CMTM5 is downregulated and suppresses tumour growth in hepatocellular carcinoma through regulating PI3K-AKT signalling

Cancer Cell International, Nov 2017

Human chemokine like factor (CKLF)-like MAL and related proteins for vesicle trafficking transmembrane, domain-containing member 5 (CMTM5) has been shown to involved and may function as a tumour suppressor in tumorigenesis. The current study aimed to investigate the expression and function of CMTM5 in human hepatocellular carcinoma (HCC). CMTM5 expression was examined by immunohistochemistry, and its clinical significance was analysed in 76 HCC specimens. The role and molecular mechanisms of CMTM5 in cell proliferation, apoptosis and invasion were examined in vitro and in vivo. CMTM5 expression was significantly downregulated in HCC tissues as well as cell lines. The expression of CMTM5 was absent in 77.6% of HCC tissues compared with 3.9% in normal liver tissues. Low CMTM5 expression was significantly correlated with poor overall survival in patients with HCC (P = 0.009). Restoring CMTM5 expression in Huh7 cells significantly inhibited cell growth, promoted cell apoptosis, and reduced cell metastatic and invasion ability compared with mock transfected cells in vitro. Overexpression of CMTM5 also suppressed xenograft tumour growth in vivo in a HCC xenograft model. Reduced cell growth and metastasis ability mediated by CMTM5 overexpression was associated with downregulation of PI3K/AKT and its downstream Bcl2, cyclinD1, cyclinE, MMP2 and MMP9 expressions, and an upregulation of p21, Bax, Bad, cleaved caspase3 expressions. Our data suggest that CMTM5 might function as a tumour suppressor in human HCC, and represent a valuable potential therapeutic target for HCC.

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CMTM5 is downregulated and suppresses tumour growth in hepatocellular carcinoma through regulating PI3K-AKT signalling

Xu and Dang Cancer Cell Int CMTM5 is downregulated and suppresses tumour growth in hepatocellular carcinoma through regulating PI3K-AKT signalling Gang Xu 0 Chengxue Dang 0 0 Department of Surgical Oncology, The First Affiliated Hospital Xi'an Jiaotong University , No. 277 West Yanta Road, Xi'an 710061, Shaanxi , People's Republic of China Background: Human chemokine like factor (CKLF)-like MAL and related proteins for vesicle trafficking transmembrane, domain-containing member 5 (CMTM5) has been shown to involved and may function as a tumour suppressor in tumorigenesis. The current study aimed to investigate the expression and function of CMTM5 in human hepatocellular carcinoma (HCC). Methods: CMTM5 expression was examined by immunohistochemistry, and its clinical significance was analysed in 76 HCC specimens. The role and molecular mechanisms of CMTM5 in cell proliferation, apoptosis and invasion were examined in vitro and in vivo. Results: CMTM5 expression was significantly downregulated in HCC tissues as well as cell lines. The expression of CMTM5 was absent in 77.6% of HCC tissues compared with 3.9% in normal liver tissues. Low CMTM5 expression was significantly correlated with poor overall survival in patients with HCC (P = 0.009). Restoring CMTM5 expression in Huh7 cells significantly inhibited cell growth, promoted cell apoptosis, and reduced cell metastatic and invasion ability compared with mock transfected cells in vitro. Overexpression of CMTM5 also suppressed xenograft tumour growth in vivo in a HCC xenograft model. Reduced cell growth and metastasis ability mediated by CMTM5 overexpression was associated with downregulation of PI3K/AKT and its downstream Bcl2, cyclinD1, cyclinE, MMP2 and MMP9 expressions, and an upregulation of p21, Bax, Bad, cleaved caspase3 expressions. Conclusions: Our data suggest that CMTM5 might function as a tumour suppressor in human HCC, and represent a valuable potential therapeutic target for HCC. CMTM5; Hepatocellular carcinoma; Tumour suppressor; PI3K-AKT Background Liver cancer is a common malignant and the fourth leading cause of cancer deaths in China [ 1 ]. It is estimated 466,100 new cases of liver cancer in 2015 in China, with 422,100 new deaths due to this disease [ 1 ]. Hepatocellular carcinoma (HCC) is the most common type and accounts for 70–85%of liver cancer [ 2 ]. People with early-stage HCC can be treated with surgery, either removing part of the liver or transplantation, with 5-year survival rates that exceed 70%. Most people, however, cannot have surgical treatment and so the overall 5-year survival is about 15% [ 3 ]. Therefore, it is important to understand the molecular mechanisms involved in HCC carcinogenesis, and find novel approaches that can effectively inhibit HCC cell growth and metastasis. Human chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) is a novel family consisting of nine genes, CKLF and CMTMI to CMTM8. CMTMs, linking classical chemokines and the transmembrane-4 superfamily (TM4SF), play important roles in immune system, male reproductive system and carcinogenesis [ 4, 5 ]. CMTM5 was firstly reported by in 2003, and located at 14q11.2 [4]. It is structurally similar to the TM4SF which can by collecting a variety of other molecules (such as AKT, EGFR) form four cross membrane protein network, thus mediated cell proliferation, apoptosis, migration, adhesion, differentiation, and closely related to tumour formation [ 4, 6, 7 ]. It has been reported that CMTM5 acted as a tumour-suppressor gene and was specifically down-regulated in many human cancers, such as cervical carcinoma [ 8 ], pancreatic cancer [ 9 ], myeloid leukemia [ 10 ], ovarian cancer [ 11 ], oral squamous cell carcinoma (OSCC) [ 12 ] and prostate cancer [ 13 ]. However, the clinical significance and function of CMTM5 in HCC remains unclear. In this study, we aimed to detect the expression patterns of CMTM5 and their correlations with clinicopathological characteristics in HCC patients. Furthermore, we explored the effect and mechanisms of CMTM5 on cell growth and metastasis based on HCC cell line in vitro and in vivo. Methods Tissue samples and cell culture The study was approved by the ethics committee of Chinese PLA General Hospital (CHN-PLAGH-ZL-002), and informed consent was obtained from each patient according to the committee’s regulations. Tissue samples collected from 76 patients who underwent curative liver resection at the Department of Gastroenterology and Hepatology at the Chinese PLA General Hospital between 2007 and 2010 were used for CMTM5 immunohistochemistry detection. TNM classification was determined according to the 2002 International Union Against Cancer guidelines. Tumour differentiation was graded according to the Edmondson-Steiner classification. Clinical characteristics of all patients are shown in Table  1. The time to overall survival (OS) time were defined as the inter (...truncated)


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Gang Xu, Chengxue Dang. CMTM5 is downregulated and suppresses tumour growth in hepatocellular carcinoma through regulating PI3K-AKT signalling, Cancer Cell International, pp. 113,