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

BMC Cancer volume 23, Article number: 302 (2023) Cite this article

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.

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Background

Skin cancers are the most common neoplasms in humans, imposing high rates of disease burden globally [1, 2]. They are generally classified as melanoma and non-melanoma skin cancers (NMSC), with squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) being the most prevalent non-melanoma subtypes [3]. NMSCs are responsible for most skin cancer cases; however, melanoma is the leading cause of death due to skin cancer and one of the most aggressive cancers [4,5,6], with an estimation of 99,780 new cases and 7650 deaths in 2022 in the United States alone [7]. NMSCs have a relatively low mortality risk, however, due to their high prevalence, they impose a high burden on public health [3, 6, 8, 9]. Although melanoma comprises only 1% of skin cancers, it has a reputation for rapid metastasis and resistance to therapy, and the mechanisms of cellular invasion remain mostly unclear [10, 11]. Early-stage melanoma is easily curable with excision, however, with metastasis, the survival rates decrease drastically [12]. Despite many new treatment options for advanced melanoma today, the response to treatment differs in patients, and many patients may develop resistance to therapy or adverse effects [13,14,15]. Diagnostic and prognostic biomarkers are increasingly important in melanoma treatment so that they may have improved survival and treatment [16,17,18]. In clinical settings, proper prognostication of patients is necessary to select the suitable treatment plan for each patient to maximize efficacy and decrease the expenses and adverse effects of the treatment. Although many new genomic and protein markers including the S-100b and Lactate dehydrogenase (LDH) proteins have been suggested for advanced melanoma prognostication, no feasible lab tests are available today to stratify high-risk patients with high accuracy in clinical settings [19, 20]. New prognostic markers and therapeutic targets for both melanoma and NMSCs are urgently needed to optimize patient management and decrease the morbidity and mortality of the disease [18].

Talin-1 is a large protein interacting with the cytoplasmic domain of the integrin β subunit, connecting it to focal adhesion molecules such as focal adhesion kinase (FAK) and vinculin and regulatory molecules, including deleted in liver cancer-1 (DLC-1), RIAM and KANK [21,22,23,24,25]. As the main component of focal adhesions (FAs), Talin-1 links the extracellular matrix (ECM) and actin cytoskeleton, acting as a mechanosensitive signaling hub regulating the cell behavior such as proliferation, migration, and cell shape according to changes in the ECM [26,27,28,29,30,31]. In healthy skin tissue, Talin-1 is present at the epidermal-dermal interface and in cell-cell junctions of the melanocytes, emphasizing its crucial function in cell-cell and cell-ECM adhesion and signaling [32, 33].

The role of Talin-1 dysregulation in cancer has been studied widely; however, a substantial controversy in the literature exists today regarding the regulation of Talin-1 in different cancers. Upregulation of Talin-1 expression is documented in gastric cancer, mucosal SCC, and prostate cancers; conversely, its downregulation is shown in colorectal cancer and hepatocellular carcinoma [34,35,36,37,38,39]. High expression levels of Talin-1 correlated with invasion and lower survival rates in prostate cancer, colon cancer, nasopharyngeal carcinoma, and oral SCC [35, 40,41,42]. Furthermore, Talin-1 knockdown in prostate cancer and colorectal cancer cell lines has been shown to reduce their migration and proliferation [43, 44].

The role and clinical significance of Talin-1 protein in melanoma and NMSCs remain unexplored. In the present study, at the primary search stage, comprehensive alterations in mRNA levels of Talin-1 in patients with skin cancer were analyzed using Gene Expression Profiling Interactive Analysis (GEPIA2) and Gene Expression database of Normal and Tumor tissues 2 (GENT2) databases. Then, Talin-1 protein expression levels were evaluated by formalin-fixed paraffin-embedded (FFPE) tissue samples which were assembled on tissue microarray (TMA) slides using Immunohistochemical (IHC) technique. The IHC assay is a standard procedure applied to assess novel molecular biomarkers, and TMA technology enables simultaneous staining of hundreds of tissue samples [45]. Then, we sought to determine the association of Talin-1 expression with clinicopathological characteristics and survival information of skin cancer patients.

Methods

Investigations of Talin-1 based on data mining

To investigate alteration in the expression of Talin-1 in mRNA levels for patients with skin cancer, GEPIA2 and GENT2 databases were applied. GEPIA2 (http://gepia2.cancer-pku.cn/) is an online database using RNA expression data of tumor and normal samples obtained from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) [46]. While GENT2 (http://gent2.appex.kr) is included gene expression data of cancer and normal tissues from the NCBI-GEO database with two microarray platforms (Affymetrix U133A or U133Plus2) [47]. Therefore, boxplot mRNA expression analysis for skin cancer and normal tissues was constructed through these databases. Moreover, the UCSC Xena Browser database (https://xenabrowser.net/) was used to evaluate expression data with metastasis feature in RNA-sequencing data for Talin-1 expression from skin cancer patients. UCSC Xena Browser is an online visual exploration tool for public and private, multi-omic, and clinical/phenotype data including TCGA and Genomic Data Commons (GDC) [48]. Finally, a bioinformatics analysis of the survival data as it relates to Talin-1 in mRNA levels for skin cancer patients was performed using these mentioned online databases.

Study population

A total of 106 FFPE archival specimens of skin cancer including melanoma skin cancer (N = 33), NMSC consisting of SCC and BCC (N = 73), and normal skin tissues (N = 11) were collected from Razi referral skin hospital and Imam Khomeini tertiary complex in Tehran, Iran. Samples were obtained from patients between the years 2013–2020, and it was confirmed that none of the patients were subject to chemotherapy or radiotherapy prior to tissue sampling. Hematoxylin and eosin (H&E) stained slides associated with each FFPE sample were collected for TMA construction. We reviewed patients’ medical records for clinicopathological characteristics including gender, age, TNM stage, histologic grade, Breslow thickness, ulceration, lymphovascular invasion (LVI), perineural invasion (PNI), lymphocyte infiltration, distant metastasis, and tumor recurrence. Next, patients’ survival information was gathered by telephone follow-ups. The time between the initial treatment and death due to skin cancer was defined as disease-specific survival (DSS), and progression-free survival (PFS) was defined as the interval between the initial treatment and the last follow-up without evidence of disease progression and metastasis. The TNM stage was determined according to the American Joint Committee on Cancer (AJCC) [49]. All patients’ information was handled with confidentiality, and the research process was approved by the medical ethics committee of Tehran University of medical sciences under the code IR.TUMS.REC.1401.034.

