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J. Biol. Chem., Vol. 282, Issue 11, 8256-8264, March 16, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/11/8256    most recent M607712200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Meng, F. Articles by Patel, T. Search for Related Content PubMed PubMed Citation Articles by Meng, F. Articles by Patel, T. Social Bookmarking                      What's this?

The MicroRNA let-7a Modulates Interleukin-6-dependent STAT-3 Survival Signaling in Malignant Human Cholangiocytes^*

Fanyin Meng, Roger Henson, Hania Wehbe-Janek, Heather Smith, Yoshiyuki Ueno, and Tushar Patel¹

From the Division of Gastroenterology, Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, Texas 76508 and the Division of Gastroenterology, Tohoku University, Sendai 980-8577, Japan

The inflammation-associated cytokine interleukin-6 (IL-6) can contribute to tumor growth and resistance to therapy by the activation of survival mechanisms. In several human cancers, IL-6-activated survival signaling involves the signal transducers and activators of transcription (Stat) factors or protein kinase cascades. microRNAs (miRNAs) are endogenous regulators of gene expression that are altered in expression in many cancers. However, the effect of inflammatory cytokines on miRNA expression and the role of miRNA in modulating IL-6-mediated cell survival are unknown. We investigated the involvement of miRNA in malignant cholangiocytes stably transfected to overexpress IL-6, which enhances tumor growth in vivo by inhibition of apoptosis. We provide evidence that (i) miRNA expression both in vitro and in vivo is altered by overexpression of IL-6; (ii) selective miRNAs including let-7a are up-regulated and contribute to the survival effects of enforced IL-6 activity; and (iii) let-7a contributes to the constitutively increased phosphorylation of Stat-3 by a mechanism involving the neurofibromatosis 2 (NF2) gene. These findings reveal a novel mechanism by which IL-6 mediates tumor cell survival that may be therapeutically targeted and emphasize the presence of complex interrelationships between deregulated expression of miRNA and transcription factors in human cancers.

Received for publication, August 11, 2006 , and in revised form, December 6, 2006.

^* This study was supported by grant DK069370 from the National Institutes of Health and the Scott and White Hospital Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ To whom correspondence should be addressed: Division of Gastroenterology and Hepatology, The Ohio State University Medical Center, N201 Doan Hall, 410 West 10^th Ave., Columbus, OH 43210. Tel.: 614-293-6202; Fax: 614-293-0861; E-mail: patel.lab{at}gmail.com.

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