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High expression of Talin-1 is associated with tumor progression and recurrence in melanoma skin cancer patients

High expression of Talin-1 is associated with tumor progression and recurrence in melanoma skin... Background Talin-1 as a component of multi-protein adhesion complexes plays a role in tumor formation and migration in various malignancies. This study investigated Talin-1 in protein levels as a potential prognosis biomarker in skin tumors. Methods Talin-1 was evaluated in 106 skin cancer (33 melanomas and 73 non-melanomas skin cancer (NMSC)) and 11 normal skin formalin-fixed paraffin-embedded (FFPE) tissue samples using immunohistochemical technique on tissue microarrays ( TMAs). The association between the expression of Talin-1 and clinicopathological parameters, as well as survival outcomes, were assessed. Results Our findings from data minings through bioinformatics tools indicated dysregulation of Talin-1 in mRNA levels for skin cancer samples. In addition, there was a statistically significant difference in Talin-1 expression in terms of intensity of staining, percentage of positive tumor cells, and H-score in melanoma tissues compared to NMSC (P = 0.001, P < 0.001, and P < 0.001, respectively). Moreover, high cytoplasmic expression of Talin-1 was found to be associated with significantly advanced stages (P = 0.024), lymphovascular invasion (P = 0.023), and recurrence (P = 0.006) in melanoma cancer tissues. Our results on NMSC showed a statistically significant association between high intensity of staining and the poor differentiation (P = 0.044). No significant associations were observed between Talin-1 expression levels and survival outcomes of melanoma and NMSC patients. Conclusion Our observations showed that higher expression of Talin1 in protein level may be significantly associated with more aggressive tumor behavior and advanced disease in patients with skin cancer. However, further studies are required to find the mechanism of action of Talin-1 in skin cancers. Keywords Talin-1, Skin cancer, Melanoma, Non-melanoma skin cancer, Bioinformatics, IHC *Correspondence: School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Zahra Madjd Department of Dermatopathology, Razi Hospital, Tehran University of zahra.madjd@yahoo.com Medical Sciences ( TUMS), Tehran, Iran Leili Saeednejad Zanjani Department of Pathology and Genomic Medicine, Sidney Kimmel saeednejadleily@yahoo.com Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran 14496-14535, Iran © The Author(s) 2023. 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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 in a credit line to the data. Rezaie et al. BMC Cancer (2023) 23:302 Page 2 of 13 Background The role of Talin-1 dysregulation in cancer has been Skin cancers are the most common neoplasms in studied widely; however, a substantial controversy in the humans, imposing high rates of disease burden globally literature exists today regarding the regulation of Talin-1 [1, 2]. They are generally classified as melanoma and non- in different cancers. Upregulation of Talin-1 expression melanoma skin cancers (NMSC), with squamous cell is documented in gastric cancer, mucosal SCC, and pros- carcinoma (SCC) and basal cell carcinoma (BCC) being tate cancers; conversely, its downregulation is shown in the most prevalent non-melanoma subtypes [3]. NMSCs colorectal cancer and hepatocellular carcinoma [34–39]. are responsible for most skin cancer cases; however, mel- High expression levels of Talin-1 correlated with invasion anoma is the leading cause of death due to skin cancer and lower survival rates in prostate cancer, colon cancer, and one of the most aggressive cancers [4–6], with an nasopharyngeal carcinoma, and oral SCC [35, 40–42]. estimation of 99,780 new cases and 7650 deaths in 2022 Furthermore, Talin-1 knockdown in prostate cancer and in the United States alone [7]. NMSCs have a relatively colorectal cancer cell lines has been shown to reduce low mortality risk, however, due to their high prevalence, their migration and proliferation [43, 44]. they impose a high burden on public health [3, 6, 8, 9]. The role and clinical significance of Talin-1 protein in Although melanoma comprises only 1% of skin cancers, melanoma and NMSCs remain unexplored. In the pres- it has a reputation for rapid metastasis and resistance to ent study, at the primary search stage, comprehensive therapy, and the mechanisms of cellular invasion remain alterations in mRNA levels of Talin-1 in patients with mostly unclear [10, 11]. Early-stage melanoma is eas- skin cancer were analyzed using Gene Expression Pro- ily curable with excision, however, with metastasis, the filing Interactive Analysis (GEPIA2) and Gene Expres - survival rates decrease drastically [12]. Despite many sion database of Normal and Tumor tissues 2 (GENT2) new treatment options for advanced melanoma today, databases. Then, Talin-1 protein expression levels were the response to treatment differs in patients, and many evaluated by formalin-fixed paraffin-embedded (FFPE) patients may develop resistance to therapy or adverse tissue samples which were assembled on tissue micro- effects [ 13–15]. Diagnostic and prognostic biomark- array (TMA) slides using Immunohistochemical (IHC) ers are increasingly important in melanoma treatment technique. The IHC assay is a standard procedure applied so that they may have improved survival and treatment to assess novel molecular biomarkers, and TMA technol- [16–18]. In clinical settings, proper prognostication of ogy enables simultaneous staining of hundreds of tissue patients is necessary to select the suitable treatment plan samples [45]. Then, we sought to determine the asso - for each patient to maximize efficacy and decrease the ciation of Talin-1 expression with clinicopathological expenses and adverse effects of the treatment. Although characteristics and survival information of skin cancer many new genomic and protein markers including the patients. S-100b and Lactate dehydrogenase (LDH) proteins have been suggested for advanced melanoma prognostication, Methods no feasible lab tests are available today to stratify high- Investigations of Talin-1 based on data mining risk patients with high accuracy in clinical settings [19, To investigate alteration in the expression of Talin-1 in 20]. New prognostic markers and therapeutic targets for mRNA levels for patients with skin cancer, GEPIA2 and both melanoma and NMSCs are urgently needed to opti- GENT2 databases were applied. GEPIA2 (http://gepia2. mize patient management and decrease the morbidity cancer-pku.cn/) is an online database using RNA expres- and mortality of the disease [18]. sion data of tumor and normal samples obtained from Talin-1 is a large protein interacting with the cytoplas- The Cancer Genome Atlas (TCGA) and the Genotype- mic domain of the integrin β subunit, connecting it to Tissue Expression (GTEx) [46]. While GENT2 (http:// focal adhesion molecules such as focal adhesion kinase gent2.appex.kr) is included gene expression data of can- (FAK) and vinculin and regulatory molecules, including cer and normal tissues from the NCBI-GEO database deleted in liver cancer-1 (DLC-1), RIAM and KANK [21– with two microarray platforms (Affymetrix U133A or 25]. As the main component of focal adhesions (FAs), U133Plus2) [47]. Therefore, boxplot mRNA expression Talin-1 links the extracellular matrix (ECM) and actin analysis for skin cancer and normal tissues was con- cytoskeleton, acting as a mechanosensitive signaling hub structed through these databases. Moreover, the UCSC regulating the cell behavior such as proliferation, migra- Xena Browser database (https://xenabrowser.net/) was tion, and cell shape according to changes in the ECM used to evaluate expression data with metastasis feature [26–31]. In healthy skin tissue, Talin-1 is present at the in RNA-sequencing data for Talin-1 expression from skin epidermal-dermal interface and in cell-cell junctions of cancer patients. UCSC Xena Browser is an online visual the melanocytes, emphasizing its crucial function in cell- exploration tool for public and private, multi-omic, and cell and cell-ECM adhesion and signaling [32, 33]. clinical/phenotype data including TCGA and Genomic Data Commons (GDC) [48]. Finally, a bioinformatics Rezaie et al. BMC Cancer (2023) 23:302 Page 3 of 13 analysis of the survival data as it relates to Talin-1 in 20  min at room temperature. After washing the slides, mRNA levels for skin cancer patients was performed we autoclaved the samples in citrate buffer (ph = 6.0) for using these mentioned online databases. 