TMA construction

Skin cancer TMAs were constructed as described in the literature [50, 51]. Briefly, our pathologists (SM and KK) evaluated the H&E stained slides and FFPE blocks and marked the most representative area of the tumor. The selected spots were punched by a precision arraying instrument (Tissue Arrayer Minicore; ALPHELYS, Plaisir, France), and tissue cylinders were separated and transferred to the recipient block. For more accurate results, TMA blocks were triplicated, and from each block, separate slides were constructed and stained. The final staining score of each sample was determined by the mean staining score of the cores.

Immunohistochemical (IHC) staining

First, all TMA slides were deparaffinized for 20 min and were transferred in xylene; then, the rehydration process was carried out via serial-graded alcohols. To block the endogenous peroxidase activity and prevent non-reactive staining, we used a 3% hydrogen peroxide solution for 20 min at room temperature. After washing the slides, we autoclaved the samples in citrate buffer (ph = 6.0) for 10 min to retrieve sample antigens. Next, we blocked sections (blocker protein, Dako, Denmark) for 20 min and incubated them with a primary rabbit polyclonal antibody to Talin-1 (1:500, ab71333, Abcam Inc., Cambridge, MA, UK) at 4 °C overnight. The next day, slides were washed three times with Tris-buffered saline (TBS) and incubated with anti-rabbit/anti-mouse envision IgG–HRPO (EnVision, Dako, Denmark) as the secondary antibody for 1 h. Afterward, TMA slides were treated for 3 min at room temperature with 3,3′-diaminobenzidine (DAB) (Dako, Denmark) substrate as a chromogen. Finally, slides were counterstained with hematoxylin (Dako, Denmark), dehydrated with serial-graded alcohol, cleared with xylene, and mounted. Human normal kidney tissue was used as a positive control, and for negative control samples, the primary antibody was replaced with TBS to ensure no nonspecific bindings happened. The optimal dilution of the Talin-1 antibody was examined by applying serial-prepared dilutions of the antibody to the tissue.

Immunostaining assessment

Two experienced dermatopathologists (SM and KK) independently evaluated immunostained sections blinded to patients’ information. Any inconsistency in results was resolved by reaching a consensus. The intensity and area of staining were the primary reported outcomes. The intensity of staining was reported in a semi-quantitative fashion, represented by 0 (no staining), 1 (weak), 2 (moderate), and 3 (strong). The staining area was reported as the percentage of positive tumor cells in the sample and classified into four groups: <25%, 25–50%, 51–75%, and > 75%. We reported the final Talin-1 expression results as histochemical score (H-score), calculated by multiplying the staining intensity by the staining area, ranging from 0 to 300. In this study, the median H-score was used to categorize the samples as expressing high or low levels of talin-1.

Statistical analysis

All patients’ data and scoring results were documented and analyzed using “statistical software SPSS, version 22.0. Armonk, NY: IBM Corp”. We reported the categorical data by N (%), valid percent, and quantitative data as follows: mean (SD) and median (Q1, Q3). First, the Mann-Whitney U test was applied to compare the significance of staining differences in melanoma and NMSC tissues. Afterward, Pearson’s chi-square test and Spearman’s correlation tests were used to analyze the significance of association and correlation between Talin-1 expression and clinicopathological characteristics of patients. Ultimately, we analyzed survival data regarding Talin-1 expression by the Kaplan-Meier method with a 95% confidence interval and compared the results with the log-rank test. The Cox proportional hazards regression model was adopted to perform univariate and multivariate analyses. Any differences with a p-value < 0.05 were considered significant.

Results

Data mining

The results of the TCGA database via GEPIA2 revealed that mRNA expression of the Talin-1 gene was higher (|Log2FC| Cut-off ≥ 0.5) in 461 skin cutaneous melanoma tissues compared to the 558 normal skin tissues (P < 0.01, Fig. 1). Furthermore, obtained data based on GENT2 from the displayed GEO mRNA expression level of Talin-1 was significantly higher in skin cancer tissues compared to the normal skin tissues (GPL570 platform) (Supplementary Tables 1 and Supplementary Fig. 1). After analyzing of the skin cancer patient data from the TCGA database using the UCSC Xena web-based tool, a higher expression of Talin-1 was observed in skin cancer patients with metastases (n = 366) compared to primary tumor tissues (n = 102) (Welch’s t-test, p = 0.008 (t = -2.679)). The comparison between gene expression of data from normal tissues, primary tumors, and metastatic tissues was shown in the heat map and boxplot in Fig. 2. Although no significant data was found in the evaluation of prognosis biomarkers from Talin-1 at RNA level through survival analysis.

Fig. 1
figure 1

The mRNA levels of Talin-1 (TLN1) in Skin Cutaneous Melanoma 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).

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Fig. 2
figure 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))

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Demographics of skin cancer patients

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 (melanoma and NMSC tissues). Moreover, normal human kidney tissue used as a positive control showed strong staining in renal epithelial cells (Fig. 3).

Fig. 3
figure 3

Immunohistochemical staining of Talin-1 protein expression in skin cancer and normal skin tissues. Talin-1 protein expression in melanoma 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×

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Table 1 Expression of Talin-1 (Intensity of staining, percentage of positive tumor cells, and H-score) in melanoma skin cancer tissues, non-melanoma skin cancer, and normal skin tissues
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Associations of Talin-1 expression and clinicopathological characteristics in melanoma tissues

We collected patients’ data, including age, gender, TNM stage, Breslow thickness, ulceration, LVI, PNI, lymphocytic infiltration, distant metastasis, and tumor recurrence. Pearson’s χ2 test was utilized to find the association of Talin-1 expression with clinicopathological features. Our findings indicated that there is a statistically significant association between high expression levels of Talin-1 and advanced TNM stage (Hscore P = 0.024), LVI (intensity of staining P = 0.024; H-score P = 0.023) as well as tumor recurrence (Hscore P = 0.006). No significant associations were detected between Talin-1 expression and other clinicopathological parameters (Table 2). Moreover, Bivariate analysis showed a statistically significant positive correlation between increased Talin-1 expression and increase in TNM stage (Spearman’s rho, P = 0.025), and between high Talin-1 expression and LVI (P = 0.023) as well as tumor recurrence (P = 0.005).

