Abstract
BACKGROUND: Deregulated methylation of tumor suppressor genes is a hallmark event in colorectal cancer (CRC) carcinogenesis. UNC5 receptors, down-regulated in various human malignancies due to epigenetic alterations, have been proposed as putative tumor suppressor genes. In this study, we focused on the methylation-mediated inhibition of UNC5 receptors and the associated clinical significance in CRC. METHODS: Methylation and expression analysis was performed in TCGA datasets. And the results were confirmed in vitro in CRC cell lines treated with 5-aza-deoxycytidine. Then, the expression and epigenetic alterations of UNC5 receptors were evaluated in clinical specimens. Moreover, the diagnostic and prognostic values of the methylation alterations were also analyzed. RESULTS: Methylation-mediated repression was observed in UNC5C and UNC5D, but not in UNC5A and UNC5B, which was confirmed in CRC cell lines. Except for UNC5B, significantly elevated methylation was observed in UNC5A, UNC5C, and UNC5D in CRC. The discrimination efficiency of the three receptors was comparable with that of SEPT9. Kaplan-Meier curve survival analysis showed that hypermethylation of UNC5A, UNC5C and UNC5D was associated with poor progression-free and overall survival. Moreover, methylation levels of UNC5C and UNC5D were independent predictors of CRC progression-free (P = 0.001, P = 0.003, respectively) and overall survival (P = 0.008, P = 0.004, respectively). CONCLUSIONS: Hypermethylation of UNC5C and UNC5D mediates the repression and has promising diagnostic and prognostic values in CRC.