Background & Aims-microRNAs (miRNAs) are short noncoding RNAs that regulate gene expression negatively. Although a role for aberrant miRNA expression in cancer has been postulated, the pathophysiologic role and relevance of aberrantly expressed miRNA to tumor biology has not been established.

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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.Increased expression of the inflammation-associated cytokine interleukin-6 (IL-6) 2 occurs in chronic inflammatory conditions and in several human cancers such as multiple myeloma, prostate cancer, and cholangiocarcinoma. IL-6 has been implicated in tumor growth in many of these tumors, and elevated IL-6 expression has been associated with poor outcomes and resistance to chemotherapy (1). Experimentally, growth of prostate cancer and cholangiocarcinoma xenografts in athymic mice has been shown to be increased by enforced expression of IL-6 by activation of cell survival signaling (2, 3). The mechanisms by which IL-6 promotes cell survival in cancers are of considerable interest because they may be therapeutically targeted.IL-6-activated survival signaling has been shown to involve the signal transducers and activators of transcription (Stat) factors or various protein kinase cascades (4, 5). Although constitutive activation of Stat has been described in many cancers, the precise mechanisms involved are incompletely understood. Cholangiocarcinomas are highly resistant to chemotherapy. However, inhibition of IL-6-dependent pathways such as the Jak-Stat pathway, phosphatidylinositol 3-kinase, or the p38 MAPK pathways can enhance chemotherapy-induced cell death. Thus, aberrant IL-6-dependent survival signaling may contribute to the refractoriness of cholangiocarcinoma to most chemotherapeutic agents.We sought to understand the role of microRNAs (miRNAs) in IL-6-mediated tumor cell survival. miRNAs are endogenous regulators of gene expression that are altered in expression in many cancers (6-8). The expression of several miRNAs in cholangiocarcinoma xe...

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