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)
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Associations of Talin-1 expression and clinicopathological characteristics in non-melanoma skin cancers (NMSC) tissues

The results of Pearson’s χ2 test exhibited no significant associations between Talin- 1 expression and clinicopathological parameters, including age, gender, TNM stage, histologic grade, ulceration, lymphocyte infiltration, distant metastasis, and recurrence in NMSC tissues, except that high expression of Talin-1 in terms of intensity of staining was associated with an increase in histologic grade in NMSC tissues (P = 0.044) (Table 3).

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)
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Survival outcomes in patients with melanoma and non-melanoma skin cancers (NMSC)

Information on survival outcomes of melanoma skin cancer tissues and non-melanoma patients is demonstrated in Table 4 in detail. As listed in the table, out of 33 melanoma patients, follow-up data was lost for five patients, and the remaining patients were followed for a mean duration of 39 months (min = 5, max = 138). In this interval, 24 (72.7%) patients experienced recurrence, and 19 (57.6%) patients died due to melanoma. In NMSC patients, follow-up data were available for 38 patients being followed for a mean duration of 41.26 months (min = 7, max = 80). Fourteen (19.2%) patients experienced tumor recurrence, and two (2.7%) patients died due to cancer-related complications.

Table 4 The main characteristics of patients enrolled for survival analysis in melanoma skin cancer tissues and non-melanoma skin cancer
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Prognostic value of Talin-1 expression in melanoma and non-melanoma skin cancers (NMSC) patients

We used Kaplan–Meier survival analysis to compare DSS or PFS based on Talin-1 expression (H-score) in melanoma and NMSC patients. Our findings showed that no significant associations between DSS or PFS and the patients with high and low expression of the Talin-1 protein in melanoma (Log-rank test: DSS P = 0.503, PFS P = 0.800) and NMSC cases (Log-rank test: DSS P = 0.263, PFS P = 0.385). (Fig. 4).

Fig. 4
figure 4

Kaplan-Meier survival curves for disease-specific survival (DSS) and progression-free survival (PFS) based on Talin-1 cytoplasmic protein 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

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Utilizing univariate and multivariate analyses, we assessed the clinical significance of various parameters that might influence DSS and PFS in these patients. The results indicated that the listed clinicopathologic variables are not significant factors affecting the DSS and PFS of melanoma and NMSC patients.

Discussion

Considering the significant burden of skin cancers on public health, identification and characterization of molecular and cellular processes involved in oncogenesis and tumor progression are vital to uncovering novel prognostic markers and therapeutic targets [8, 9, 52]. In this regard, this study was conducted to evaluate the potential of Talin-1 protein as a biomarker of skin cancer. In in-silico analysis, using the bioinformatics approach, we explored the omics data and identified significantly dysregulated gene expression of Talin-1 in skin cancers. Additionally, in-silico data indicated increased expression of Talin-1 in metastatic tissues in mRNA level. Furthermore, experimental expression of Talin-1 protein through IHC method indicated a significant difference in cytoplasmic expression of this protein in melanoma and NMSC tumor cells compared to normal skin tissue. The expression of Talin-1 protein in melanoma invasion has not been investigated prior to our study, although many studies have reported the involvement of proteins associated with Talin-1 in melanoma progression [53].

Vinculin is one of the main proteins connecting Talin-1 to the actin cytoskeleton [54]. Vinculin stabilizes the actin-FA binding, and its underexpression promotes melanoma motility and metastasis, whereas its activation inhibits tumor growth and sensitizes the tumor to chemotherapy [55,56,57,58,59]. As one of the main molecules in Talin-1 dependent integrin signaling and FA assembly, FAK plays a substantial role in PI3K/AKT signaling pathway [54, 60, 61], which is an important oncogenic pathway and therapeutic target in melanoma and NMSCs[62, 63]. AKT mutations in melanoma cell lines were associated with reduced inhibition of FAK and increased brain metastasis [64]. Furthermore, phosphorylation and constitutive activation of FAK have been suggested as the mechanisms accountable for anchorage-independent phenotype resulting in melanoma metastasis [59, 65,66,67]. In order to gain stemness properties and invasive phenotype, malignant melanocytes and keratinocytes undergo epidermal-mesenchymal transition (EMT), resulting in loss of their E-cadherin adhesions and invasion [68,69,70]. As a critical signaling molecule of the cytoskeleton, Talin-1 regulates cadherin adhesions and may play a role in the EMT process of skin cancers [43, 71,72,73]. In our study, Talin-1 staining was nearly exclusive to the cytoplasm of the skin tumor cells, confirming the previous evidence regarding the expression and function of Talin-1 [40, 74]. Moreover, our results show that the staining was not limited to the epidermal-dermal junction unlike normal skin tissue [32]. These differences can be explained, in part, by considering the fact that disruption occurs by the tumor. Cancer-associated Talin-1 mutation and dysregulations induce metastasis by disrupting integrin activity, leading to the loss of cell adhesion and organization [75, 76].

The evaluation of the staining pattern in melanoma and NMSCs exhibited differential expression of Talin-1 protein with a range of intensities from weak to strong. Moreover, there was a statistically significant difference between the cytoplasmic expression of Talin-1 protein in melanoma and NMSCs tissues. These findings are in line with the fact that melanoma and NMSCs vary significantly in their oncogenesis and progression [77]. Therefore, there is an urgent need to investigate each type separately because each type of skin cancer could be related to different prognostic values and behaviors and effective to select the best therapeutic decisions.