10  min to retrieve sample antigens. Next, we blocked sections (blocker protein, Dako, Denmark) for 20  min Study population and incubated them with a primary rabbit polyclonal A total of 106 FFPE archival specimens of skin cancer antibody to Talin-1 (1:500, ab71333, Abcam Inc., Cam- including melanoma skin cancer (N = 33), NMSC con- bridge, MA, UK) at 4 °C overnight. The next day, slides sisting of SCC and BCC (N = 73), and normal skin tis- were washed three times with Tris-buffered saline (TBS) sues (N = 11) were collected from Razi referral skin and incubated with anti-rabbit/anti-mouse envision hospital and Imam Khomeini tertiary complex in Tehran, IgG–HRPO (EnVision, Dako, Denmark) as the second- Iran. Samples were obtained from patients between the ary antibody for 1 h. Afterward, TMA slides were treated years 2013–2020, and it was confirmed that none of the for 3  min at room temperature with 3,3′-diaminobenzi- patients were subject to chemotherapy or radiotherapy dine (DAB) (Dako, Denmark) substrate as a chromogen. prior to tissue sampling. Hematoxylin and eosin (H&E) Finally, slides were counterstained with hematoxylin stained slides associated with each FFPE sample were (Dako, Denmark), dehydrated with serial-graded alcohol, collected for TMA construction. We reviewed patients’ cleared with xylene, and mounted. Human normal kid- medical records for clinicopathological characteristics ney tissue was used as a positive control, and for negative including gender, age, TNM stage, histologic grade, Bres- control samples, the primary antibody was replaced with low thickness, ulceration, lymphovascular invasion (LVI), TBS to ensure no nonspecific bindings happened. The perineural invasion (PNI), lymphocyte infiltration, dis - optimal dilution of the Talin-1 antibody was examined by tant metastasis, and tumor recurrence. Next, patients’ applying serial-prepared dilutions of the antibody to the survival information was gathered by telephone follow- tissue. ups. The time between the initial treatment and death due to skin cancer was defined as disease-specific survival Immunostaining assessment (DSS), and progression-free survival (PFS) was defined Two experienced dermatopathologists (SM and KK) as the interval between the initial treatment and the last independently evaluated immunostained sections follow-up without evidence of disease progression and blinded to patients’ information. Any inconsistency in metastasis. The TNM stage was determined according to results was resolved by reaching a consensus. The inten - the American Joint Committee on Cancer (AJCC) [49]. sity and area of staining were the primary reported All patients’ information was handled with confidential - outcomes. The intensity of staining was reported in a ity, and the research process was approved by the medical semi-quantitative fashion, represented by 0 (no staining), ethics committee of Tehran University of medical sci- 1 (weak), 2 (moderate), and 3 (strong). The staining area ences under the code IR.TUMS.REC.1401.034. was reported as the percentage of positive tumor cells in the sample and classified into four groups: <25%, 25–50%, TMA construction 51–75%, and > 75%. We reported the final Talin-1 expres - Skin cancer TMAs were constructed as described in sion results as histochemical score (H-score), calculated the literature [50, 51]. Briefly, our pathologists (SM and by multiplying the staining intensity by the staining area, KK) evaluated the H&E stained slides and FFPE blocks ranging from 0 to 300. In this study, the median H-score and marked the most representative area of the tumor. was used to categorize the samples as expressing high or The selected spots were punched by a precision array - low levels of talin-1. ing instrument (Tissue Arrayer Minicore; ALPHELYS, Plaisir, France), and tissue cylinders were separated and Statistical analysis transferred to the recipient block. For more accurate All patients’ data and scoring results were documented results, TMA blocks were triplicated, and from each and analyzed using “statistical software SPSS, version block, separate slides were constructed and stained. The 22.0. Armonk, NY: IBM Corp”. We reported the cat- final staining score of each sample was determined by the egorical data by N (%), valid percent, and quantitative mean staining score of the cores. data as follows: mean (SD) and median (Q1, Q3). First, the Mann-Whitney U test was applied to compare the Immunohistochemical (IHC) staining significance of staining differences in melanoma and First, all TMA slides were deparaffinized for 20 min and NMSC tissues. Afterward, Pearson’s chi-square test and were transferred in xylene; then, the rehydration process Spearman’s correlation tests were used to analyze the sig- was carried out via serial-graded alcohols. To block the nificance of association and correlation between Talin-1 endogenous peroxidase activity and prevent non-reactive expression and clinicopathological characteristics of staining, we used a 3% hydrogen peroxide solution for patients. Ultimately, we analyzed survival data regarding Rezaie et al. BMC Cancer (2023) 23:302 Page 4 of 13 Talin-1 expression by the Kaplan-Meier method with a compared to the normal skin tissues (GPL570 platform) 95% confidence interval and compared the results with (Supplementary Tables  1 and Supplementary Fig.  1). the log-rank test. The Cox proportional hazards regres - After analyzing of the skin cancer patient data from the sion model was adopted to perform univariate and mul- TCGA database using the UCSC Xena web-based tool, tivariate analyses. Any differences with a p-value < 0.05 a higher expression of Talin-1 was observed in skin can- were considered significant. cer patients with metastases (n = 366) compared to pri- mary tumor tissues (n = 102) (Welch’s t-test, p = 0.008 (t Results = -2.679)). The comparison between gene expression of Data mining data from normal tissues, primary tumors, and meta- The results of the TCGA database via GEPIA2 revealed static tissues was shown in the heat map and boxplot that mRNA expression of the Talin-1 gene was higher in Fig.  2. Although no significant data was found in the (|Log2FC| Cut-off ≥ 0.5) in 461 skin cutaneous mela- evaluation of prognosis biomarkers from Talin-1 at RNA noma tissues compared to the 558 normal skin tissues level through survival analysis. (P < 0.01, Fig.  1). Furthermore, obtained data based on GENT2 from the displayed GEO mRNA expression level Demographics of skin cancer patients of Talin-1 was significantly higher in skin cancer tissues Following the IHC staining of tissue samples, a total of 106 archival FFPE samples as TMA slides were included in the study, of which 33 (31.1%) were melanoma skin cancer and 73 (68.7%) were NMSC tissues (34 BCC and 39 SCC samples). Eleven samples of normal skin tissues were used as controls. Melanoma samples belonged to 18 (54.5%) male and 15 (45.5%) female patients with a mean age of 65 ± 13.9 (range: 35–91). NMSC samples were obtained from 57 (78.0%) male and 16 (21.9%) female patients with a mean age of 68.4 ± 1.34 (range:38–94). Clinicopathological characteristics of melanoma and NMSC patients are demonstrated in Supplementary Tables 2 and 3, respectively. Expression of Talin-1 Comparison of Talin-1 expression in melanoma and non- melanoma skin cancers (NMSC) tissue samples The expression level of Talin-1 in skin cancer tissues was evaluated through the IHC method on TMA sections by measuring the intensity of staining, area of staining, and H-score. All cores showed different levels of staining in the cytoplasm (Fig.  3). We divided samples into low expression and high expression groups according to the median cytoplasmic expression of H-scores (cutoff = 200 and 90 in melanoma and NMSC tissues, respectively). The results showed that there is a statistically significant difference in Talin-1 expression in terms of intensity of staining, percentage of positive tumor cells, and H-score in melanoma tissues compared to NMSC samples (P = 0.001, P < 0.001, and P < 0.001, respectively) (Table 1). Higher expression levels of Talin-1 were observed in skin tumor tissues compared to normal tissue samples (mel- anoma and NMSC tissues). Moreover, normal human kidney tissue used as a positive control showed strong Fig. 1 The mRNA levels of Talin-1 (TLN1) in Skin Cutaneous Mela- staining in renal epithelial cells (Fig. 3). noma using Gene Expression Profiling Interactive Analysis 2 (GEPIA2). High expression of Talin-1 was found in mRNA levels in tumors compared with normal tissues (|Log2FC| Cut-off ≥ 0.5 and P < 0.01) by Gene Expression Profiling Interactive Analysis (GEPIA2). Rezaie et al. BMC Cancer (2023) 23:302 Page 5 of 13 Fig. 2 Comparison between Talin-1 (TLN1) expression from normal tissues, primary tumors, and metastatic tissues for skin data on UCSC Xena web-based tool. (A) heat map and (B) boxplot showed a high expression levels of Talin-1 in melanoma skin cancer patients with metastases rather than primary tumor tissues ( Welch’s t-test, P = 0.008 (t = -2.679)) Fig. 3 Immunohistochemical staining of Talin-1 protein expression in skin cancer and normal skin tissues. Talin-1 protein expression in mela- noma skin cancer tissues: low expression (A, A-1) and high expression (B, B-1). Talin-1 protein expression in non melanoma skin cancer (NMSCs) tissues low expression (C, C-1), and high expression (D, D-1). IHC staining of skin normal tissue (E), and human normal kidney as (F) positive and (G) negative controls. Figures are shown with a magnification of 100 × and 200× Rezaie et al. BMC Cancer (2023) 23:302 Page 6 of 13 Table 1 Expression of Talin-1 (Intensity of staining, percentage Survival outcomes in patients with melanoma and non- of positive tumor cells, and H-score) in melanoma skin cancer melanoma skin cancers (NMSC) tissues, non-melanoma skin cancer, and normal skin tissues Information on survival outcomes of melanoma skin Scoring system Melanoma Non-mela- P-value Normal cancer tissues and non-melanoma patients is demon- skin cancer noma skin skin strated in Table  4 in detail. As listed in the table, out of tissues N cancer tissues tissues 33 melanoma patients, follow-up data was lost for five (%) N (%) N (%) patients, and the remaining patients were followed for a Intensity of 0 (0.0) 0 (0.0) 0.001 0 (0.0) staining 10 (30.3) 49 (67.1) 7 (63.6) mean duration of 39 months (min = 5, max = 138). In this Negative (0) 18 (54.5) 19 (26.0) 4 (36.4) interval, 24 (72.7%) patients experienced recurrence, and Weak (+ 1) 5 (15.2) 5 (6.8) 0 (0.0) 19 (57.6%) patients died due to melanoma. In NMSC Moderate (+ 2) patients, follow-up data were available for 38 patients Strong (+ 3) being followed for a mean duration of 41.26 months Percentage of 0 (0.0) 12 (16.4) < 0.001 2 (18.2) positive tumor 1 (3.0) 8 (11.0) 1 (9.1) (min = 7, max = 80). Fourteen (19.2%) patients experi- cells 2 (6.1) 13 (17.8) 2 (18.2) enced tumor recurrence, and two (2.7%) patients died < 25% 30 (90.9) 40 (54.8) 6 (54.5) due to cancer-related complications. 