CMTM6 promotes migration, invasion, and EMT by interacting with and stabilizing vimentin in hepatocellular carcinoma cells

Abstract

Background CKLF like MARVEL transmembrane domain containing 6 (CMTM6) has been associated with the development in many kinds of cancers. However, the roles of CMTM6 in hepatocellular carcinoma (HCC) are largely unknown. Thus, the present study aimed to investigate the function of CMTM6 in HCC. Methods We analysed CMTM6 levels and functions using human HCC cell lines, paired HCC and adjacent non-tumorous tissues, and a tissue microarray. CMTM6 expression was silenced using short hairpin RNAs and its was overexpressed from a lentivirus vector. CMTM6 mRNA and protein levels were determined using quantitative real-time reverse transcription PCR and western blotting, respectively. Proliferation, colony formation, migration, and invasion were assessed using a Cell counting kit-8, colony formation, wound-healing, and Matrigel invasion assays, respectively. Immunohistochemistry was used to score the expression of CMTM6 in tissue samples. The localization and binding partners of CMTM6 were investigated using immunofluorescence and coimmunoprecipitation experiments, respectively. A mouse xenograft model was used for in vivo studies. Results Compared with that in adjacent, non-cancerous tissue, Here, CMTM6 levels were increased in HCC tissue samples. Silencing of CMTM6 suppressed the proliferation, migration, and invasion of HCC cells. Conversely, CMTM6 overexpression enhanced HCC cell invasion, migration, and proliferation. Mechanistically, CMTM6 physically interacts with and stabilizes vimentin, thus inducing epithelial–mesenchymal transition (EMT), which promotes proliferation, migration and invasion. Importantly, in HCC tissues, CMTM6 expression correlated positively with vimentin levels. Poor prognosis of HCC was associated significantly with higher CMTM6 expression. Conclusions CMTM6 has an important function in HCC proliferation, migration, and invasion, via its interaction with and stabilization of vimentin. CMTM6 might represent a potential biomarker and therapeutic target to treat HCC.

Loss of CMTM6 promotes DNA damage-induced cellular senescence and antitumor immunity

“… 12–14 Meanwhile, CMTM6 promotes cell migration and invasion by enhancing EMT progression, a fundamental mechanism for the metastatic phenotype of malignant tumors. 13 , 30 In our study, we found that CMTM6 was overexpressed in ccRCC tissues and was significantly associated with advanced tumor grade, early lymph node and distant metastases, and adverse prognosis. Interestingly, HKC cells, a commonly used human renal tubular epithelial cell line with characteristics of being immortalized, expressed similar level of CMTM6 in comparison with that in most of ccRCC cell lines ( Figure 2a ).…”

CMTM Family and Gastrointestinal Tract Cancers: A Comprehensive Review

“… 58 , 59 Furthermore, the upregulated CMTM4 expression in HCC facilitates escaping from antitumor T-cell immunity and contributes to an immunosuppressive tumor microenvironment. 59 Similar to CMTM4, CMTM6 expression was downregulated 78 or upregulated 80 , 110 in HCC tissues. The reasons for the contradiction between these studies are still ambiguous; however, small-scale specimens, heterogeneity of tumor tissue, and observational bias are possible factors.…”

“…Recent studies have shown that CMTM6 expression is upregulated in HCC tissues, and its overexpression increases cell proliferation and enhances cell invasion and migration and induces epithelial–mesenchymal transition (EMT) mechanistically by stabilizing vimentin. 80 In addition, the co-expression of CMTM6/PD-L1 can regulate inflammatory cell density 77 and has a close relationship with tumor recurrence. 81 Given the participation of CMTM6 in PD-L1 stabilization, 9 , 10 combined treatment with anti-CMTM6 and anti-PD-L1 may be a new method to enhance the therapeutic benefits in HCC.…”

CMTM6 and CMTM4 as two novel regulators of PD-L1 modulate the tumor microenvironment

“…CMTM6 and CMTM4 can affect tumor proliferation, metastasis, maintain the tumor stem cells phenotypes and promote epithelial-mesenchymal transition (EMT). CMTM6 promoted tumor proliferation, migration, and invasion in various tumors, such as RCC ( 27 ), gliomas ( 19 ), and HCC ( 105 ). Wei et al.…”

“…EMT-induced epithelial plasticity could be manifested by changes in the expression of epithelial markers including E-cadherin and mesenchymal proteins including N-cadherin and vimentin ( 113 ). Recent study demonstrated that CMTM6 induces EMT by stabilizing vimentin, which in turn promote migration and invasion of tumor cells in HCC ( 105 ). The effect of CMTM6 on EMT may be mediated through Wnt/β-catenin signaling ( 18 ).…”