In the current study, we observed a positive correlation between Talin-1 expression and LVI in melanoma skin cancer tissues. The LVI has been shown to be an independent prognostic factor increasing the risk of metastasis in melanoma [78]. Furthermore, higher expression levels of Talin-1 associated with an increase in the stage of melanoma, showing the probable potential of Talin-1 for risk assessment in melanoma patients. Our results highlighted upregulation of Talin-1 in melanoma progression and LVI. Previous evidence suggested that Talin-1 is a critical molecule in integrin activation, signaling pathway, and cell adhesion [29, 79,80,81]. Per our results, in the literature, the association of Talin-1 upregulation with invasive cancer phenotype and higher stages of gastric and prostate cancer as well as nasopharyngeal carcinoma and oral SCC has been reported [35, 40, 42, 82]. The mentioned evidence implies Talin-1 is a crucial player in the integrin activation process and may have a promotive effect on malignant melanocytes, which may be hijacked in invasive melanoma by upregulating its expression for tumor invasion and progression.

Compared to melanoma, NMSCs have a less aggressive nature and tend to be localized [8, 83]. Other than tumor grade in SCC specimens, we observed no significant correlations between Talin-1 expression and NMSC clinicopathological characteristics. Poor histological grading in cutaneous SCC is associated with tumor recurrence, metastasis, and invasive phenotype of the tumor [84, 85], and it was associated with Talin-1 upregulation in our study. Previously Lai et al. reported the association of Talin-1 upregulation with poorly differentiated oral SCC, however, the tumor microenvironment and pathogenesis vary significantly in oral and cutaneous SCC [86, 87]. This finding may suggest Talin-1 as a predictor of invasive SCC, although more studies are needed to conclude.

Previous investigations indicated dysregulation of Talin-1 is associated with patients’ survival outcomes in colorectal and prostate cancers and oral SCC and nasopharyngeal carcinoma [35, 38, 39, 88]. Our Kaplan-Meier curve results showed no significant association of Talin-1 expression with melanoma and NMSC patients’ survival. However, upregulation of Talin-1 was significantly associated with melanoma recurrence after tumor resection in our study. These results may be due to the small and lost-to-follow-up patient population.

More than half of the melanoma tumors harbor an activating mutation in BRAF, a serine/threonine kinase protein, which enhances tumor proliferation and invasion, hence targeted BRAF inhibitor therapies such as Vemurafenib have been developed with high efficacy [89]. On the other hand, Immune Checkpoint Inhibitor therapies such as Pembrolizumab and Nivolumab target the immune evasion mechanisms of the tumor [90,91,92]. Unfortunately, despite all the advancements in melanoma targeted therapy and immunotherapy, resistance to novel therapies remains a major clinical problem [93]. The molecular mechanisms of resistance to immune checkpoint inhibitors (ICIs) and BRAF inhibitors (BRAFi) are mostly unknown, but the role of cytoskeletal remodeling and myosin reactivation is well established [94, 95]. Many studies have reported the change in the cellular shape of the BRAFi resistant sublines of melanoma, making them more fibroblast and spindle-like [96,97,98,99,100]. Rho GTPase is the main molecule responsible for the contraction of the actin cytoskeleton, cellular shape, and resistance to BRAFi therapy [101]. Rho GTPase is activated by DLC-1, which inhibits the actin contraction and promotes the Talin-1 refolding [24, 102]. Furthermore, the Yes-associated protein (YAP) pathway has been shown to regulate actin remodeling in BRAFi resistant cell lines via accumulation of YAP in the nucleus [98]. Talin-1 unfolding leads to its binding to vinculin and translocation of YAP to nucleus and further adhesion growth [103]. Talin-1 can alter the myosin-driven machinery via DLC-1 binding [54]. The loss of DLC-1 protein function in melanoma tissue samples significantly promotes melanoma’s aggressiveness and deteriorates patients’ prognosis [54, 104]. The changes in the actomyosin skeleton render resistant melanoma cells highly dependent on cytoskeletal signaling pathways [95]. Furthermore, mutations in integrin signaling pathways improve melanoma patients’ outcomes after ICI therapy [105]. Considering the substantial role of Talin-1 in cytoskeletal and integrin signaling pathways, presuming a pivotal role for Talin-1 in response to ICI and BRAFi therapy is highly probable and warrants further investigations in the future.

As the evidence in other cancers implies, Talin-1 may have a presumptive effect on skin cancer patients’ survival outcomes, and more studies are needed to establish the prognostic value of Talin-1 in skin cancers. A limitation of our study was the small patient population, which may have restricted our observations. Therefore, a larger sample can lead to more generalizable results.

Conclusion

In conclusion, our data mining analysis indicated upregulation of Talin-1 in skin cancer patients in mRNA level in comparison with normal skin tissues. Our finding from protein evaluation also demonstrated increased expression of Talin-1 protein in skin cancer tissues compared to normal tissues. Moreover, our results exhibited differential expression of Talin-1 protein between melanoma and NMSCs tissues with a statistically significant difference between the two groups, which may affect their prognosis and treatment options. Furthermore, overexpression of Talin-1 was associated with higher stages, local invasion, and recurrence of melanoma, emphasizing the role of cytoskeletal adhesion and signaling in melanoma progression and invasion. Our findings suggest Talin-1 may have a presumptive effect on prognosis. Therefore, further studies are needed on the function of Talin-1 as a potential biomarker in skin cancers as well as its prognostic value.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on request.

Abbreviations

NMSC:

Non-Melanoma Skin Cancer

FFPE:

Formalin-Fixed Parafin Embedded

TMA:

Tissue MicroArray

IHC:

ImmunoHistoChemistry

SCC:

Squamous Cell Carcinoma

BCC:

Basal Cell Carcinoma

LDH:

Lactate Dehydrogenase

FAK:

Focal Adhession Kinase

FA:

Focal Adhession

DLC-1:

Deleted in Liver Cancer-1

ECM:

Extracellular Matrix

GEPIA:

Gene Expression Profiling Interactive Analysis

GENT2:

Gene Expression database of Normal and Tumor tissues 2

TCGA:

The Cancer Genome Atlas

GTEx:

Genotype-Tissue Expression

GDC:

Genomic Data Commons

H&E:

Hematoxylin and eosin

LVI:

LymphoVascular Invasion

PNI:

Perineural Invasion

DSS:

Disease-Specific Survival

PFS:

Progression-Free Survival

AJCC:

American Joint Committee on Cancer

TBS:

Tris-Buffered Saline

DAB:

3,3′-diaminobenzidine

H-Score:

Histochemical Score

SD:

Standard Deviation

EMT:

Epidermal-Mesenchymal Transition

ICI:

Immune Check-point Inhibitor

References

  1. Aggarwal P, Knabel P, Fleischer AB Jr. United States burden of melanoma and non-melanoma skin cancer from 1990 to 2019. J Am Acad Dermatol. 2021;85(2):388–95.