25–50% 51–75% Prognostic value of Talin-1 expression in melanoma and > 75% non-melanoma skin cancers (NMSC) patients H-score cut off 200 90 < 0.001 4 (36.4) Low 29 (87.9) 42 (57.5) 7 (63.6) We used Kaplan–Meier survival analysis to compare High 4 (12.1) 31 (42.5) DSS or PFS based on Talin-1 expression (H-score) in Total 33 73 11 melanoma and NMSC patients. Our findings showed H-score histological score that no significant associations between DSS or PFS and P value is based on Mann-Whitney U test the patients with high and low expression of the Talin-1 protein in melanoma (Log-rank test: DSS P = 0.503, PFS Associations of Talin-1 expression and clinicopathological P = 0.800) and NMSC cases (Log-rank test: DSS P = 0.263, characteristics in melanoma tissues PFS P = 0.385). (Fig. 4). We collected patients’ data, including age, gender, TNM Utilizing univariate and multivariate analyses, we stage, Breslow thickness, ulceration, LVI, PNI, lym- assessed the clinical significance of various parameters phocytic infiltration, distant metastasis, and tumor that might influence DSS and PFS in these patients. The recurrence. Pearson’s χ2 test was utilized to find the asso - results indicated that the listed clinicopathologic vari- ciation of Talin-1 expression with clinicopathological fea- ables are not significant factors affecting the DSS and PFS tures. Our findings indicated that there is a statistically of melanoma and NMSC patients. significant association between high expression levels of Talin-1 and advanced TNM stage (Hscore P = 0.024), Discussion LVI (intensity of staining P = 0.024; H-score P = 0.023) as Considering the significant burden of skin cancers on well as tumor recurrence (Hscore P = 0.006). No signifi - public health, identification and characterization of cant associations were detected between Talin-1 expres- molecular and cellular processes involved in oncogen- sion and other clinicopathological parameters (Table  2). esis and tumor progression are vital to uncovering novel Moreover, Bivariate analysis showed a statistically sig- prognostic markers and therapeutic targets [8, 9, 52]. nificant positive correlation between increased Talin-1 In this regard, this study was conducted to evaluate the expression and increase in TNM stage (Spearman’s rho, potential of Talin-1 protein as a biomarker of skin cancer. P = 0.025), and between high Talin-1 expression and LVI In in-silico analysis, using the bioinformatics approach, (P = 0.023) as well as tumor recurrence (P = 0.005). we explored the omics data and identified significantly dysregulated gene expression of Talin-1 in skin cancers. Associations of Talin-1 expression and clinicopathological Additionally, in-silico data indicated increased expres- characteristics in non-melanoma skin cancers (NMSC) tissues sion of Talin-1 in metastatic tissues in mRNA level. Fur- The results of Pearson’s χ2 test exhibited no significant thermore, experimental expression of Talin-1 protein associations between Talin- 1 expression and clinico- through IHC method indicated a significant difference in pathological parameters, including age, gender, TNM cytoplasmic expression of this protein in melanoma and stage, histologic grade, ulceration, lymphocyte infiltra - NMSC tumor cells compared to normal skin tissue. The tion, distant metastasis, and recurrence in NMSC tissues, expression of Talin-1 protein in melanoma invasion has except that high expression of Talin-1 in terms of inten- not been investigated prior to our study, although many sity of staining was associated with an increase in histo- studies have reported the involvement of proteins associ- logic grade in NMSC tissues (P = 0.044) (Table 3). ated with Talin-1 in melanoma progression [53]. Rezaie et al. BMC Cancer (2023) 23:302 Page 7 of 13 Table 2 The association between expression of Talin-1 and clinicopathological parameters of melanoma skin cancer tissues (Intensity of staining and H-score) (P value; Pearson’s χ2 test) Tumor characteristics Total Intensity of staining N (%) P-value H-score (cut off P- samples = 200) N (%) value N (%) 0 (Negative) 1+ 2+ (Moderate) 3+ Low High (Weak) (Strong) (≤ 200) (> 200) Mean age, years (Range) 45 (16–74) 0 (0.0) 7 (21.2) 8 (24.2) 3 (9.1) 0.413 15 (51.7) 3 (75.0) 0.381 ≤ Median age 18 (39.1) 0 (0.0) 3 (9.1) 10 (30.3) 2 (6.1) 14 (48.3) 1 (25.0) > Median age 28 (60.9) Gender 18 (54.5) 0 (0.0) 5 (15.2) 10 (30.3) 3 (9.1) 0.927 16 (48.5) 2 (6.1) 0.846 Male 15 (45.5) 0 (0.0) 5 (15.2) 8 (24.2) 2 (6.1) 13 (39.4) 2 (6.1) Female TNM stage 3 (9.1) 0 (0.0) 0 (0.0) 1 (3.0) 2 (6.1) 0.91 1 (3.0) 2 (6.1) 0.024 I 3 (9.1) 0 (0.0) 1 (3.0) 2 (6.1) 0 (0.0) 3 (9.1) 0 (0.0) II 2 (6.1) 0 (0.0) 1 (3.0) 0 (0.0) 1 (3.0) 2 (6.1) 0 (0.0) III 25 (75.8) 0 (0.0) 8 (24.2) 15 (45.5) 2 (6.1) 23 (69.7) 2 (6.1) IV Breslow thickness (Range) 3 (21.4) 0 (0.0) 0 (0.0) 1 (7.1) 2 (14.3) 0.572 1 (7.1) 2 (14.3) 0.078 < 1 5 (35.7) 0 (0.0) 1 (7.1) 3 (21.4) 1 (7.1) 5 (35.7) 0 (0.0) 1–4 6 (42.9) 0 (0.0) 1 (7.1) 4 (28.6) 1 (7.1) 5 (35.7) 1 (7.1) 4 > Ulceration 10 (38.5) 0 (0.0) 1 (3.8) 7 (26.9) 2 (7.7) 0.304 8 (30.8) 2 (7.7) 0.286 Yes 16 (61.5) 0 (0.0) 6 (23.1) 8 (30.8) 2 (7.7) 15 (57.7) 1 (3.8) No Lymphovascular invasion (LVI) 10 (58.8) 0 (0.0) 3 (17.6) 7 (41.2) 0 (0.0) 0.024 10 (58.8) 0 (0.0) 0.023 Yes 7 (41.1) 0 (0.0) 1 (5.9) 2 (11.8) 4 (23.5) 4 (23.5) 3 (17.6) No Perineural invasion (PNI) 4 (16.6) 0 (0.0) 1 (4.2) 2 (8.3) 1 (4.2) 0.885 3 (12.5) 1 (4.2) 0.408 Yes 20 (83.3) 0 (0.0) 6 (25.0) 11 (45.8) 3 (12.5) 18 (75.0) 2 (8.3) No Lymphocyte infiltration 12 (75.0) 0 (0.0) 2 (12.5) 7 (43.8) 3 (18.8) 0.306 10 (62.5) 2 (12.5) 0.383 Yes 4 (25.0) 0 (0.0) 2 (12.5) 2 (12.5) 0 (0.0) 4 (25.0) 0 (0.0) No Distant metastasis 25 (75.8) 0 (0.0) 8 (32.0) 15 (45.5) 2 (6.1) 0.126 23 (69.7) 2 (6.1) 0.200 Yes 8 (24.2) 0 (0.0) 2 (6.1) 3 (9.1) 3 (9.1) 6 (18.2) 2 (6.1) No Tumor recurrence 24 (85.7) 0 (0.0) 8 (28.6) 14 (50.0) 2 (7.1) 0.063 23 (82.1) 1 (3.6) 0.006 Yes 4 (14.2) 0 (0.0) 0 (0.0) 2 (7.1) 2 (7.1) 2 (7.1) 2 (7.1) No H-score histological score Values in bold are statistically significant Vinculin is one of the main proteins connecting Talin-1 phenotype, malignant melanocytes and keratinocytes to the actin cytoskeleton [54]. Vinculin stabilizes the undergo epidermal-mesenchymal transition (EMT), actin-FA binding, and its underexpression promotes resulting in loss of their E-cadherin adhesions and inva- melanoma motility and metastasis, whereas its activa- sion [68–70]. As a critical signaling molecule of the tion inhibits tumor growth and sensitizes the tumor to cytoskeleton, Talin-1 regulates cadherin adhesions and chemotherapy [55–59]. As one of the main molecules in may play a role in the EMT process of skin cancers [43, Talin-1 dependent integrin signaling and FA assembly, 71–73]. In our study, Talin-1 staining was nearly exclu- FAK plays a substantial role in PI3K/AKT signaling path- sive to the cytoplasm of the skin tumor cells, confirm - way [54, 60, 61], which is an important oncogenic path- ing the previous evidence regarding the expression and way and therapeutic target in melanoma and NMSCs[62, function of Talin-1 [40, 74]. Moreover, our results show 63]. AKT mutations in melanoma cell lines were associ- that the staining was not limited to the epidermal-dermal ated with reduced inhibition of FAK and increased brain junction unlike normal skin tissue [32]. These differences metastasis [64]. Furthermore, phosphorylation and con- can be explained, in part, by considering the fact that dis- stitutive activation of FAK have been suggested as the ruption occurs by the tumor. Cancer-associated Talin-1 mechanisms accountable for anchorage-independent mutation and dysregulations induce metastasis by dis- phenotype resulting in melanoma metastasis [59, 65– rupting integrin activity, leading to the loss of cell adhe- 67]. In order to gain stemness properties and invasive sion and organization [75, 76]. Rezaie et al. BMC Cancer (2023) 23:302 Page 8 of 13 Table 3 The association between expression of Talin-1 and clinicopathological parameters of non-melanoma skin cancer (NMSC) tissues (Intensity of staining and H-score) (P-value; Pearson’s χ2 test) Tumor characteristics Total Intensity of staining N (%) P-value H-score (cut off = 90) P- samples N (%) val- N (%) ue 0 (Negative) 1+ 2+ (Moderate) 3+ Low High (Weak) (Strong) (≤ 90) (> 90) Mean age, years (Range) 45 (16–74) 0 (0.0) 26 (35.6) 9 (12.3) 3 (4.1) 0.855 22 (30.1) 16 (21.9) 0.948 ≤ Median age 38 (52.1) 0 (0.0) 23 (31.5) 10 (13.7) 2 (2.7) 20 (27.4) 15 (20.5) > Median age 35 (47.9) Gender 57 (78.1) 0 (0.0) 36 (49.3) 17 (23.3) 4 (5.5) 0.357 33 (45.2) 24 (32.9) 0.906 Male 16 (21.9) 0 (0.0) 13 (17.8) 2 (2.7) 1 (1.4) 9 (12.3) 7 (9.6) Female TNM stage* 17 (43.6) 0 (0.0) 10 (25.6) 7 (17.9) 0 (0.0) 0.701 10 (25.6) 7 (17.9) 0.758 I 15 (38.5) 0 (0.0) 8 (20.5) 6 (15.4) 1 (2.6) 8 (20.5) 7 (17.9) II 2 (5.1) 0 (0.0) 1 (2.6) 1 (2.6) 0 (0.0) 1 (2.6) 1 (2.6) III 5 (12.8) 0 (0.0) 3 (7.7) 1 (2.6) 1 (2.6) 4 (10.3) 1 (2.6) IV Histological grade* 21 (53.8) 0 (0.0) 16 (41.0) 5 (12.8) 0 (0.0) 0.044 15 (38.5) 6 (15.4) 0.226 Well 13 (33.3) 0 (0.0) 4 (10.3) 7 (17.9) 2 (5.1) 6 (15.4) 7 (17.9) Moderate 5 (12.8) 0 (0.0) 2 (5.1) 3 (7.7) 0 (0.0) 2 (5.1) 3 (7.7) Poor Ulceration 15 (34.1) 0 (0.0) 11 (25.0) 3 (6.8) 1 (2.3) 0.975 9 (20.5) 6 (13.6) 0.759 Yes 29 (65.9) 0 (0.0) 22 (50.0) 5 (11.4) 2 (4.5) 16 (36.4) 13 (39.5) no Lymphocyte infiltration 3 (42.9) 0 (0.0) 2 (28.6) 1 (14.3) 0 (0.0) 0.212 2 (28.6) 1 (14.3) 0.809 Yes 4 (57.1) 0 (0.0) 4 (57.1) 0 (0.0) 0 (0.0) 3(42.9) 1 (14.3) No Distant metastasis 5 (22.7) 0 (0.0) 3 (13.6) 1 (4.5) 1 (4.5) 0.127 4 (18.2) 1 (4.5) 0.519 Yes 17 (77.3) 0 (0.0) 9 (40.9) 8 (36.4) 0 (0.0) 11 (50.0) 6 (27.3) No Tumor recurrence 14 (36.8) 0 (0.0) 11 (28.9) 3 (7.9) 0 (0.0) 0.619 7 (18.4) 7 (18.4) 