Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer.

Abstract

MicroRNAs are small, non-coding RNAs that influence gene regulatory networks by post-transcriptional regulation of specific messenger RNA targets. MicroRNA expression is dysregulated in human malignancies, frequently leading to loss of expression of certain microRNAs. We report that expression of hsa-miR-342, a microRNA encoded in an intron of the gene EVL, is commonly suppressed in human colorectal cancer. The expression of hsa-miR-342 is coordinated with that of EVL and our results indicate that the mechanism of silencing is CpG island methylation upstream of EVL. We found methylation at the EVL/hsa-miR-342 locus in 86% of colorectal adenocarcinomas and in 67% of adenomas, indicating that it is an early event in colorectal carcinogenesis. In addition, we observed a higher frequency of methylation (56%) in histologically normal colorectal mucosa from individuals with concurrent cancer compared to mucosa from individuals without colorectal cancer (12%), suggesting the existence of a 'field defect' involving methylated EVL/hsa-miR-342. Furthermore, reconstitution of hsa-miR-342 in the colorectal cancer cell line HT-29 induced apoptosis, suggesting that this microRNA could function as a proapoptotic tumor suppressor. In aggregate, these results support a novel mechanism for silencing intronic microRNAs in cancer by epigenetic alterations of cognate host genes.

• Authors: W M Grady, R K Parkin, P S Mitchell, J H Lee, Y-H Kim, K D Tsuchiya, M K Washington, C Paraskeva, J K V Willson, A M Kaz, E M Kroh, A Allen, B R Fritz, S D Markowitz, M Tewari
• Journal: Oncogene (Oncogene) Vol. 27 Issue 27 Pg. 3880-8 (Jun 19 2008) ISSN: 1476-5594 [Electronic] England
• PMID: 18264139 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• DNA, Neoplasm
• EVL protein, human
• MicroRNAs

Topics

• Apoptosis
• Cell Adhesion Molecules (genetics)
• Cell Line, Tumor
• Colorectal Neoplasms (genetics, pathology)
• DNA Methylation
• DNA, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Humans
• Introns
• MicroRNAs (genetics)