    Article  PubMed  Google Scholar 

  2. Urban K, Mehrmal S, Uppal P, Giesey RL, Delost GR. The global burden of skin cancer: a longitudinal analysis from the global burden of Disease Study, 1990–2017. JAAD Int. 2021;2:98–108.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lomas A, Leonardi-Bee J, Bath‐Hextall FJBJoD. A systematic review of worldwide incidence of nonmelanoma skin cancer. 2012;166(5):1069–80.

  4. Ward WH, Farma JM. Cutaneous melanoma: etiology and therapy [Internet]. 2017.

  5. Bolick NL, Geller AC. Epidemiology of melanoma. Hematology/Oncology Clin. 2021;35(1):57–72.

    Article  Google Scholar 

  6. Lai V, Cranwell W, Sinclair RJCid. Epidemiol skin cancer mature patient. 2018;36(2):167–76.

    Google Scholar 

  7. Siegel RL, Miller KD, Fuchs HE, Jemal AJCacjfc. Cancer statistics, 2022. 2022.

  8. Aggarwal P, Knabel P, Fleischer Jr, ABJJotAAoD. United States burden of melanoma and non-melanoma skin cancer from 1990 to 2019. 2021;85(2):388–95.

  9. Urban K, Mehrmal S, Uppal P, Giesey RL, Delost GRJJi. The global burden of skin cancer: A longitudinal analysis from the Global Burden of Disease Study, 1990–2017. 2021;2:98–108.

  10. Braeuer RR, Watson IR, Wu CJ, Mobley AK, Kamiya T, Shoshan E, et al. Why is melanoma so metastatic? Pigment cell & melanoma research. 2014;27(1):19–36.

    Article  CAS  Google Scholar 

  11. [Available from: https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html.

  12. Svedman FC, Pillas D, Taylor A, Kaur M, Linder R, Hansson JJCe. Stage-specific survival and recurrence in patients with cutaneous malignant melanoma in Europe–a systematic review of the literature. 2016;8:109.

  13. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, De Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. The Lancet. 2015;386(9992):444–51.

    Article  CAS  Google Scholar 

  15. Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76.

    Article  PubMed  Google Scholar 

  16. Weinstein D, Leininger J, Hamby C, Safai B. Diagnostic and prognostic biomarkers in melanoma. J Clin Aesthet Dermatol. 2014;7(6):13–24.

    PubMed  PubMed Central  Google Scholar 

  17. Bridge JA, Lee JC, Daud A, Wells JW. Bluestone JAJFim. Cytokines, chemokines, and other biomarkers of response for checkpoint inhibitor therapy in skin cancer. 2018;5:351.

  18. Pandey SN. Skin Cancer: molecular biomarker for diagnosis, prognosis, Prevention, and targeted therapy. Skin Cancer: Pathogenesis and Diagnosis: Springer; 2021. pp. 101–30.

    Google Scholar 

  19. Tonella L, Pala V, Ponti R, Rubatto M, Gallo G, Mastorino L et al. Prognostic and predictive biomarkers in stage iii melanoma: Current insights and clinical implications. 2021;22(9):4561.

  20. Mårtenson ED, Hansson L, Nilsson B, Von Schoultz E, Brahme EM, Ringborg U et al. Serum S-100b protein as a prognostic marker in malignant cutaneous melanoma. 2001;19(3):824–31.

  21. Nayal A, Webb DJ. Horwitz AFJCoicb. Talin: an emerging focal point of adhesion dynamics. 2004;16(1):94 – 8.

  22. Critchley DJBST. Cytoskeletal proteins talin and vinculin in integrin-mediated adhesion. 2004;32(5):831–6.

  23. Haining AWM, Rahikainen R, Cortes E, Lachowski D, Rice A, von Essen M, et al. Mechanotransduction in talin through the interaction of the R8 domain with DLC1. PLoS Biol. 2018;16(7):e2005599.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Zacharchenko T, Qian X, Goult BT, Jethwa D, Almeida TB, Ballestrem C, et al. LD motif recognition by talin: structure of the talin-DLC1 complex. Structure. 2016;24(7):1130–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sun Z, Tseng H-Y, Tan S, Senger F, Kurzawa L, Dedden D, et al. Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation. Nat Cell Biol. 2016;18(9):941–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chakraborty S, Banerjee S, Raina M, Haldar SJB. Force-directed “mechanointeractome. of Talin–Integrin. 2019;58(47):4677–95.

    CAS  Google Scholar 

  27. Yao M, Goult BT, Klapholz B, Hu X, Toseland CP, Guo Y, et al. Mech response talin. 2016;7(1):1–11.

    Google Scholar 

  28. Haining AW, Lieberthal TJ, Hernández AdRJTFJ. Talin: a mechanosensitive molecule in health and disease. 2016;30(6):2073–85.

  29. Critchley DR. Gingras ARJJocs. Talin at a glance. 2008;121(9):1345–7.

    CAS  Google Scholar 

  30. Murrell M, Oakes PW, Lenz M, Gardel ML. Forcing cells into shape: the mechanics of actomyosin contractility. Nat Rev Mol Cell Biol. 2015;16(8):486–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nagano M, Hoshino D, Koshikawa N, Akizawa T, Seiki M. Turnover of focal adhesions and cancer cell migration. International journal of cell biology. 2012;2012.

  32. Kaiser HW, Ness W, Offers M, O’Keefe EJ. Kreysel HWJJoid. Talin: adherens junction protein is localized at the epidermal-dermal interface in skin. 1993;101(6):789 – 93.