0.311 Yes 24 (63.15) 0 (0.0) 16 (42.1) 7 (18.4) 1 (2.6) 16 (42.1) 8 (21.1) No H-score:histological score Values in bold are statistically significant *TNM stage and histological grade are defined only in squamous cell carcinoma (SCC) type. Table 4 The main characteristics of patients enrolled for survival The evaluation of the staining pattern in melanoma analysis in melanoma skin cancer tissues and non-melanoma and NMSCs exhibited differential expression of Talin-1 skin cancer protein with a range of intensities from weak to strong. Features Melanoma Non- Moreover, there was a statistically significant difference skin cancer melanoma between the cytoplasmic expression of Talin-1 protein tissues N (%) skin cancer in melanoma and NMSCs tissues. These findings are in tissues N (%) line with the fact that melanoma and NMSCs vary sig- Number of patients (N) 28 38 nificantly in their oncogenesis and progression [ 77]. Range of follow-up duration for DSS (5-138), (5-116) (7–80), (1–80) or PFS (months) Therefore, there is an urgent need to investigate each Mean duration of follow-up time for 39 (35.4), 22.1 41.26 (26.3), type separately because each type of skin cancer could be DSS or PFS (months) (SD) (22.5) 33.68 (24.2) related to different prognostic values and behaviors and Median duration of follow-up time for 22 (16-52.7), 31 (19–67), effective to select the best therapeutic decisions. DSS or PFS (months) (Q1, Q3) 12.5 (12–24) 24 (18.7–61.7) In the current study, we observed a positive correlation Cancer-related death (N %) 19 (57.6) 2 (2.7) between Talin-1 expression and LVI in melanoma skin Distant metastasis during follow-up 22 (66.7) 5 (6.8) cancer tissues. The LVI has been shown to be an indepen - (N %) dent prognostic factor increasing the risk of metastasis Tumor recurrence during follow-up 24 (72.7) 14 (19.2) in melanoma [78]. Furthermore, higher expression lev- (N %) els of Talin-1 associated with an increase in the stage of Patients without distant metastasis 3 (9.1) 23 (31.5) and tumor recurrence (N %) melanoma, showing the probable potential of Talin-1 for risk assessment in melanoma patients. Our results high- lighted upregulation of Talin-1 in melanoma progression Rezaie et al. BMC Cancer (2023) 23:302 Page 9 of 13 Fig. 4 Kaplan-Meier survival curves for disease-specific survival (DSS) and progression-free survival (PFS) based on Talin-1 cytoplasmic pro - tein expression in skin cancer tissue samples. The Kaplan-Meier survival curves showed no significant differences between DSS (A) or PFS (B) of melanoma skin cancer patients with high or low expression of Talin-1. Likewise, no significant differences were seen between DSS (C) or PFS (D) of non melanoma skin cancer (NMSC) patients with high or low expression of Talin-1. However, shorter DSS durations were seen in melanoma patients with higher levels of Talin-1 and LVI. Previous evidence suggested that Talin-1 is a Compared to melanoma, NMSCs have a less aggressive critical molecule in integrin activation, signaling path- nature and tend to be localized [8, 83]. Other than tumor way, and cell adhesion [29, 79–81]. Per our results, in the grade in SCC specimens, we observed no significant cor - literature, the association of Talin-1 upregulation with relations between Talin-1 expression and NMSC clini- invasive cancer phenotype and higher stages of gastric copathological characteristics. Poor histological grading and prostate cancer as well as nasopharyngeal carcinoma in cutaneous SCC is associated with tumor recurrence, and oral SCC has been reported [35, 40, 42, 82]. The metastasis, and invasive phenotype of the tumor [84, 85], mentioned evidence implies Talin-1 is a crucial player in and it was associated with Talin-1 upregulation in our the integrin activation process and may have a promotive study. Previously Lai et al. reported the association of effect on malignant melanocytes, which may be hijacked Talin-1 upregulation with poorly differentiated oral SCC, in invasive melanoma by upregulating its expression for however, the tumor microenvironment and pathogen- tumor invasion and progression. esis vary significantly in oral and cutaneous SCC [ 86, 87]. Rezaie et al. BMC Cancer (2023) 23:302 Page 10 of 13 This finding may suggest Talin-1 as a predictor of inva - As the evidence in other cancers implies, Talin-1 may sive SCC, although more studies are needed to conclude. have a presumptive effect on skin cancer patients’ sur - Previous investigations indicated dysregulation of vival outcomes, and more studies are needed to establish Talin-1 is associated with patients’ survival outcomes in the prognostic value of Talin-1 in skin cancers. A limita- colorectal and prostate cancers and oral SCC and naso- tion of our study was the small patient population, which pharyngeal carcinoma [35, 38, 39, 88]. Our Kaplan-Meier may have restricted our observations. Therefore, a larger curve results showed no significant association of Talin-1 sample can lead to more generalizable results. expression with melanoma and NMSC patients’ survival. However, upregulation of Talin-1 was significantly asso - Conclusion ciated with melanoma recurrence after tumor resection In conclusion, our data mining analysis indicated upregu- in our study. These results may be due to the small and lation of Talin-1 in skin cancer patients in mRNA level in lost-to-follow-up patient population. comparison with normal skin tissues. Our finding from More than half of the melanoma tumors harbor an protein evaluation also demonstrated increased expres- activating mutation in BRAF, a serine/threonine kinase sion of Talin-1 protein in skin cancer tissues compared to protein, which enhances tumor proliferation and inva- normal tissues. Moreover, our results exhibited differen - sion, hence targeted BRAF inhibitor therapies such as tial expression of Talin-1 protein between melanoma and Vemurafenib have been developed with high efficacy NMSCs tissues with a statistically significant difference [89]. On the other hand, Immune Checkpoint Inhibitor between the two groups, which may affect their prog - therapies such as Pembrolizumab and Nivolumab target nosis and treatment options. Furthermore, overexpres- the immune evasion mechanisms of the tumor [90–92]. sion of Talin-1 was associated with higher stages, local Unfortunately, despite all the advancements in melanoma invasion, and recurrence of melanoma, emphasizing the targeted therapy and immunotherapy, resistance to novel role of cytoskeletal adhesion and signaling in melanoma therapies remains a major clinical problem [93]. The progression and invasion. Our findings suggest Talin-1 molecular mechanisms of resistance to immune check- may have a presumptive effect on prognosis. Therefore, point inhibitors (ICIs) and BRAF inhibitors (BRAFi) are further studies are needed on the function of Talin-1 as mostly unknown, but the role of cytoskeletal remodeling a potential biomarker in skin cancers as well as its prog- and myosin reactivation is well established [94, 95]. Many nostic value. studies have reported the change in the cellular shape of List of abbreviations the BRAFi resistant sublines of melanoma, making them NMSC Non-Melanoma Skin Cancer more fibroblast and spindle-like [ 96–100]. Rho GTPase FFPE Formalin-Fixed Parafin Embedded TMA Tissue MicroArray is the main molecule responsible for the contraction of IHC ImmunoHistoChemistry the actin cytoskeleton, cellular shape, and resistance to SCC Squamous Cell Carcinoma BRAFi therapy [101]. Rho GTPase is activated by DLC- BCC Basal Cell Carcinoma LDH Lactate Dehydrogenase 1, which inhibits the actin contraction and promotes the FAK Focal Adhession Kinase Talin-1 refolding [24, 102]. Furthermore, the Yes-associ- FA Focal Adhession ated protein (YAP) pathway has been shown to regulate DLC-1 Deleted in Liver Cancer-1 ECM Extracellular Matrix actin remodeling in BRAFi resistant cell lines via accu- GEPIA Gene Expression Profiling Interactive Analysis mulation of YAP in the nucleus [98]. Talin-1 unfolding GENT2 Gene Expression database of Normal and Tumor tissues 2 leads to its binding to vinculin and translocation of YAP TCGA The Cancer Genome Atlas GTEx Genotype-Tissue Expression to nucleus and further adhesion growth [103]. Talin-1 GDC Genomic Data Commons can alter the myosin-driven machinery via DLC-1 bind- H&E Hematoxylin and eosin ing [54]. The loss of DLC-1 protein function in mela -LVI LymphoVascular Invasion PNI Perineural Invasion noma tissue samples significantly promotes melanoma’s DSS Disease-Specific Survival aggressiveness and deteriorates patients’ prognosis [54, PFS Progression-Free Survival 104]. The changes in the actomyosin skeleton render AJCC American Joint Committee on Cancer TBS Tris-Buffered Saline resistant melanoma cells highly dependent on cytoskel- DAB 3,3′-diaminobenzidine etal signaling pathways [95]. Furthermore, mutations in H-Score Histochemical Score integrin signaling pathways improve melanoma patients’ SD Standard Deviation EMT Epidermal-Mesenchymal Transition outcomes after ICI therapy [105]. Considering the sub- ICI Immune Check-point Inhibitor stantial role of Talin-1 in cytoskeletal and integrin sig- naling pathways, presuming a pivotal role for Talin-1 in response to ICI and BRAFi therapy is highly probable and Supplementary Information The online version contains supplementary material available at https://doi. warrants further investigations in the future. org/10.1186/s12885-023-10771-z. Rezaie et al. BMC Cancer (2023) 23:302 Page 11 of 13 8. Aggarwal P, Knabel P, Fleischer Jr, ABJJotAAoD. 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New Strategies and Rational Therapeutic ConceptsVemurafenib Resistance signature in Melanoma. Mol Cancer Ther. 2015;14(3):757–68. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Cancer Springer Journals

