in pyroptosis in tumors [86].DiscussionsPyroptosis-induced inflammatory responses can stimulate potent anti-tumor immunity and act synergistically with checkpoint blockade [87]. Additionally, it has also been found that pyroptosis plays an essential role in facilitating tumor necrosis and provoking more obvious adverse effects of tumor treatment [83, 88]. These findings provide important ideas for reducing adverse effects of tumor treatment, achieving better treatment outcomes, and exploring new therapeutic approaches. In summary, inhibition of the pyroptosis pathway may treat diseases associated with excessive immune activity in the body, including various chronic inflammatory conditions, autoimmune diseases, and sepsis caused by bacterial infections, while activation of the pyroptosis pathway may kill cancer cells, treat various cancers, or enhance the killing efficiency of other cancer drugs. Zhang et al. showed that the chemotherapeutic agent cisplatin induced cell scorching in lung cancer cells A549 by activating GSDME [89]. GSDME-mediated cell scorching has been shown to recruit T cells in tumor tissue through the release of chemokines, thus providing a new anti-tumor mechanism for cisplatin treatment. The identification of GSDME’s immunomodulatory effect on cancer also provides a new prospective target for the development of anti-cancer immunotherapy [90]. NcRNA has become a research hotspot. It is a type of nucleic acid molecule that plays an important regulatory role in immunity and cell death. A new lncRNA signature associated with pyroptosis is an independent prognostic indicator for breast cancer patients [91] The lncRNA small ribonucleic acid host gene 7 (SNHG7)/miR-34a/SIRT1 axis is responsible for NLRP3-dependent pyroptosis during hepatocellular carcinoma [86]. On the other hand, ncRNA regulates the NF-κB signaling pathway and is related to pyroptosis [92]. The pyroptosis of extracellular is intimately linked to inflammatory response signaling circuit, especially the NF-κB signal pathway. Activation of NF-kB signaling can cause cells to pyroptosis. Combined with the effects of NF-kB signaling on pyroptosis, targeting NF-kB can effectively enhance the development of pyroptosis and inhibit the development of tumors.Pyrotosis, as an inflammatory cell death mode, plays a crucial role in tumor suppression by stimulating anti-tumor immune reaction. In some situations, inducing cytokinesis single may be enough to prevent tumor growth. However, one of the most challenging aspects of the therapeutic application of pyroptosis is the variability in the expression and function of cytokine-related elements, not only between distinct cancers, but also within the same kind of cancer. As the study progresses, more ncRNAs associated with pyroptosis action will be identified and their regulatory mechanisms on the pyroptosis action pathway will become clearer. In conclusion, it will be intriguing to examine whether pyroptosis action can also affect ncRNAs expression. Therefore, using new technology to expand the scope of research on ncRNAs and screen out therapeutic drugs may be a hopeful alternative for the diagnosis and management of diseases associated with pyroptosis. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png ONCOLOGIE de Gruyter

Pyroptosis-related noncoding RNAs and cancer involvement

ONCOLOGIE , Volume 25 (4): 9 – Jul 1, 2023

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Publisher
de Gruyter
Copyright
© 2023 the author(s), published by De Gruyter, Berlin/Boston
eISSN
1765-2839
DOI
10.1515/oncologie-2023-0045
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Abstract