  33. Hume AN, Collinson LM, Hopkins CR, Strom M, Barral DC, Bossi G, et al. The leaden gene product is required with Rab27a to recruit myosin va to melanosomes in melanocytes. Traffic. 2002;3(3):193–202.

    Article  CAS  PubMed  Google Scholar 

  34. Jevnikar Z, Rojnik M, Jamnik P, Doljak B, Fonović UP, Kos JJJoBC. Cathepsin H mediates the processing of talin and regulates migration of prostate cancer cells. 2013;288(4):2201–9.

  35. Lai MT, Hua CH, Tsai MH, Wan L, Lin YJ, Chen CM et al. Talin-1 overexpression defines high risk for aggressive oral squamous cell carcinoma and promotes cancer metastasis. 2011;224(3):367 – 76.

  36. Fang K-P, Zhang J-L, Ren Y-H, Qian Y-B. Talin-1 correlates with reduced invasion and migration in human hepatocellular carcinoma cells. Asian Pac J Cancer Prev. 2014;15(6):2655–61.

    Article  PubMed  Google Scholar 

  37. Yan H, Guo M, Zou J, Xiao F, Yi L, He Y, et al. Promotive effect of Talin-1 protein on gastric cancer progression through PTK2‐PXN‐VCL‐E‐Cadherin‐CAPN2‐MAPK1 signaling axis. J Clin Lab Anal. 2020;34(12):e23555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xu Y-F, Ren X-Y, Li Y-Q, He Q-M, Tang X-R, Sun Y, et al. High expression of Talin-1 is associated with poor prognosis in patients with nasopharyngeal carcinoma. BMC Cancer. 2015;15(1):1–10.

    Article  Google Scholar 

  39. Vafaei S, Saeednejad Zanjani L, Habibi Shams Z, Naseri M, Fattahi F, Gheytanchi E, et al. Low expression of Talin1 is associated with advanced pathological features in colorectal cancer patients. Sci Rep. 2020;10(1):1–18.

    Article  Google Scholar 

  40. Xu N, Chen H-J, Chen S-H, Xue X-Y, Chen H, Zheng Q-S et al. Upregulation of Talin-1 expression associates with advanced pathological features and predicts lymph node metastases and biochemical recurrence of prostate cancer. 2016;95(29).

  41. Bostanci O, Kemik O, Kemik A, Battal M, Demir U, Purisa S, et al. A novel screening test for colon cancer. Talin-1. 2014;18(17):2533–7.

    CAS  Google Scholar 

  42. Xu Y-F, Ren X-Y, Li Y-Q, He Q-M, Tang X-R, Sun Y et al. High expression of Talin-1 is associated with poor prognosis in patients with nasopharyngeal carcinoma. 2015;15(1):1–10.

  43. Ji L, Jiang F, Cui X. Qin CJOl. Talin1 knockdown prohibits the proliferation and migration of colorectal cancer cells via the EMT signaling pathway Retraction in/10.3892/ol. 2021.12943. 2019;18(5):5408-16.

  44. Sakamoto S, McCann RO, Dhir R. Kyprianou NJCr. Talin1 promotes tumor invasion and metastasis via focal adhesion signaling and anoikis resistance. 2010;70(5):1885-95.

  45. Duraiyan J, Govindarajan R, Kaliyappan K. Palanisamy MJJop, sciences b. Appl Immunohistochem. 2012;4(Suppl 2):307.

    Google Scholar 

  46. Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47(W1):W556–W60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Park S-J, Yoon B-H, Kim S-K, Kim S-Y. GENT2: an updated gene expression database for normal and tumor tissues. BMC Med Genom. 2019;12(5):101.

    Article  Google Scholar 

  48. Goldman M, Craft B, Hastie M, Repečka K, Kamath A, McDade F et al. The UCSC Xena platform for public and private cancer genomics data visualization and interpretation.bioRxiv. 2019:326470.

  49. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, Jessup JM, Brierley JD, Gaspar LE, Schilsky RL. Balch. AJCC Cancer Staging Manual (8th edition): Springer International Publishing: American Joint Commission on Cancer; 2017

  50. Kallioniemi O-P, Wagner U, Kononen J, Sauter GJHmg. Tissue microarray technology for high-throughput molecular profiling of cancer. 2001;10(7):657–62.

  51. Fedor HL, Marzo AMDJPC. Practical methods for tissue microarray construction. 2005:89–101.

  52. Guy GP Jr, Machlin SR, Ekwueme DU, Yabroff KRJAjopm. Prevalence and costs of skin cancer treatment in the US, 2002 – 2006 and 2007 – 2011. 2015;48(2):183–7.

  53. Kuphal S, Bauer R, Bosserhoff A-K. Integrin signaling in malignant melanoma. Cancer Metastasis Rev. 2005;24(2):195–222.

    Article  CAS  PubMed  Google Scholar 

  54. Zhao Y, Lykov N, Tzeng CJIJoMM. Talin–1 interaction network in cellular mechanotransduction. 2022;49(5):1–12.

  55. Helige C, Hofmann-Wellenhof R, Fink-Puches R, Smolle J. Mofarotene-induced inhibition of melanoma cell motility by increasing vinculin-containing focal contacts. Melanoma Res. 2004;14(6):547–54.

    Article  CAS  PubMed  Google Scholar 

  56. Toma-Jonik A, Widlak W, Korfanty J, Cichon T, Smolarczyk R, Gogler-Piglowska A, et al. Active heat shock transcription factor 1 supports migration of the melanoma cells via vinculin down-regulation. Cell Signal. 2015;27(2):394–401.

    Article  CAS  PubMed  Google Scholar 

  57. Nelson ES, Folkmann AW, Henry MD, DeMali KA. Vinculin activators target integrins from within the cell to increase melanoma sensitivity to chemotherapy. Mol Cancer Res. 2011;9(6):712–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sadano H, Inoue M, Taniguchi S. Differential expression of vinculin between weakly and highly metastatic B16-melanoma cell lines. Jpn J Cancer Res. 1992;83(6):625–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Brézillon S, Radwanska A, Zeltz C, Malkowski A, Ploton D, Bobichon H, et al. Lumican core protein inhibits melanoma cell migration via alterations of focal adhesion complexes. Cancer Lett. 2009;283(1):92–100.