High expression of Talin-1 is associated with tumor progression and recurrence in melanoma skin cancer patients

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Copyright © The Author(s) 2023
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10.1186/s12885-023-10771-z
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Abstract

Background Talin-1 as a component of multi-protein adhesion complexes plays a role in tumor formation and migration in various malignancies. This study investigated Talin-1 in protein levels as a potential prognosis biomarker in skin tumors. Methods Talin-1 was evaluated in 106 skin cancer (33 melanomas and 73 non-melanomas skin cancer (NMSC)) and 11 normal skin formalin-fixed paraffin-embedded (FFPE) tissue samples using immunohistochemical technique on tissue microarrays ( TMAs). The association between the expression of Talin-1 and clinicopathological parameters, as well as survival outcomes, were assessed. Results Our findings from data minings through bioinformatics tools indicated dysregulation of Talin-1 in mRNA levels for skin cancer samples. In addition, there was a statistically significant difference in Talin-1 expression in terms of intensity of staining, percentage of positive tumor cells, and H-score in melanoma tissues compared to NMSC (P = 0.001, P < 0.001, and P < 0.001, respectively). Moreover, high cytoplasmic expression of Talin-1 was found to be associated with significantly advanced stages (P = 0.024), lymphovascular invasion (P = 0.023), and recurrence (P = 0.006) in melanoma cancer tissues. Our results on NMSC showed a statistically significant association between high intensity of staining and the poor differentiation (P = 0.044). No significant associations were observed between Talin-1 expression levels and survival outcomes of melanoma and NMSC patients. Conclusion Our observations showed that higher expression of Talin1 in protein level may be significantly associated with more aggressive tumor behavior and advanced disease in patients with skin cancer. However, further studies are required to find the mechanism of action of Talin-1 in skin cancers. Keywords Talin-1, Skin cancer, Melanoma, Non-melanoma skin cancer, Bioinformatics, IHC *Correspondence: School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Zahra Madjd Department of Dermatopathology, Razi Hospital, Tehran University of zahra.madjd@yahoo.com Medical Sciences ( TUMS), Tehran, Iran Leili Saeednejad Zanjani Department of Pathology and Genomic Medicine, Sidney Kimmel saeednejadleily@yahoo.com Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran 14496-14535, Iran © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data. Rezaie et al. BMC Cancer (2023) 23:302 Page 2 of 13 Background The role of Talin-1 dysregulation in cancer has been Skin cancers are the most common neoplasms in studied widely; however, a substantial controversy in the humans, imposing high rates of disease burden globally literature exists today regarding the regulation of Talin-1 [1, 2]. They are generally classified as melanoma and non- in different cancers. Upregulation of Talin-1 expression melanoma skin cancers (NMSC), with squamous cell is documented in gastric cancer, mucosal SCC, and pros- carcinoma (SCC) and basal cell carcinoma (BCC) being tate cancers; conversely, its downregulation is shown in the most prevalent non-melanoma subtypes [3]. NMSCs colorectal cancer and hepatocellular carcinoma [34–39]. are responsible for most skin cancer cases; however, mel- High expression levels of Talin-1 correlated with invasion anoma is the leading cause of death due to skin cancer and lower survival rates in prostate cancer, colon cancer, and one of the most aggressive cancers [4–6], with an nasopharyngeal carcinoma, and oral SCC [35, 40–42]. estimation of 99,780 new cases and 7650 deaths in 2022 Furthermore, Talin-1 knockdown in prostate cancer and in the United States alone [7]. NMSCs have a relatively colorectal cancer cell lines has been shown to reduce low mortality risk, however, due to their high prevalence, their migration and proliferation [43, 44]. they impose a high burden on public health [3, 6, 8, 9]. The role and clinical significance of Talin-1 protein in Although melanoma comprises only 1% of skin cancers, melanoma and NMSCs remain unexplored. In the pres- it has a reputation for rapid metastasis and resistance to ent study, at the primary search stage, comprehensive therapy, and the mechanisms of cellular invasion remain alterations in mRNA levels of Talin-1 in patients with mostly unclear [10, 11]. Early-stage melanoma is eas- skin cancer were analyzed using Gene Expression Pro- ily curable with excision, however, with metastasis, the filing Interactive Analysis (GEPIA2) and Gene Expres - survival rates decrease drastically [12]. Despite many sion database of Normal and Tumor tissues 2 (GENT2) new treatment options for advanced melanoma today, databases. Then, Talin-1 protein expression levels were the response to treatment differs in patients, and many evaluated by formalin-fixed paraffin-embedded (FFPE) patients may develop resistance to therapy or adverse tissue samples which were assembled on tissue micro- effects [ 13–15]. Diagnostic and prognostic biomark- array (TMA) slides using Immunohistochemical (IHC) ers are increasingly important in melanoma treatment technique. The IHC assay is a standard procedure applied so that they may have improved survival and treatment to assess novel molecular biomarkers, and TMA technol- [16–18]. In clinical settings, proper prognostication of ogy enables simultaneous staining of hundreds of tissue patients is necessary to select the suitable treatment plan samples [45]. Then, we sought to determine the asso - for each patient to maximize efficacy and decrease the ciation of Talin-1 expression with clinicopathological expenses and adverse effects of the treatment. Although characteristics and survival information of skin cancer many new genomic and protein markers including the patients. S-100b and Lactate dehydrogenase (LDH) proteins have been suggested for advanced melanoma prognostication, Methods no feasible lab tests are available today to stratify high- Investigations of Talin-1 based on data mining risk patients with high accuracy in clinical settings [19, To investigate alteration in the expression of Talin-1 in 20]. New prognostic markers and therapeutic targets for mRNA levels for patients with skin cancer, GEPIA2 and both melanoma and NMSCs are urgently needed to opti- GENT2 databases were applied. GEPIA2 (http://gepia2. mize patient management and decrease the morbidity cancer-pku.cn/) is an online database using RNA expres- and mortality of the disease [18]. sion data of tumor and normal samples obtained from Talin-1 is a large protein interacting with the cytoplas- The Cancer Genome Atlas (TCGA) and the Genotype- mic domain of the integrin β subunit, connecting it to Tissue Expression (GTEx) [46]. While GENT2 (http:// focal adhesion molecules such as focal adhesion kinase gent2.appex.kr) is included gene expression data of can- (FAK) and vinculin and regulatory molecules, including cer and normal tissues from the NCBI-GEO database deleted in liver cancer-1 (DLC-1), RIAM and KANK [21– with two microarray platforms (Affymetrix U133A or 25]. As the main component of focal adhesions (FAs), U133Plus2) [47]. Therefore, boxplot mRNA expression Talin-1 links the extracellular matrix (ECM) and actin analysis for skin cancer and normal tissues was con- cytoskeleton, acting as a mechanosensitive signaling hub structed through these databases. Moreover, the UCSC regulating the cell behavior such as proliferation, migra- Xena Browser database (https://xenabrowser.net/) was tion, and cell shape according to changes in the ECM used to evaluate expression data with metastasis feature [26–31]. In healthy skin tissue, Talin-1 is present at the in RNA-sequencing data for Talin-1 expression from skin epidermal-dermal interface and in cell-cell junctions of cancer patients. UCSC Xena Browser is an online visual the melanocytes, emphasizing its crucial function in cell- exploration tool for public and private, multi-omic, and cell and cell-ECM adhesion and signaling [32, 33]. clinical/phenotype data including TCGA and Genomic Data Commons (GDC) [48]. Finally, a bioinformatics Rezaie et al. BMC Cancer (2023) 23:302 Page 3 of 13 analysis of the survival data as it relates to Talin-1 in 20  min at room temperature. After washing the slides, mRNA levels for skin cancer patients was performed we autoclaved the samples in citrate buffer (ph = 6.0) for using these mentioned online databases. 