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

Oncogene volume 27, pages 3880–3888 (2008)Cite this article

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.

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Acknowledgements

We thank Dr Beatrice Knudsen for advice regarding tissue processing and Dr Julio Vasquez and Dr Dave McDonald for confocal microscopy. We acknowledge support from the Damon Runyon Lilly Cancer Research Fund (to WMG), the Presidential Early Career Award for Scientists and Engineers (to WMG), the Fred Hutchinson Cancer Research Center (FHCRC) Early Detection Initiative Pilot Project Program (to WMG), the V Foundation Scholar Grant (to MT) and the FHCRC Molecular Diagnostics Pilot Project Program (to MT). These studies were carried out with the use of the experimental histopathology, genomics and scientific imaging shared resources at the FHCRC. The Cooperative Human Tissue Network provided some of the primary tissue samples used in the studies.

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Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    W M Grady, J H Lee, Y-H Kim, K D Tsuchiya, A M Kaz & M Tewari

  2. Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA, USA

    W M Grady & A M Kaz

  3. VA Puget Sound Healthcare System, Seattle, WA, USA

    W M Grady & A M Kaz

  4. Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    R K Parkin, P S Mitchell, E M Kroh, B R Fritz & M Tewari

  5. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    J H Lee & Y-H Kim

  6. Seattle Children's Hospital and Regional Medical Center, Seattle, WA, USA

    K D Tsuchiya

  7. Vanderbilt University Medical School, Nashville, TN, USA

    M K Washington

  8. University of Bristol, Bristol, UK

    C Paraskeva

  9. University of Texas Southwestern Medical School, Dallas, TX, USA

    J K V Willson

  10. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    A Allen

  11. Case Western Reserve University Medical School, Cleveland, OH, USA

    S D Markowitz

  12. University Hospitals of Cleveland, Cleveland, OH, USA

    S D Markowitz

  13. Howard Hughes Medical Institute, Cleveland, OH, USA

    S D Markowitz

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  1. W M Grady
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Correspondence to M Tewari.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Grady, W., Parkin, R., Mitchell, P. et al. Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer. Oncogene 27, 3880–3888 (2008). https://doi.org/10.1038/onc.2008.10

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