    Article  PubMed  Google Scholar 

  60. Das M, Ithychanda SS, Qin J, Plow EFJBEBA-B. Mech talin-dependent integrin Signal crosstalk. 2014;1838(2):579–88.

    CAS  Google Scholar 

  61. Katoh KJC. FAK-dependent cell motility and cell elongation. 2020;9(1):192.

    CAS  Google Scholar 

  62. Chamcheu JC, Roy T, Uddin MB, Banang-Mbeumi S, Chamcheu R-CN, Walker AL et al. Role and therapeutic targeting of the PI3K/Akt/mTOR signaling pathway in skin cancer: a review of current status and future trends on natural and synthetic agents therapy. 2019;8(8):803.

  63. Davies MAJTCJ. The role of the PI3K-AKT pathway in melanoma. 2012;18(2):142–7.

  64. Kircher DA, Trombetti KA, Silvis MR, Parkman GL, Fischer GM, Angel SN, et al. AKT1E17K activates focal adhesion kinase and promotes melanoma brain metastasis. Mol Cancer Res. 2019;17(9):1787–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Akasaka T, van Leeuwen RL, Yoshinaga IG, Mihm MC Jr, Byers HR. Focal adhesion kinase (p125FAK) expression correlates with motility of human melanoma cell lines. J Invest dermatology. 1995;105(1):104–8.

    Article  CAS  Google Scholar 

  66. Kahana O, Micksche M, Witz IP, Yron I. The focal adhesion kinase (P125FAK) is constitutively active in human malignant melanoma. Oncogene. 2002;21(25):3969–77.

    Article  CAS  PubMed  Google Scholar 

  67. Hess AR, Postovit L-M, Margaryan NV, Seftor EA, Schneider GB, Seftor RE, et al. Focal adhesion kinase promotes the aggressive melanoma phenotype. Cancer Res. 2005;65(21):9851–60.

    Article  CAS  PubMed  Google Scholar 

  68. Hodorogea A, Calinescu A, Antohe M, Balaban M, Nedelcu RI, Turcu G et al.Epithelial-mesenchymal transition in skin cancers: a review. 2019;2019.

  69. Kuphal S, Martyn AC, Pedley J, Crowther LM, Bonazzi VF, Parsons PG, et al. H-cadherin expression reduces invasion of malignant melanoma. 2009;22(3):296–306.

    CAS  Google Scholar 

  70. Bauer R, Hein R, Bosserhoff, AKJEcr. A secreted form of P-cadherin is expressed in malignant melanoma. 2005;305(2):418–26.

  71. Bécam IE, Tanentzapf G, Lepesant J-A, Brown NH, Huynh J-RJNcb. Integrin-independent repression of cadherin transcription by talin during axis formation in Drosophila. 2005;7(5):510–6.

  72. Krajewski A, Gagat M, Mikołajczyk K, Izdebska M, Żuryń A, Grzanka AJCM et al. Cyclin F downregulation affects epithelial-mesenchymal transition increasing proliferation and migration of the A-375 melanoma cell line. 2020;12:13085.

  73. Thapa N, Tan X, Choi S, Wise T, Anderson RJO. PIPKIγ and talin couple phosphoinositide and adhesion signaling to control the epithelial to mesenchymal transition. 2017;36(7):899–911.

  74. Vafaei S, Saeednejad Zanjani L, Habibi Shams Z, Naseri M, Fattahi F, Gheytanchi E et al. Low expression of Talin1 is associated with advanced pathological features in colorectal cancer patients. 2020;10(1):1–18.

  75. Azizi L, Cowell AR, Mykuliak VV, Goult BT, Turkki P, Hytönen VP. Cancer associated talin point mutations disorganise cell adhesion and migration. Sci Rep. 2021;11(1):1–16.

    Article  Google Scholar 

  76. Czarnecka AM, Bartnik E, Fiedorowicz M, Rutkowski PJIJoMS. Target therapy melanoma Mech Resist. 2020;21(13):4576.

    CAS  Google Scholar 

  77. Liu-Smith F, Jia J. Zheng YJUlihh, diseases, environment. UV-induced molecular signaling differences in melanoma and non-melanoma skin cancer. 2017:27–40.

  78. Xu X, Chen L, Guerry D, Dawson PR, Hwang W-t, VanBelle P et al. Lymphatic invasion is independently prognostic of metastasis in primary cutaneous melanoma. 2012;18(1):229–37.

  79. Tadokoro S, Shattil SJ, Eto K, Tai V, Liddington RC, de Pereda JM, et al. Talin binding to integrin ß tails: a final common step in integrin activation. Science. 2003;302(5642):103–6.

    Article  CAS  PubMed  Google Scholar 

  80. Lagarrigue F, Paul DS, Gingras AR, Valadez AJ, Sun H, Lin J, et al. Talin-1 is the principal platelet Rap1 effector of integrin activation. Blood. 2020;136(10):1180–90.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Nieswandt B, Varga-Szabo D, Elvers M. Integrins in platelet activation. J Thromb Haemost. 2009;7:206–9.

    Article  CAS  PubMed  Google Scholar 

  82. Yan H, Guo M, Zou J, Xiao F, Yi L, He Y et al. Promotive effect of Talin-1 protein on gastric cancer progression through PTK2‐PXN‐VCL‐E‐Cadherin‐CAPN2‐MAPK1 signaling axis. 2020;34(12):e23555.

  83. Apalla Z, Lallas A, Sotiriou E, Lazaridou E. Ioannides DJDp, conceptual. Epidemiol trends skin cancer. 2017;7(2):1.

    Google Scholar 

  84. Weinberg AS, Ogle CA, Shim EKJDs. Metastatic cutaneous squamous cell carcinoma: an update. 2007;33(8):885–99.

  85. Rahimi-Nedjat RK, Tuettenberg A, Sagheb K, Loquai C, Rybczynski B, Grabbe S et al. Factors accelerating recurrences and secondary tumors in cutaneous squamous cell carcinoma. 2021;49(4):317–22.