IntroductionPyroptosis is a kind of cell programmed necrosis accompanied by a strong inflammatory response [1]. In 2015, scientists reported that Gasdermin D (GSDMD) which was the substrate of caspases, was essential for pyroptosis [2]. Now, pyroptosis is regarded as an important event in cancer [3] or inflammatory diseases, such as sepsis [4].Noncoding RNA (ncRNA) is a type of small regulatory RNA that affects the life processes of cells, resulting in cancer and inflammation. NcRNAs take part in the activation of inflammatory vesicles and have a key role in regulating pyroptosis [21]. Wang et al. showed that the m6A-inducible lncRNA FENDRR attenuated and promoted HPAEC cell scorching through regulation of DRP1 promoter methylation, thus providing a new potential target for hypoxic pulmonary hypertension (HPH) therapy [22]. Yang et al. identified NEAT1 as an important long-stranded non-coding RNA (lncRNA) for exercise-mediated amelioration of atherosclerosis. METTL14 is an m6A methylation-modifying enzyme that has a key role in exercise and endothelial cell scorching. m6A modification of NEAT1 was increased by METTL14, and NEAT1 expression was promoted by subsequent recognition of YTHDC1 to induce endothelial cell scorching. However, exercise can ameliorate the evolution of atherosclerosis by down-regulating METTL14 and weakening the action of NEAT1 [23]. Li et al. showed that lncRNA MALAT1 was involved in the scorching process of renal tubular epithelial cells in diabetic nephropathy, the increased expression of ELAVL1 promotes downstream production of NLRP3, Caspase-1, IL-1β and IL-1, which ultimately leads to renal inflammatory response and cell pyroptosis [24]. Yuan et al. identified a novel circRNA-DICAR as an endogenous protective factor against cardiomyocyte pyroptosis in diabetic cardiomyopathy. DICAR inhibited diabetes-induced cardiomyocyte pyroptosis by suppressing VCP protein-induced Med12 protein degradation through its specific junction site (DICAR-JP) [25]. Cancer has been an important human disease. Lung cancer now has the number one spot with 1.8 million deaths, accounting for 18 % of the world’s cancer deaths, far outstripping the cancers that rank behind it [26]. Here, we summarized the role of noncoding RNAs in regulating pyroptosis in cancer and other diseases.Pyroptosis and GasderminPyroptosis is induced by inflammatory cysteine aspartate protease (Caspase) [27]. Previous studies have shown that apoptotic caspase can actually participate in pyroptosis [28], activation of inflammatory caspases usually, but not always, completes pyroptosis [29]. GSDMD is essential for noncanonical inflammation signaling and pyroptosis as a response to cytosolic LPS (lipopolysaccharide, an important component of PAMP) [30, 31]. Kayagaki et al. showed that GSDMD was required for cytosolic LPS to trigger IL-1 production [32].Pyroptosis makes the surface of cells form membrane pores, then the membrane broken, and cell contents are freed. So it played a pivotal role in tumorigenesis [33].Pyroptosis is an essential immune response in the body and has a major role in the evolution and advancement of tumors [34], infectious diseases [29], metabolic diseases [35], neurologically related diseases [36] and atherosclerotic diseases [37]. The induction of pyroptosis in tumors can effectively regulate the tumor microenvironment, thereby enhancing the effectiveness of tumor immunotherapy. The latest research has revealed that after the pyroptosis 15 % of tumor cells, due to the release of some inflammatory factors, the anti-tumor immune response of the body can be stronger activated, resulting in the emergence of a large number of effective killer T cells in the tumor microenvironment to remove almost all of the tumor cells [38]. In addition to improving the effect of tumor immunotherapy, Zhang et al. have discovered that pyroptosis can convert “cold” tumors not recognized by the immune system into “hot” tumors that can be controlled by the immune system, thus further enhancing immune checkpoint inhibitor treatment for the purpose of inhibiting tumor growth [39].Shao et al. revealed that serine protease Granzyme A (a granular enzyme) released by lymphocytes such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells can enter tumor cells through perforin on the surface of tumor cells, thereby inducing tumor cell pyroptosis [40], and further activating T-cell immunity through inflammatory properties to enhance the anti-tumor immune response of the body [41]. In addition to immunotherapy, pyroptosis can also be used to relieve immunosuppression, promote systemic immune response and reduce the toxicity and side effects of chemotherapy drugs on normal tissues in the treatment