10  min to retrieve sample antigens. Next, we blocked sections (blocker protein, Dako, Denmark) for 20  min Study population and incubated them with a primary rabbit polyclonal A total of 106 FFPE archival specimens of skin cancer antibody to Talin-1 (1:500, ab71333, Abcam Inc., Cam- including melanoma skin cancer (N = 33), NMSC con- bridge, MA, UK) at 4 °C overnight. The next day, slides sisting of SCC and BCC (N = 73), and normal skin tis- were washed three times with Tris-buffered saline (TBS) sues (N = 11) were collected from Razi referral skin and incubated with anti-rabbit/anti-mouse envision hospital and Imam Khomeini tertiary complex in Tehran, IgG–HRPO (EnVision, Dako, Denmark) as the second- Iran. Samples were obtained from patients between the ary antibody for 1 h. Afterward, TMA slides were treated years 2013–2020, and it was confirmed that none of the for 3  min at room temperature with 3,3′-diaminobenzi- patients were subject to chemotherapy or radiotherapy dine (DAB) (Dako, Denmark) substrate as a chromogen. prior to tissue sampling. Hematoxylin and eosin (H&E) Finally, slides were counterstained with hematoxylin stained slides associated with each FFPE sample were (Dako, Denmark), dehydrated with serial-graded alcohol, collected for TMA construction. We reviewed patients’ cleared with xylene, and mounted. Human normal kid- medical records for clinicopathological characteristics ney tissue was used as a positive control, and for negative including gender, age, TNM stage, histologic grade, Bres- control samples, the primary antibody was replaced with low thickness, ulceration, lymphovascular invasion (LVI), TBS to ensure no nonspecific bindings happened. The perineural invasion (PNI), lymphocyte infiltration, dis - optimal dilution of the Talin-1 antibody was examined by tant metastasis, and tumor recurrence. Next, patients’ applying serial-prepared dilutions of the antibody to the survival information was gathered by telephone follow- tissue. ups. The time between the initial treatment and death due to skin cancer was defined as disease-specific survival Immunostaining assessment (DSS), and progression-free survival (PFS) was defined Two experienced dermatopathologists (SM and KK) as the interval between the initial treatment and the last independently evaluated immunostained sections follow-up without evidence of disease progression and blinded to patients’ information. Any inconsistency in metastasis. The TNM stage was determined according to results was resolved by reaching a consensus. The inten - the American Joint Committee on Cancer (AJCC) [49]. sity and area of staining were the primary reported All patients’ information was handled with confidential - outcomes. The intensity of staining was reported in a ity, and the research process was approved by the medical semi-quantitative fashion, represented by 0 (no staining), ethics committee of Tehran University of medical sci- 1 (weak), 2 (moderate), and 3 (strong). The staining area ences under the code IR.TUMS.REC.1401.034. was reported as the percentage of positive tumor cells in the sample and classified into four groups: <25%, 25–50%, TMA construction 51–75%, and > 75%. We reported the final Talin-1 expres - Skin cancer TMAs were constructed as described in sion results as histochemical score (H-score), calculated the literature [50, 51]. Briefly, our pathologists (SM and by multiplying the staining intensity by the staining area, KK) evaluated the H&E stained slides and FFPE blocks ranging from 0 to 300. In this study, the median H-score and marked the most representative area of the tumor. was used to categorize the samples as expressing high or The selected spots were punched by a precision array - low levels of talin-1. ing instrument (Tissue Arrayer Minicore; ALPHELYS, Plaisir, France), and tissue cylinders were separated and Statistical analysis transferred to the recipient block. For more accurate All patients’ data and scoring results were documented results, TMA blocks were triplicated, and from each and analyzed using “statistical software SPSS, version block, separate slides were constructed and stained. The 22.0. Armonk, NY: IBM Corp”. We reported the cat- final staining score of each sample was determined by the egorical data by N (%), valid percent, and quantitative mean staining score of the cores. data as follows: mean (SD) and median (Q1, Q3). First, the Mann-Whitney U test was applied to compare the Immunohistochemical (IHC) staining significance of staining differences in melanoma and First, all TMA slides were deparaffinized for 20 min and NMSC tissues. Afterward, Pearson’s chi-square test and were transferred in xylene; then, the rehydration process Spearman’s correlation tests were used to analyze the sig- was carried out via serial-graded alcohols. To block the nificance of association and correlation between Talin-1 endogenous peroxidase activity and prevent non-reactive expression and clinicopathological characteristics of staining, we used a 3% hydrogen peroxide solution for patients. Ultimately, we analyzed survival data regarding Rezaie et al. BMC Cancer (2023) 23:302 Page 4 of 13 Talin-1 expression by the Kaplan-Meier method with a compared to the normal skin tissues (GPL570 platform) 95% confidence interval and compared the results with (Supplementary Tables  1 and Supplementary Fig.  1). the log-rank test. The Cox proportional hazards regres - After analyzing of the skin cancer patient data from the sion model was adopted to perform univariate and mul- TCGA database using the UCSC Xena web-based tool, tivariate analyses. Any differences with a p-value < 0.05 a higher expression of Talin-1 was observed in skin can- were considered significant. cer patients with metastases (n = 366) compared to pri- mary tumor tissues (n = 102) (Welch’s t-test, p = 0.008 (t Results = -2.679)). The comparison between gene expression of Data mining data from normal tissues, primary tumors, and meta- The results of the TCGA database via GEPIA2 revealed static tissues was shown in the heat map and boxplot that mRNA expression of the Talin-1 gene was higher in Fig.  2. Although no significant data was found in the (|Log2FC| Cut-off ≥ 0.5) in 461 skin cutaneous mela- evaluation of prognosis biomarkers from Talin-1 at RNA noma tissues compared to the 558 normal skin tissues level through survival analysis. (P < 0.01, Fig.  1). Furthermore, obtained data based on GENT2 from the displayed GEO mRNA expression level Demographics of skin cancer patients of Talin-1 was significantly higher in skin cancer tissues Following the IHC staining of tissue samples, a total of 106 archival FFPE samples as TMA slides were included in the study, of which 33 (31.1%) were melanoma skin cancer and 73 (68.7%) were NMSC tissues (34 BCC and 39 SCC samples). Eleven samples of normal skin tissues were used as controls. Melanoma samples belonged to 18 (54.5%) male and 15 (45.5%) female patients with a mean age of 65 ± 13.9 (range: 35–91). NMSC samples were obtained from 57 (78.0%) male and 16 (21.9%) female patients with a mean age of 68.4 ± 1.34 (range:38–94). Clinicopathological characteristics of melanoma and NMSC patients are demonstrated in Supplementary Tables 2 and 3, respectively. Expression of Talin-1 Comparison of Talin-1 expression in melanoma and non- melanoma skin cancers (NMSC) tissue samples The expression level of Talin-1 in skin cancer tissues was evaluated through the IHC method on TMA sections by measuring the intensity of staining, area of staining, and H-score. All cores showed different levels of staining in the cytoplasm (Fig.  3). We divided samples into low expression and high expression groups according to the median cytoplasmic expression of H-scores (cutoff = 200 and 90 in melanoma and NMSC tissues, respectively). The results showed that there is a statistically significant difference in Talin-1 expression in terms of intensity of staining, percentage of positive tumor cells, and H-score in melanoma tissues compared to NMSC samples (P = 0.001, P < 0.001, and P < 0.001, respectively) (Table 1). Higher expression levels of Talin-1 were observed in skin tumor tissues compared to normal tissue samples (mel- anoma and NMSC tissues). Moreover, normal human kidney tissue used as a positive control showed strong Fig. 1 The mRNA levels of Talin-1 (TLN1) in Skin Cutaneous Mela- staining in renal epithelial cells (Fig. 3). noma using Gene Expression Profiling Interactive Analysis 2 (GEPIA2). High expression of Talin-1 was found in mRNA levels in tumors compared with normal tissues (|Log2FC| Cut-off ≥ 0.5 and P < 0.01) by Gene Expression Profiling Interactive Analysis (GEPIA2). Rezaie et al. BMC Cancer (2023) 23:302 Page 5 of 13 Fig. 2 Comparison between Talin-1 (TLN1) expression from normal tissues, primary tumors, and metastatic tissues for skin data on UCSC Xena web-based tool. (A) heat map and (B) boxplot showed a high expression levels of Talin-1 in melanoma skin cancer patients with metastases rather than primary tumor tissues ( Welch’s t-test, P = 0.008 (t = -2.679)) Fig. 3 Immunohistochemical staining of Talin-1 protein expression in skin cancer and normal skin tissues. Talin-1 protein expression in mela- noma skin cancer tissues: low expression (A, A-1) and high expression (B, B-1). Talin-1 protein expression in non melanoma skin cancer (NMSCs) tissues low expression (C, C-1), and high expression (D, D-1). IHC staining of skin normal tissue (E), and human normal kidney as (F) positive and (G) negative controls. Figures are shown with a magnification of 100 × and 200× Rezaie et al. BMC Cancer (2023) 23:302 Page 6 of 13 Table 1 Expression of Talin-1 (Intensity of staining, percentage Survival outcomes in patients with melanoma and non- of positive tumor cells, and H-score) in melanoma skin cancer melanoma skin cancers (NMSC) tissues, non-melanoma skin cancer, and normal skin tissues Information on survival outcomes of melanoma skin Scoring system Melanoma Non-mela- P-value Normal cancer tissues and non-melanoma patients is demon- skin cancer noma skin skin strated in Table  4 in detail. As listed in the table, out of tissues N cancer tissues tissues 33 melanoma patients, follow-up data was lost for five (%) N (%) N (%) patients, and the remaining patients were followed for a Intensity of 0 (0.0) 0 (0.0) 0.001 0 (0.0) staining 10 (30.3) 49 (67.1) 7 (63.6) mean duration of 39 months (min = 5, max = 138). In this Negative (0) 18 (54.5) 19 (26.0) 4 (36.4) interval, 24 (72.7%) patients experienced recurrence, and Weak (+ 1) 5 (15.2) 5 (6.8) 0 (0.0) 19 (57.6%) patients died due to melanoma. In NMSC Moderate (+ 2) patients, follow-up data were available for 38 patients Strong (+ 3) being followed for a mean duration of 41.26 months Percentage of 0 (0.0) 12 (16.4) < 0.001 2 (18.2) positive tumor 1 (3.0) 8 (11.0) 1 (9.1) (min = 7, max = 80). Fourteen (19.2%) patients experi- cells 2 (6.1) 13 (17.8) 2 (18.2) enced tumor recurrence, and two (2.7%) patients died < 25% 30 (90.9) 40 (54.8) 6 (54.5) due to cancer-related complications. 