  86. Hardisson DJEAoO-R-L. Molecular pathogenesis of head and neck squamous cell carcinoma. 2003;260(9):502–8.

  87. Ratushny V, Gober MD, Hick R, Ridky TW, Seykora JTJTJoci. From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma. 2012;122(2):464–72.

  88. Xu N, Chen H-J, Chen S-H, Xue X-Y, Chen H, Zheng Q-S et al. Upregulation of Talin-1 expression associates with advanced pathological features and predicts lymph node metastases and biochemical recurrence of prostate cancer.Medicine. 2016;95(29).

  89. Ascierto PA, Kirkwood JM, Grob J-J, Simeone E, Grimaldi AM, Maio M, et al. The role of BRAF V600 mutation in melanoma. J translational Med. 2012;10:1–9.

    Article  Google Scholar 

  90. Marquez-Rodas I, Cerezuela P, Soria A, Berrocal A, Riso A, Gonzalez-Cao M et al.Immune checkpoint inhibitors: therapeutic advances in melanoma. 2015;3(18).

  91. Furue M, Ito T, Wada N, Wada M, Kadono T. Uchi HJCor. Melanoma and immune checkpoint inhibitors. 2018;20(3):1–8.

    CAS  Google Scholar 

  92. Carlino MS, Larkin J, Long GVJTL. Immune Checkp inhibitors melanoma. 2021;398(10304):1002–14.

    CAS  Google Scholar 

  93. Kozar I, Margue C, Rothengatter S, Haan C, Kreis S. Many ways to resistance: how melanoma cells evade targeted therapies. Biochim et Biophys Acta (BBA)-Reviews Cancer. 2019;1871(2):313–22.

    Article  CAS  Google Scholar 

  94. Orgaz JL, Crosas-Molist E, Sadok A, Perdrix-Rosell A, Maiques O, Rodriguez-Hernandez I et al. Myosin II reactivation and cytoskeletal remodeling as a hallmark and a vulnerability in melanoma therapy resistance. 2020;37(1):85–103. e9.

  95. Barreno A, Orgaz JLJC. Cytoskeletal Remodelling as an Achilles’ Heel for Therapy Resistance in Melanoma. 2022;11(3):518.

  96. Misek S, Appleton K, Dexheimer T, Lisabeth E, Lo R, Larsen S, et al. Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells. Oncogene. 2020;39(7):1466–83.

    Article  CAS  PubMed  Google Scholar 

  97. Paulitschke V, Berger W, Paulitschke P, Hofstätter E, Knapp B, Dingelmaier-Hovorka R, et al. Vemurafenib Resistance signature by Proteome Analysis offers New Strategies and Rational Therapeutic ConceptsVemurafenib Resistance signature in Melanoma. Mol Cancer Ther. 2015;14(3):757–68.

    Article  CAS  PubMed  Google Scholar 

  98. Kim MH, Kim J, Hong H, Lee SH, Lee JK, Jung E, et al. Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J. 2016;35(5):462–78.

    Article  CAS  PubMed  Google Scholar 

  99. Orgaz JL, Crosas-Molist E, Sadok A, Perdrix-Rosell A, Maiques O, Rodriguez-Hernandez I, et al. Myosin II reactivation and cytoskeletal remodeling as a hallmark and a vulnerability in melanoma therapy resistance. Cancer Cell. 2020;37(1):85–103. e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF (V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468(7326):973–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Barreno A, Orgaz JL. Cytoskeletal remodelling as an Achilles’ heel for Therapy Resistance in Melanoma. Cells. 2022;11(3):518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhao Y, Lykov N, Tzeng C. Talin–1 interaction network in cellular mechanotransduction. Int J Mol Med. 2022;49(5):1–12.

    Article  Google Scholar 

  103. Elosegui-Artola A, Oria R, Chen Y, Kosmalska A, Pérez-González C, Castro N, et al. Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity. Nat Cell Biol. 2016;18(5):540–8.

    Article  CAS  PubMed  Google Scholar 

  104. Sjoestroem C, Khosravi S, Cheng Y, Safaee Ardekani G, Martinka M, Li G. DLC1 expression is reduced in human cutaneous melanoma and correlates with patient survival. Mod Pathol. 2014;27(9):1203–11.

    Article  CAS  PubMed  Google Scholar 

  105. Vlachostergios PJJAjotr. Integrin signaling gene alterations and outcomes of cancer patients receiving immune checkpoint inhibitors. 2021;13(11):12386.

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Authors and Affiliations

  1. Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14535, Iran

    Yasaman Rezaie, Fahimeh Fattahi, Baharnaz Mashinchi, Elham Kalantari, Zahra Madjd & Leili Saeednejad Zanjani

  2. School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Yasaman Rezaie & Baharnaz Mashinchi

  3. Department of Dermatopathology, Razi Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran

    Kambiz Kamyab Hesari & Sahar Montazeri

  4. Department of Pathology and Genomic Medicine, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    Leili Saeednejad Zanjani

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Contributions

YR and BM gathered the paraffin-embedded tissues, collected the patient data, prepared the information of patient survival outcomes, and wrote the manuscript; EK performed the immunohistochemistry examinations and contributed to writing some sections of the manuscript; SM and KK examined hematoxylin and eosin slides, marked the most representative areas in different parts of the tumor for preparing the TMAs blocks, and scored TMAs slides after immunohistochemical staining; FF performed the bioinformatic analysis, and wrote the bioinformatic sections. LS and ZM designed and supervised the work. LS also analyzed the data and contributed to writing some sections of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Zahra Madjd or Leili Saeednejad Zanjani.

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This study has been approved by the medical ethics committee of Tehran University of medical sciences under the code IR.TUMS.REC.1401.034. All procedures performed in this study were in accordance with the 1964 Helsinki Declaration and its later amendments. Informed consent was obtained from all individual participants included in the study at the time of sample collection with routine consent forms.

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Rezaie, Y., Fattahi, F., Mashinchi, B. et al. High expression of Talin-1 is associated with tumor progression and recurrence in melanoma skin cancer patients. BMC Cancer 23, 302 (2023). https://doi.org/10.1186/s12885-023-10771-z

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BMC Cancer

ISSN: 1471-2407

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