of chemotherapy and radiotherapy for solid tumors [42, 43].The Gasdermin familyIn humans, Gasdermin family members have six members: GSDMA, GSDMB, GSDMC, GSDMD, GSDME and PJVK [40]. These members which have the function of punching holes in the cell membrane, are the performers of cell pyroptosis, and participate in cell growth regulation, inflammatory response and host defense [44].Gasdermin family members have three basic structures: N-terminal pore-forming domain (PFD), C-terminal repressor domain (RD), and linker [45]. Among them, PFD and RD are highly conserved, and the linking region is less conserved. Each member has its own relatively unique linking sequence. Usually, PFD and RD combine with each other and exist in the cell in a self-inhibiting form [46].When the body is infected by a pathogen, caspase cleaves Gasdermin, and PFD is released and to be integrated into the cell membrane, creating a diameter of 10–15 nm (or 21 nm). Besides, cellular osmolarity changes, increases in volume followed by swelling and release of cytokine interleukin-1β (interleukin-1β, IL-1β) and interleukin IL-18 (interleukin-18, IL-18), which can promote immune cell infiltration, helper T cell (helper T cell, Th) response, activate NF-κB (nuclear factor κB signaling, NF-κB) and other signaling pathways, triggering the inflammatory cascade [47].Pyroptosis pathwayPyroptosis will release a variety of cytokines, including IL-1β, IL-18, interleukin-6 (interleukin-6, IL-6), interleukin-12 (interleukin-12, IL-12), interleukin IL-17A (interleukin-17A, IL-17A), etc. Pro-inflammatory cytokines are the main mediators of the inflammatory response, and changes in these levels affect the process of inflammatory response.Pyroptosis falls into classical and non-classical pathways. When cells sense signals of microbial infection or other injury, they assemble to form a multi-protein complex, the inflammatory vesicle. The pyroptosis of extracellular is closely related to the inflammatory response signal pathway, especially the NF-κB signal pathway. There has been a detailed discussion of the NF-κB signaling pathway before, so it is omitted [48]. According to reports, TLR-4 recognition of LPS and activation of caspase-1 may be a key mechanism of the upstream pathway of extracellular pyroptosis. Activation of inflammatory vesicles such as NLRP3, NLRC4, AIM2, and Pyrin will activate and cleave Pro-Caspase-1 to form active Caspase-1. Activated Caspase-1 cleaves the GSDMD protein to form the active N-terminal and C-terminal ends, with the N-terminal end contributing to cell membrane perforation and cell death. Meanwhile, activated Caspase-1 cleaves GSDMD protein and processes IL-1β and IL-18 precursors into mature IL-1β and IL-18 and makes the cell pyroptosis osmotically release IL-1β and IL-18 to recruit more inflammatory cells to aggregate and amplify the inflammatory response. This extracellular pyroptosis dependent on inflammasomes is considered a classic form of pyroptosis.TLR-4 is not required for intracellular pyroptosis. Shao et al. used different methods to study and found that Caspase-4/5/11 can directly recognize LPS produced in the cell, and then cleave the GSDMD protein to cause pyroptosis [49–51]. This process is the non-classical pathway of pyroptosis. In the non-classical pyroptosis pathway, LPS can directly bind to Caspase-4/5/11. In one aspect, activated Caspase-4/5/11 can cleave the GSDMD protein, which can mediate both cell membrane lysis and cell scorch, and activate NLRP3 inflammatory vesicles to activate Caspase-1, which eventually produces IL-1β. In the other aspect, activated Caspase-4/5/11 activates the channel Pannexin-1, which releases ATP to open the cell membrane channel P2X7, causing the formation of small pores in the cell membrane to induce cell scorching, and the activated Pannexin-1 also activates NLRP3 inflammatory vesicles by exocytosis of K+, which eventually produces IL-1β and exocytosis. The classical and non-classical pathways of pyroptosis cross each other. Although Caspase-4/5/11 cannot directly process IL-1β and IL-18 precursors, potassium ions released from the ruptured cell membrane can induce the activation of