CMTM4 inhibits cell proliferation and migration via AKT, ERK1/2, and STAT3 pathway in colorectal cancer

CMTM4 (CKLF-like MARVEL transmembrane domain containing 4), a potential tumor suppressor gene, is involved in several types of malignancies. It has been reported to be downregulated and exhibit anti-tumorigenic activities by regulating cell growth and cell cycle in clear cell renal cell carcinoma. It has also been identified as a tumor suppressor in hepatocellular carcinoma (HCC), and its negative expression is a risk factor for poor prognosis of HCC patients. In the present study, an integrated bioinformatics analysis based on The Cancer Genome Atlas (TCGA) database showed that CMTM4 was frequently reduced in colorectal cancer (CRC) and high expression of CMTM4 was associated with increased overall survival rates. Based on these findings, we adopted gain-of-function and lost-of-function strategies using SW480 and HT29 CRC cell lines which have relatively low and high endogenous CMTM4 levels, respectively. We observed impeded cell proliferation and migration upon overexpression of CMTM4 in SW480 cells, and the opposite effects were observed upon knockdown of CMTM4 in HT-29 cells. Cell signaling pathways essential for CRC progression were then examined, and the phosphorylation levels of AKT, ERK1/2, and STAT3 were found to be decreased by CMTM4 overexpression in SW480 cells and elevated by CMTM4 silencing in HT29 cells. Their inhibitors were used to validate that the three signaling pathways contributed to the inhibitory effects of CMTM4 on CRC cells. Taken together, our results suggest that CMTM4 plays a tumor suppressive role in CRC.