25–50% 51–75% Prognostic value of Talin-1 expression in melanoma and > 75% non-melanoma skin cancers (NMSC) patients H-score cut off 200 90 < 0.001 4 (36.4) Low 29 (87.9) 42 (57.5) 7 (63.6) We used Kaplan–Meier survival analysis to compare High 4 (12.1) 31 (42.5) DSS or PFS based on Talin-1 expression (H-score) in Total 33 73 11 melanoma and NMSC patients. Our findings showed H-score histological score that no significant associations between DSS or PFS and P value is based on Mann-Whitney U test the patients with high and low expression of the Talin-1 protein in melanoma (Log-rank test: DSS P = 0.503, PFS Associations of Talin-1 expression and clinicopathological P = 0.800) and NMSC cases (Log-rank test: DSS P = 0.263, characteristics in melanoma tissues PFS P = 0.385). (Fig. 4). We collected patients’ data, including age, gender, TNM Utilizing univariate and multivariate analyses, we stage, Breslow thickness, ulceration, LVI, PNI, lym- assessed the clinical significance of various parameters phocytic infiltration, distant metastasis, and tumor that might influence DSS and PFS in these patients. The recurrence. Pearson’s χ2 test was utilized to find the asso - results indicated that the listed clinicopathologic vari- ciation of Talin-1 expression with clinicopathological fea- ables are not significant factors affecting the DSS and PFS tures. Our findings indicated that there is a statistically of melanoma and NMSC patients. significant association between high expression levels of Talin-1 and advanced TNM stage (Hscore P = 0.024), Discussion LVI (intensity of staining P = 0.024; H-score P = 0.023) as Considering the significant burden of skin cancers on well as tumor recurrence (Hscore P = 0.006). No signifi - public health, identification and characterization of cant associations were detected between Talin-1 expres- molecular and cellular processes involved in oncogen- sion and other clinicopathological parameters (Table  2). esis and tumor progression are vital to uncovering novel Moreover, Bivariate analysis showed a statistically sig- prognostic markers and therapeutic targets [8, 9, 52]. nificant positive correlation between increased Talin-1 In this regard, this study was conducted to evaluate the expression and increase in TNM stage (Spearman’s rho, potential of Talin-1 protein as a biomarker of skin cancer. P = 0.025), and between high Talin-1 expression and LVI In in-silico analysis, using the bioinformatics approach, (P = 0.023) as well as tumor recurrence (P = 0.005). we explored the omics data and identified significantly dysregulated gene expression of Talin-1 in skin cancers. Associations of Talin-1 expression and clinicopathological Additionally, in-silico data indicated increased expres- characteristics in non-melanoma skin cancers (NMSC) tissues sion of Talin-1 in metastatic tissues in mRNA level. Fur- The results of Pearson’s χ2 test exhibited no significant thermore, experimental expression of Talin-1 protein associations between Talin- 1 expression and clinico- through IHC method indicated a significant difference in pathological parameters, including age, gender, TNM cytoplasmic expression of this protein in melanoma and stage, histologic grade, ulceration, lymphocyte infiltra - NMSC tumor cells compared to normal skin tissue. The tion, distant metastasis, and recurrence in NMSC tissues, expression of Talin-1 protein in melanoma invasion has except that high expression of Talin-1 in terms of inten- not been investigated prior to our study, although many sity of staining was associated with an increase in histo- studies have reported the involvement of proteins associ- logic grade in NMSC tissues (P = 0.044) (Table 3). ated with Talin-1 in melanoma progression [53]. Rezaie et al. BMC Cancer (2023) 23:302 Page 7 of 13 Table 2 The association between expression of Talin-1 and clinicopathological parameters of melanoma skin cancer tissues (Intensity of staining and H-score) (P value; Pearson’s χ2 test) Tumor characteristics Total Intensity of staining N (%) P-value H-score (cut off P- samples = 200) N (%) value N (%) 0 (Negative) 1+ 2+ (Moderate) 3+ Low High (Weak) (Strong) (≤ 200) (> 200) Mean age, years (Range) 45 (16–74) 0 (0.0) 7 (21.2) 8 (24.2) 3 (9.1) 0.413 15 (51.7) 3 (75.0) 0.381 ≤ Median age 18 (39.1) 0 (0.0) 3 (9.1) 10 (30.3) 2 (6.1) 14 (48.3) 1 (25.0) > Median age 28 (60.9) Gender 18 (54.5) 0 (0.0) 5 (15.2) 10 (30.3) 3 (9.1) 0.927 16 (48.5) 2 (6.1) 0.846 Male 15 (45.5) 0 (0.0) 5 (15.2) 8 (24.2) 2 (6.1) 13 (39.4) 2 (6.1) Female TNM stage 3 (9.1) 0 (0.0) 0 (0.0) 1 (3.0) 2 (6.1) 0.91 1 (3.0) 2 (6.1) 0.024 I 3 (9.1) 0 (0.0) 1 (3.0) 2 (6.1) 0 (0.0) 3 (9.1) 0 (0.0) II 2 (6.1) 0 (0.0) 1 (3.0) 0 (0.0) 1 (3.0) 2 (6.1) 0 (0.0) III 25 (75.8) 0 (0.0) 8 (24.2) 15 (45.5) 2 (6.1) 23 (69.7) 2 (6.1) IV Breslow thickness (Range) 3 (21.4) 0 (0.0) 0 (0.0) 1 (7.1) 2 (14.3) 0.572 1 (7.1) 2 (14.3) 0.078 < 1 5 (35.7) 0 (0.0) 1 (7.1) 3 (21.4) 1 (7.1) 5 (35.7) 0 (0.0) 1–4 6 (42.9) 0 (0.0) 1 (7.1) 4 (28.6) 1 (7.1) 5 (35.7) 1 (7.1) 4 > Ulceration 10 (38.5) 0 (0.0) 1 (3.8) 7 (26.9) 2 (7.7) 0.304 8 (30.8) 2 (7.7) 0.286 Yes 16 (61.5) 0 (0.0) 6 (23.1) 8 (30.8) 2 (7.7) 15 (57.7) 1 (3.8) No Lymphovascular invasion (LVI) 10 (58.8) 0 (0.0) 3 (17.6) 7 (41.2) 0 (0.0) 0.024 10 (58.8) 0 (0.0) 0.023 Yes 7 (41.1) 0 (0.0) 1 (5.9) 2 (11.8) 4 (23.5) 4 (23.5) 3 (17.6) No Perineural invasion (PNI) 4 (16.6) 0 (0.0) 1 (4.2) 2 (8.3) 1 (4.2) 0.885 3 (12.5) 1 (4.2) 0.408 Yes 20 (83.3) 0 (0.0) 6 (25.0) 11 (45.8) 3 (12.5) 18 (75.0) 2 (8.3) No Lymphocyte infiltration 12 (75.0) 0 (0.0) 2 (12.5) 7 (43.8) 3 (18.8) 0.306 10 (62.5) 2 (12.5) 0.383 Yes 4 (25.0) 0 (0.0) 2 (12.5) 2 (12.5) 0 (0.0) 4 (25.0) 0 (0.0) No Distant metastasis 25 (75.8) 0 (0.0) 8 (32.0) 15 (45.5) 2 (6.1) 0.126 23 (69.7) 2 (6.1) 0.200 Yes 8 (24.2) 0 (0.0) 2 (6.1) 3 (9.1) 3 (9.1) 6 (18.2) 2 (6.1) No Tumor recurrence 24 (85.7) 0 (0.0) 8 (28.6) 14 (50.0) 2 (7.1) 0.063 23 (82.1) 1 (3.6) 0.006 Yes 4 (14.2) 0 (0.0) 0 (0.0) 2 (7.1) 2 (7.1) 2 (7.1) 2 (7.1) No H-score histological score Values in bold are statistically significant Vinculin is one of the main proteins connecting Talin-1 phenotype, malignant melanocytes and keratinocytes to the actin cytoskeleton [54]. Vinculin stabilizes the undergo epidermal-mesenchymal transition (EMT), actin-FA binding, and its underexpression promotes resulting in loss of their E-cadherin adhesions and inva- melanoma motility and metastasis, whereas its activa- sion [68–70]. As a critical signaling molecule of the tion inhibits tumor growth and sensitizes the tumor to cytoskeleton, Talin-1 regulates cadherin adhesions and chemotherapy [55–59]. As one of the main molecules in may play a role in the EMT process of skin cancers [43, Talin-1 dependent integrin signaling and FA assembly, 71–73]. In our study, Talin-1 staining was nearly exclu- FAK plays a substantial role in PI3K/AKT signaling path- sive to the cytoplasm of the skin tumor cells, confirm - way [54, 60, 61], which is an important oncogenic path- ing the previous evidence regarding the expression and way and therapeutic target in melanoma and NMSCs[62, function of Talin-1 [40, 74]. Moreover, our results show 63]. AKT mutations in melanoma cell lines were associ- that the staining was not limited to the epidermal-dermal ated with reduced inhibition of FAK and increased brain junction unlike normal skin tissue [32]. These differences metastasis [64]. Furthermore, phosphorylation and con- can be explained, in part, by considering the fact that dis- stitutive activation of FAK have been suggested as the ruption occurs by the tumor. Cancer-associated Talin-1 mechanisms accountable for anchorage-independent mutation and dysregulations induce metastasis by dis- phenotype resulting in melanoma metastasis [59, 65– rupting integrin activity, leading to the loss of cell adhe- 67]. In order to gain stemness properties and invasive sion and organization [75, 76]. Rezaie et al. BMC Cancer (2023) 23:302 Page 8 of 13 Table 3 The association between expression of Talin-1 and clinicopathological parameters of non-melanoma skin cancer (NMSC) tissues (Intensity of staining and H-score) (P-value; Pearson’s χ2 test) Tumor characteristics Total Intensity of staining N (%) P-value H-score (cut off = 90) P- samples N (%) val- N (%) ue 0 (Negative) 1+ 2+ (Moderate) 3+ Low High (Weak) (Strong) (≤ 90) (> 90) Mean age, years (Range) 45 (16–74) 0 (0.0) 26 (35.6) 9 (12.3) 3 (4.1) 0.855 22 (30.1) 16 (21.9) 0.948 ≤ Median age 38 (52.1) 0 (0.0) 23 (31.5) 10 (13.7) 2 (2.7) 20 (27.4) 15 (20.5) > Median age 35 (47.9) Gender 57 (78.1) 0 (0.0) 36 (49.3) 17 (23.3) 4 (5.5) 0.357 33 (45.2) 24 (32.9) 0.906 Male 16 (21.9) 0 (0.0) 13 (17.8) 2 (2.7) 1 (1.4) 9 (12.3) 7 (9.6) Female TNM stage* 17 (43.6) 0 (0.0) 10 (25.6) 7 (17.9) 0 (0.0) 0.701 10 (25.6) 7 (17.9) 0.758 I 15 (38.5) 0 (0.0) 8 (20.5) 6 (15.4) 1 (2.6) 8 (20.5) 7 (17.9) II 2 (5.1) 0 (0.0) 1 (2.6) 1 (2.6) 0 (0.0) 1 (2.6) 1 (2.6) III 5 (12.8) 0 (0.0) 3 (7.7) 1 (2.6) 1 (2.6) 4 (10.3) 1 (2.6) IV Histological grade* 21 (53.8) 0 (0.0) 16 (41.0) 5 (12.8) 0 (0.0) 0.044 15 (38.5) 6 (15.4) 0.226 Well 13 (33.3) 0 (0.0) 4 (10.3) 7 (17.9) 2 (5.1) 6 (15.4) 7 (17.9) Moderate 5 (12.8) 0 (0.0) 2 (5.1) 3 (7.7) 0 (0.0) 2 (5.1) 3 (7.7) Poor Ulceration 15 (34.1) 0 (0.0) 11 (25.0) 3 (6.8) 1 (2.3) 0.975 9 (20.5) 6 (13.6) 0.759 Yes 29 (65.9) 0 (0.0) 22 (50.0) 5 (11.4) 2 (4.5) 16 (36.4) 13 (39.5) no Lymphocyte infiltration 3 (42.9) 0 (0.0) 2 (28.6) 1 (14.3) 0 (0.0) 0.212 2 (28.6) 1 (14.3) 0.809 Yes 4 (57.1) 0 (0.0) 4 (57.1) 0 (0.0) 0 (0.0) 3(42.9) 1 (14.3) No Distant metastasis 5 (22.7) 0 (0.0) 3 (13.6) 1 (4.5) 1 (4.5) 0.127 4 (18.2) 1 (4.5) 0.519 Yes 17 (77.3) 0 (0.0) 9 (40.9) 8 (36.4) 0 (0.0) 11 (50.0) 6 (27.3) No Tumor recurrence 14 (36.8) 0 (0.0) 11 (28.9) 3 (7.9) 0 (0.0) 0.619 7 (18.4) 7 (18.4) 0.311 Yes 