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

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

Research output: Contribution to journalArticle

241 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3880-3888
Number of pages9
JournalOncogene
Volume27
Issue number27
DOIs
StatePublished - Jun 19 2008

Keywords

  • Apoptosis
  • Colon cancer
  • Colorectal cancer
  • Epigenetic
  • Methylation
  • MicroRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Grady, W. M., Parkin, R. K., Mitchell, P. S., Lee, J. H., Kim, Y. H., Tsuchiya, K. D., Washington, M. K., Paraskeva, C., Willson, J. K. V., Kaz, A. M., Kroh, E. M., Allen, A., Fritz, B. R., Markowitz, S. D., & Tewari, M. (2008). Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer. Oncogene, 27(27), 3880-3888. https://doi.org/10.1038/onc.2008.10