Microrna-Dependent Regulation of Dna Methyltransferase-1... : Hepatology (original) (raw)
Autoimmune, Cholestatic and Biliary Disease
Microrna-Dependent Regulation of Dna Methyltransferase-1 and Tumor Suppressor Gene Expression by Interleukin-6 in Human Malignant Cholangiocytes
1_Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, OH_
*Address reprint requests to: Professor of Medicine, The Ohio State University Medical Center, Suite 200, Doan Office Tower, 395 W. 12thAddress reprint requests to: Avenue, Columbus, OH 43210. Email:[email protected]; fax: 614-293-0861
Received 20 August 2009; Accepted 6 October 2009
Published online 9 February 2010 in Wiley InterScience (www.interscience.wiley.com).
Supported by National Institutes of Health Grant DK06370.
Potential conflict of interest: Nothing to report.
Additional Supporting Information may be found in the online version of this article.
Abstract
Although the inflammation-associated cytokine interleukin-6 (IL-6) has been implicated in cholangiocarcinoma growth, the relationship between IL-6 and oncogenic changes is unknown. IL-6 can increase expression of DNA methyltransferase-1 (DNMT-1) and epigenetically regulate the expression of several genes, including microRNAs (miRNAs). DNMT-1 up-regulation occurs in hepatobiliary cancers and is associated with a poor prognosis. To understand the potential regulation of DNMT-1 by IL-6–dependent miRNAs, we examined the expression of a group of miRNAs which have sequence complementarity to the 3'-untranslated region of DNMT-1, namely miR-148a, miR-152, and miR-301. The expression of these miRNAs was decreased in cholangiocarcinoma cells. Moreover, the expression of all three miRNAs was decreased in IL-6–overexpressing malignant cholangiocytes in vitro and in tumor cell xenografts. There was a concomitant decrease in expression of the methylation-sensitive tumor suppressor genes Rassf1a and p16INK4a. Using luciferase reporter constructs, DNMT-1 was verified as a target for miR-148a and miR-152. Precursors to miR-148a and miR-152 decreased DNMT-1 protein expression, increased Rassf1a and p16INK4a expression, and reduced cell proliferation. Conclusion: These data indicate that IL-6 can regulate the activity of DNMT-1 and expression of methylation-dependent tumor suppressor genes by modulation of miR-148a and miR-152, and provide a link between this inflammation-associated cytokine and oncogenesis in cholangiocarcinoma. (Hepatology 2010.)
Copyright © 2010 American Association for the Study of Liver Diseases.