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  • Original Article
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Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes

Abstract

Interleukin-6 (IL-6) is overexpressed and contributes to tumor cell growth in cholangiocarcinoma. Enforced IL-6 production can alter the expression of specific microRNAs (miRNAs) involved in tumor growth, and moreover can modulate expression of methylation-dependent genes. Thus, we assessed the methylation-dependent regulation of miRNA expression in human malignant cholangiocytes stably transfected to overexpress IL-6. The expression of the methyltransferases DNA methyltransferase enzyme-1 and HASJ4442 was increased by IL-6 overexpression, but was decreased by the methylation inhibitor 5-aza-2′-deoxycytidine (5-aza-CdR). Expression profiling identified seven miRNAs that were significantly downregulated by IL-6 overexpression (<0.4-fold) and upregulated (>2-fold) by 5-aza-CdR. One of these, miR-370, is embedded in a CpG island. Although 5-aza-CdR increased miR-370 expression by 2.1-fold in malignant cells, the expression in nonmalignant cells was unchanged. The oncogene mitogen-activated protein kinase kinase kinase 8 (MAP3K8) was identified as a target of miR-370, and its expression was decreased by 5-aza-CdR in cholangiocarcinoma cells. Overexpression of IL-6 reduced miR-370 expression and reinstated MAP3K8 expression in vitro as well as in tumor cell xenografts in vivo. Thus, IL-6 may contribute to tumor growth by modulation of expression of selected miRNAs, such as miR-370. These studies define a mechanism by which inflammation-associated cytokines can epigenetically modulate gene expression and directly contribute to tumor biology.

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Abbreviations

5-aza-CdR:

5-aza-2′deoxycytidine

DNMT:

DNA methyltransferase enzyme

IBEC:

intrahepatic biliary epithelial cells

IL-6:

interleukin-6

MAP3K8:

mitogen-activated protein kinase kinase kinase 8

miRNA:

microRNA

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Acknowledgements

This study was supported by grants DK069370 from the National Institutes of Health.

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Correspondence to T Patel.

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

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Meng, F., Wehbe-Janek, H., Henson, R. et al. Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes. Oncogene 27, 378–386 (2008). https://doi.org/10.1038/sj.onc.1210648

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