24 (63.15) 0 (0.0) 16 (42.1) 7 (18.4) 1 (2.6) 16 (42.1) 8 (21.1) No H-score:histological score Values in bold are statistically significant *TNM stage and histological grade are defined only in squamous cell carcinoma (SCC) type. Table 4 The main characteristics of patients enrolled for survival The evaluation of the staining pattern in melanoma analysis in melanoma skin cancer tissues and non-melanoma and NMSCs exhibited differential expression of Talin-1 skin cancer protein with a range of intensities from weak to strong. Features Melanoma Non- Moreover, there was a statistically significant difference skin cancer melanoma between the cytoplasmic expression of Talin-1 protein tissues N (%) skin cancer in melanoma and NMSCs tissues. These findings are in tissues N (%) line with the fact that melanoma and NMSCs vary sig- Number of patients (N) 28 38 nificantly in their oncogenesis and progression [ 77]. Range of follow-up duration for DSS (5-138), (5-116) (7–80), (1–80) or PFS (months) Therefore, there is an urgent need to investigate each Mean duration of follow-up time for 39 (35.4), 22.1 41.26 (26.3), type separately because each type of skin cancer could be DSS or PFS (months) (SD) (22.5) 33.68 (24.2) related to different prognostic values and behaviors and Median duration of follow-up time for 22 (16-52.7), 31 (19–67), effective to select the best therapeutic decisions. DSS or PFS (months) (Q1, Q3) 12.5 (12–24) 24 (18.7–61.7) In the current study, we observed a positive correlation Cancer-related death (N %) 19 (57.6) 2 (2.7) between Talin-1 expression and LVI in melanoma skin Distant metastasis during follow-up 22 (66.7) 5 (6.8) cancer tissues. The LVI has been shown to be an indepen - (N %) dent prognostic factor increasing the risk of metastasis Tumor recurrence during follow-up 24 (72.7) 14 (19.2) in melanoma [78]. Furthermore, higher expression lev- (N %) els of Talin-1 associated with an increase in the stage of Patients without distant metastasis 3 (9.1) 23 (31.5) and tumor recurrence (N %) melanoma, showing the probable potential of Talin-1 for risk assessment in melanoma patients. Our results high- lighted upregulation of Talin-1 in melanoma progression Rezaie et al. BMC Cancer (2023) 23:302 Page 9 of 13 Fig. 4 Kaplan-Meier survival curves for disease-specific survival (DSS) and progression-free survival (PFS) based on Talin-1 cytoplasmic pro - tein expression in skin cancer tissue samples. The Kaplan-Meier survival curves showed no significant differences between DSS (A) or PFS (B) of melanoma skin cancer patients with high or low expression of Talin-1. Likewise, no significant differences were seen between DSS (C) or PFS (D) of non melanoma skin cancer (NMSC) patients with high or low expression of Talin-1. However, shorter DSS durations were seen in melanoma patients with higher levels of Talin-1 and LVI. Previous evidence suggested that Talin-1 is a Compared to melanoma, NMSCs have a less aggressive critical molecule in integrin activation, signaling path- nature and tend to be localized [8, 83]. Other than tumor way, and cell adhesion [29, 79–81]. Per our results, in the grade in SCC specimens, we observed no significant cor - literature, the association of Talin-1 upregulation with relations between Talin-1 expression and NMSC clini- invasive cancer phenotype and higher stages of gastric copathological characteristics. Poor histological grading and prostate cancer as well as nasopharyngeal carcinoma in cutaneous SCC is associated with tumor recurrence, and oral SCC has been reported [35, 40, 42, 82]. The metastasis, and invasive phenotype of the tumor [84, 85], mentioned evidence implies Talin-1 is a crucial player in and it was associated with Talin-1 upregulation in our the integrin activation process and may have a promotive study. Previously Lai et al. reported the association of effect on malignant melanocytes, which may be hijacked Talin-1 upregulation with poorly differentiated oral SCC, in invasive melanoma by upregulating its expression for however, the tumor microenvironment and pathogen- tumor invasion and progression. esis vary significantly in oral and cutaneous SCC [ 86, 87]. Rezaie et al. BMC Cancer (2023) 23:302 Page 10 of 13 This finding may suggest Talin-1 as a predictor of inva - As the evidence in other cancers implies, Talin-1 may sive SCC, although more studies are needed to conclude. have a presumptive effect on skin cancer patients’ sur - Previous investigations indicated dysregulation of vival outcomes, and more studies are needed to establish Talin-1 is associated with patients’ survival outcomes in the prognostic value of Talin-1 in skin cancers. A limita- colorectal and prostate cancers and oral SCC and naso- tion of our study was the small patient population, which pharyngeal carcinoma [35, 38, 39, 88]. Our Kaplan-Meier may have restricted our observations. Therefore, a larger curve results showed no significant association of Talin-1 sample can lead to more generalizable results. expression with melanoma and NMSC patients’ survival. However, upregulation of Talin-1 was significantly asso - Conclusion ciated with melanoma recurrence after tumor resection In conclusion, our data mining analysis indicated upregu- in our study. These results may be due to the small and lation of Talin-1 in skin cancer patients in mRNA level in lost-to-follow-up patient population. comparison with normal skin tissues. Our finding from More than half of the melanoma tumors harbor an protein evaluation also demonstrated increased expres- activating mutation in BRAF, a serine/threonine kinase sion of Talin-1 protein in skin cancer tissues compared to protein, which enhances tumor proliferation and inva- normal tissues. Moreover, our results exhibited differen - sion, hence targeted BRAF inhibitor therapies such as tial expression of Talin-1 protein between melanoma and Vemurafenib have been developed with high efficacy NMSCs tissues with a statistically significant difference [89]. On the other hand, Immune Checkpoint Inhibitor between the two groups, which may affect their prog - therapies such as Pembrolizumab and Nivolumab target nosis and treatment options. Furthermore, overexpres- the immune evasion mechanisms of the tumor [90–92]. sion of Talin-1 was associated with higher stages, local Unfortunately, despite all the advancements in melanoma invasion, and recurrence of melanoma, emphasizing the targeted therapy and immunotherapy, resistance to novel role of cytoskeletal adhesion and signaling in melanoma therapies remains a major clinical problem [93]. The progression and invasion. Our findings suggest Talin-1 molecular mechanisms of resistance to immune check- may have a presumptive effect on prognosis. Therefore, point inhibitors (ICIs) and BRAF inhibitors (BRAFi) are further studies are needed on the function of Talin-1 as mostly unknown, but the role of cytoskeletal remodeling a potential biomarker in skin cancers as well as its prog- and myosin reactivation is well established [94, 95]. Many nostic value. studies have reported the change in the cellular shape of List of abbreviations the BRAFi resistant sublines of melanoma, making them NMSC Non-Melanoma Skin Cancer more fibroblast and spindle-like [ 96–100]. Rho GTPase FFPE Formalin-Fixed Parafin Embedded TMA Tissue MicroArray is the main molecule responsible for the contraction of IHC ImmunoHistoChemistry the actin cytoskeleton, cellular shape, and resistance to SCC Squamous Cell Carcinoma BRAFi therapy [101]. Rho GTPase is activated by DLC- BCC Basal Cell Carcinoma LDH Lactate Dehydrogenase 1, which inhibits the actin contraction and promotes the FAK Focal Adhession Kinase Talin-1 refolding [24, 102]. Furthermore, the Yes-associ- FA Focal Adhession ated protein (YAP) pathway has been shown to regulate DLC-1 Deleted in Liver Cancer-1 ECM Extracellular Matrix actin remodeling in BRAFi resistant cell lines via accu- GEPIA Gene Expression Profiling Interactive Analysis mulation of YAP in the nucleus [98]. Talin-1 unfolding GENT2 Gene Expression database of Normal and Tumor tissues 2 leads to its binding to vinculin and translocation of YAP TCGA The Cancer Genome Atlas GTEx Genotype-Tissue Expression to nucleus and further adhesion growth [103]. Talin-1 GDC Genomic Data Commons can alter the myosin-driven machinery via DLC-1 bind- H&E Hematoxylin and eosin ing [54]. The loss of DLC-1 protein function in mela -LVI LymphoVascular Invasion PNI Perineural Invasion noma tissue samples significantly promotes melanoma’s DSS Disease-Specific Survival aggressiveness and deteriorates patients’ prognosis [54, PFS Progression-Free Survival 104]. The changes in the actomyosin skeleton render AJCC American Joint Committee on Cancer TBS Tris-Buffered Saline resistant melanoma cells highly dependent on cytoskel- DAB 3,3′-diaminobenzidine etal signaling pathways [95]. Furthermore, mutations in H-Score Histochemical Score integrin signaling pathways improve melanoma patients’ SD Standard Deviation EMT Epidermal-Mesenchymal Transition outcomes after ICI therapy [105]. Considering the sub- ICI Immune Check-point Inhibitor stantial role of Talin-1 in cytoskeletal and integrin sig- naling pathways, presuming a pivotal role for Talin-1 in response to ICI and BRAFi therapy is highly probable and Supplementary Information The online version contains supplementary material available at https://doi. warrants further investigations in the future. org/10.1186/s12885-023-10771-z. Rezaie et al. BMC Cancer (2023) 23:302 Page 11 of 13 8. Aggarwal P, Knabel P, Fleischer Jr, ABJJotAAoD. 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Journal

BMC CancerSpringer Journals

Published: Apr 3, 2023

Keywords: Talin-1; Skin cancer; Melanoma; Non-melanoma skin cancer; Bioinformatics; IHC

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