Caspase-1. Indirectly contributes to the release of IL-1β and IL-18.In addition to the above two cellular pyroptosis pathways, it was found that in macrophages lacking Caspase-1/11, the inflammatory vesicle NLRP3 activates Caspase-3/8, which in turn cleaves GSDME, triggering a form of incomplete pyroptosis. It is incomplete because the process does not involve the release of IL-1β, a key factor in pyroptosis, but the secretion of IL-1α instead. Shao et al. revealed for the first time that cytotoxic lymphocytes secreted Granzyme A (GZMA), and GZMA releases GSDMB-N fragments by cleaving GSDMB, causing cell perforation to induce cell focal death [52] (Figure 1).Figure 1:Pyroptosis signaling.Pyroptosis in tumorgenesisUntil now, the majority of studies have focused on the GSDM family in pyroptosis in cancer. The N-terminal domains of Gsdma3 and DFNA5 can form transmembrane pores on liposomes [53]. A conserved autoinhibitory mechanism was seen in GSDM family [54]. The oligomerization and pore form of the NTD was inhibited by the CTD when the lipid-binding surface was blocked [54]. GSDMA has proapoptotic activity downstream of the transforming growth factor-beta (TGF-beta)-dependent which suppressed tumorigenesis in gastric tissue [55].GSDMB acted as an oncogene, it was much higher expression in uterine cervical cancer [56] and breast cancer [57]. GSDMB promoted cell motility and invasion in breast carcinoma cell line – MCF7 [58], and increased the proliferation of HeLa cancer cells and hepatocarcinoma cancer HepG2 cells [59]. In breast cancer, GSDMB antibody reduced invasive nature of HER2-positive breast cancer [60].GSDMC increased the proliferation of colorectal cancer (CRC) cell lines, and inhibition of GSDMC reduced carcinogenesis [61]. GSDMC promotes CRC cell proliferation in colorectal carcinogenesis. GSDMC expression was also increased in metastatic melanoma [62], while decreased in esophageal and gastric cancer cells [63].GSDMD could have different role in cancers. GSDMD inhibited the growth of gastric cancer cell lines [64], whereas GSDMD promoted cell proliferation in non-small cell lung cancer [65].Noncoding RNA and pyroptosisNcRNA is a type of single-stranded nucleic acid molecule that does not code for protein. It is widely present in the human genome [66]. It can finely regulate the life activities in the protein level and chromatin level. It mainly includes microRNA (miRNA), long noncoding RNA (LncRNA) and circular RNA (CircRNA) [67].As the course of the disease changes, patients will develop a pro-inflammatory state and an immunosuppressive state. NcRNA may play an important role in the transition between these two states. Compared with healthy individuals, ncRNA levels in patients have obvious changes which are related to the inflammatory response of cells.MicroRNA and pyroptosisMiRNA can regulate the inflammatory response of sepsis by regulating the levels of pro-inflammatory cytokines, and this process involves pyroptosis. MiR-27 can promote sepsis by up-regulating the level of TNF-α [68]; down-regulation of miR-223-3p in septic innate immunity induces the expression of IL-6, IL-1β and TNF-α [69]; In the toxicosis model, miR-146a and miR-146b can inhibit the expression of IL-6 and IL-8 [70]; the use of miR-155 inhibitors will reduce the levels of TNF-α and IL-6 [71]. At present, research groups have identified the pyroptosis executive molecule GSDMD is a target gene of miR-193a-5p (Table 1).Table 1:Confirmed microRNAs in pyroptosis.MiRNAExpression levelTargetDamageReferencesmiR-204DownGSDMDSynovial tissue[5]miRNA-22DownGSDMDSpinal cord injury[6]miR-223-3pDownGSDMDPeriodontitis[7]miR-182-5pDownGSDMDMyocardial[8]miR-133aDownGSDMDAcute aortic dissection[9]miR-379-5pDownGSDMDLiver[10]MiR-326UpTLR4Lung[11]MiR-128-3pDownTGFBR2Kidney[12]LncRNA and pyroptosisWhen adding plasma obtained from patients with sepsis, cardiomyocytes and monocytes will have differential expression of LncRNA. The LncRNA gene chip analysis of the stimulated human monocytes found that the expression of 443 LncRNAs increased by two times, and the expression of 718 LncRNAs decreased to half of the original. Among them, the most up-regulated were the