(Hepatology 2014;60:1494–1507) “
“Although the inflammation-associated cytokine interleukin-6 (IL-6) has been implicated in cholangiocarcinoma NVP-BKM120 cell line 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 selleck 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 Progesterone of miR-148a and miR-152, and provide a link between this inflammation-associated cytokine and oncogenesis in cholangiocarcinoma. (HEPATOLOGY 2010.) Cholangiocarcinomas are primary malignancies of the biliary tract epithelia that are typically associated with chronic inflammation.1 The inflammation-associated cytokine interleukin-6 (IL-6) has been identified as contributing to the abnormal growth and survival of malignant cholangiocytes through an autocrine–paracrine mechanism.2–4 However, the precise role of IL-6 in cholangiocarcinogenesis has
not been fully characterized. Recent studies provide evidence for the involvement of epigenetic modifications of critical genes in mediating the effects of IL-6. IL-6 can increase overall methylation activity with the suppression of key regulatory onco-suppressor genes.5 We and others have shown that IL-6 can increase DNA methyltransferase-1 (DNMT-1), the most abundant methyltransferase in mammalian cells that play a key role in the maintenance of DNA methylation.5, 6 Although DNMT-1 is considerably more active on hemimethylated DNA as compared with unmethylated substrate in vitro, it is also active in de novo methylation, similar to other DNMTs.7 Enforced expression of IL-6 in cholangiocarcinoma increases the expression of DNMT-1 and increases overall methylation activity.6, 8, 9 The modulation of methyltransferases provides an attractive mechanism through which IL-6 can restore and maintain methylation of critical genes.