Methylation of promotes colorectal cancer progression and may serve as a marker for poor prognosis.

BACKGROUND

is a new member of the Ras gene family. It was described as a potential tumor suppressor in human glioblastomas and esophageal cancer. The role of in colorectal cancer remains unclear.

METHODS

To explore the epigenetic changes and function of in human colorectal cancer, we studied ten colorectal cancer cell lines and 146 primary colorectal cancer samples and 50 matched adjacent samples using semi-quantitative reverse transcription PCR, immunohistochemistry, methylation-specific PCR and bisulfite sequencing, western blot, flow cytometry, and transwell assays.

RESULTS

expression was found in DKO and HCT116 cells, while reduced expression was detected in LoVo, SW48, LS180, and SW620 cells, and there was no expression detected in DLD1, HT29, RKO, and SW480 cells. Complete methylation was found in the promoter region of DLD1, HT29, RKO, and SW480 cells. Partial methylation was detected in LoVo, LS180, SW48, and SW620 cells, and unmethylation was found in DKO and HCT116 cells. These results indicate that promoter region methylation correlated with loss of/reduced expression of . Re-expression of was induced by 5-aza-2'-deoxycytidine, suggesting that the expression of is regulated by promoter region methylation. was methylated in 47.3% (69/146) of primary colorectal cancer samples, no methylation was found in non-cancerous colonic tissue samples. Methylation of was significantly associated with TNM stage ( 0.05) and short survival time ( 0.0121). induced apoptosis and inhibited cell proliferation, migration, and invasion in colorectal cancer. Finally, suppressed colorectal cancer cell xenograft growth in nude mice.

CONCLUSIONS

is frequently methylated in human colorectal cancer and the expression of is regulated by promoter region methylation. Methylation of is a marker of poor prognosis in human colorectal cancer.