inflammation-related molecules mainly in the nucleus of human leukocytes. Interleukin 7 receptor (Lnc IL7R) [72], Considering the important role of IL7R in the NF-κB signaling pathway, the up-regulation of LncIL7R suggests the potential for LncRNA to regulate cell pyroptosis. In fact, due to the sponge adsorption effect of LncRNA on MiRNA, LncRNA in sepsis often forms a signal axis with MiRNA to participate in the NF-κB signaling pathway to mediate pyroptosis and jointly regulate the disease process. For illustration, the level of LncTapSAKI targeting MiR-22 was elevated in kidney injury, which can mediate the TapSAKI/miR-22/TLR4/NF-κB pathway and reduce the levels of TNF-α and IL-6 [73]; The LncMEG3-4 of miR-138 can increase the activity of IL-1β, thereby negatively feeding back the NF-κB signaling pathway [74]; LncANRIL targeting miR-125a can be used as a biomarker to predict the severity of sepsis [75]. LncNEAT1 negatively regulates miR-204, which can target the inflammasome receptor IL-6R, leading to inactivation of the NF-κB signaling pathway. Inhibiting LncNEAT1 can overexpression of miR-204, thereby reducing LPS-induced kidney damage [76]. The following year, it was reported that the long-chain non-coding RNA Lnc NEAT1 in macrophages could increase the stability of the inflammatory complex and Caspase-1 enzyme activity, up-regulate the levels of IL-1β and IL-18, and increase the pyroptosis (Table 2).Table 2:Confirmed LncRNAs in pyroptosis.LncRNAExpression levelDamageNetworkReferencesLncRNA THRILUpLung, epithelial cellmiR-19a, miR-34a, miR-424[13–15]LncRNA TapSAKIUpEpithelial cell, Kidney tubulesmiR-22[16]LncRNA MIATUpHeartmiR-330-5p[17]LncRNA H19DownCardiac musclemiR-93-5p[18]LncRNA RMRPUpCardiac musclemiR-1-5p[19]LncRNA SNHG16UpLungmiR-146a-5p[20]CircRNA and pyroptosisCircRNA is a new emerging non-coding RNA molecule, which forms a covalent closed cyclic structure after back-splicing [77]. CircUBE2G1 regulates LPS-induced osteoarthritis through the miR-373/HIF-1α axis [78]. CircPWWP2A affects LPS-induced liver fibrosis through sponge adsorption of miR-203 and miR-223 [79]; Circ_102685 and CircRSF1 can adjust miR-146a expression, thereby inhibiting pus Toxic process [69]. CircRNA plays a significant part in cell pyroptosis process. The N6-methyladenosine (m6A) modification of Circ_0029589 can induce macrophage pyroptosis and inflammation in patients with coronary artery disease [80]. Circ_4099 was induced by the inflammatory mediator TNF-α, which in turn regulates the NF-κB signaling pathway [69] (Figure 2).Figure 2:The regulation of ncRNAs in pyroptosis.Conclusions and discussionsConclusionsPyroptosis is an essential natural immune response that plays an instrumental role in opposing infections and internal danger signs. It is extensively engaged in the progression of infectious diseases, neurological disorders and atherosclerotic diseases, among others. An intensive study of pyroptosis will lead to an understanding of its contribution in the evolution and regression of these illnesses and offer new insights for clinical therapies. Research has revealed that hyperglycemia can cause increased production of reactive oxygen species, which in turn upregulates NF-κB and TXNIP, which in turn upregulates the expression of NLRP3, IL-1β precursor and IL-18 precursor; TXNIP activates Caspase-1 by altering the structure of NLRP3, and the activated Caspase-1 cleaves GSDMD on the one hand. forming a peptide containing the nitrogen-terminal active domain of GSDMD, inducing perforation and rupture of the cardiomyocyte membrane, releasing the contents and causing an inflammatory response; on the other hand, activated Caspase-1 cleaves the precursors of IL-1β and IL-18, forming active IL-1β and IL-18 and releasing them to the extracellular space, recruiting inflammatory cells to aggregate and enlarge the inflammatory response [81]. Now, great progress has been made by pyroptosis, and pyroptosis has been shown to be closely related to the development of many inflammation-related diseases, including tumors, and has shown great potential in tumor therapy. Tumors are in a complex immune microenvironment [82], and pyroptosis is a form of immune cell