The MicroRNA let-7a modulates interleukin-6-dependent STAT-3 survival signaling in malignant human cholangiocytes.
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.
Meng
Fanyin
F
Division of Gastroenterology, Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, Texas 76508, USA.
Henson
Roger
R
Wehbe-Janek
Hania
H
Smith
Heather
H
Ueno
Yoshiyuki
Y
Patel
Tushar
T
D002759:Adenoma, Bile Duct / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D025581:Neurofibromin 2 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D015850:Interleukin-6; D035683:MicroRNAs; D025581:Neurofibromin 2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C487931:mirnlet7 microRNA, human