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, Tushar Patel

Research output: Contribution to journalArticle

170 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8256-8264
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number11
DOIs
StatePublished - Mar 16 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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