death. Researchers have identified pyroptosis related with the development and treatment of all kinds of tumors, and some of the mechanisms have been elucidated [57, 83, 84]. For instance, Gasdermin-B can directly cleave GSDME and induce cancer cells to undergo pyroptosis, which to increase stimulating anti-tumor immune response and suppresses tumor development [85]. GSDMs play a key role in oncogenesis, acting as both promoters and suppressors of tumors. The basic mechanisms remain to be further explored, which will provide insight into the development of potent cancer immunotherapies.NcRNA is widely present in serum, plasma, urine or other body fluids. It may have a key role in tumors and can be regarded as a biomarker or potential therapeutic target. On the one hand, ncRNA was reported to participate in pyroptosis in tumors [86].DiscussionsPyroptosis-induced inflammatory responses can stimulate potent anti-tumor immunity and act synergistically with checkpoint blockade [87]. Additionally, it has also been found that pyroptosis plays an essential role in facilitating tumor necrosis and provoking more obvious adverse effects of tumor treatment [83, 88]. These findings provide important ideas for reducing adverse effects of tumor treatment, achieving better treatment outcomes, and exploring new therapeutic approaches. In summary, inhibition of the pyroptosis pathway may treat diseases associated with excessive immune activity in the body, including various chronic inflammatory conditions, autoimmune diseases, and sepsis caused by bacterial infections, while activation of the pyroptosis pathway may kill cancer cells, treat various cancers, or enhance the killing efficiency of other cancer drugs. Zhang et al. showed that the chemotherapeutic agent cisplatin induced cell scorching in lung cancer cells A549 by activating GSDME [89]. GSDME-mediated cell scorching has been shown to recruit T cells in tumor tissue through the release of chemokines, thus providing a new anti-tumor mechanism for cisplatin treatment. The identification of GSDME’s immunomodulatory effect on cancer also provides a new prospective target for the development of anti-cancer immunotherapy [90]. NcRNA has become a research hotspot. It is a type of nucleic acid molecule that plays an important regulatory role in immunity and cell death. A new lncRNA signature associated with pyroptosis is an independent prognostic indicator for breast cancer patients [91] The lncRNA small ribonucleic acid host gene 7 (SNHG7)/miR-34a/SIRT1 axis is responsible for NLRP3-dependent pyroptosis during hepatocellular carcinoma [86]. On the other hand, ncRNA regulates the NF-κB signaling pathway and is related to pyroptosis [92]. The pyroptosis of extracellular is intimately linked to inflammatory response signaling circuit, especially the NF-κB signal pathway. Activation of NF-kB signaling can cause cells to pyroptosis. Combined with the effects of NF-kB signaling on pyroptosis, targeting NF-kB can effectively enhance the development of pyroptosis and inhibit the development of tumors.Pyrotosis, as an inflammatory cell death mode, plays a crucial role in tumor suppression by stimulating anti-tumor immune reaction. In some situations, inducing cytokinesis single may be enough to prevent tumor growth. However, one of the most challenging aspects of the therapeutic application of pyroptosis is the variability in the expression and function of cytokine-related elements, not only between distinct cancers, but also within the same kind of cancer. As the study progresses, more ncRNAs associated with pyroptosis action will be identified and their regulatory mechanisms on the pyroptosis action pathway will become clearer. In conclusion, it will be intriguing to examine whether pyroptosis action can also affect ncRNAs expression. Therefore, using new technology to expand the scope of research on ncRNAs and screen out therapeutic drugs may be a hopeful alternative for the diagnosis and management of diseases associated with pyroptosis.

Journal

ONCOLOGIEde Gruyter

Published: Jul 1, 2023

Keywords: cancer; Gasdermin; non-coding RNAs; pyroptosis

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