MicroRNA-124a and microRNA-34b/c are frequently methylated in all histological types of colorectal cancer and polyps and in the adjacent normal mucosa

摘要

MicroRNAs (miRs) are a class of small RNAs that regulate gene expression at the post-transcriptional and/or translational level by interacting with their target mRNAs. miRs are down-regulated or up-regulated in various cancer types, triggering abnormal cell differentiation, proliferation and apoptosis. miR-124a and miR-34b/c have been reported to be expressed at lower levels in colorectal cancer (CRC) due to methylation of these genes. The present study aimed to determine the methylation status of miR-124a and miR-34b/c in CRCs and polyps of various histological types, adjacent normal mucosa and ulcerative colitis. The colon cancer cell line study showed an association of the lower expression of miR-124a and miR-34b/c with the methylation of these genes and induction of the expression of these genes with the treatment by 5-aza-2′-deoxycytidine. Among nine different cancer types examined, CRC showed the highest frequency of methylation of miR-124a (cell lines 88% and tissues 99%) and miR-34b/c (cell lines 89% and tissues 93%). Mucinous and non-mucinous CRCs and all the histological types of colorectal polyps showed a high frequency of methylation of miR-124a and miR-34b/c. Notably, methylation of miR-124a (59%) and miR-34b/c (26%) was observed in the adjacent normal mucosa of CRC patients, but not in colonic mucosa from patients without cancer or with ulcerative colitis. The methylation of miR-124a in the adjacent normal mucosa was associated with the microsatellite instability of CRC, while the methylation of miR-34b/c was associated with an older age at diagnosis of CRC. The results showed that the methylation of miR-124a and miR-34b/c occured early in colorectal carcinogenesis and certain CRCs may arise from a field defect defined by the epigenetic inactivation of miRs.