STAT3 induction of miR-146b forms a feedback loop to inhibit the NF-κB to IL-6 signaling axis and STAT3-driven cancer phenotypes

Michael Xiang, Nicolai J. Birkbak, Vida Vafaizadeh, Sarah R. Walker, Jennifer E. Yeh, Suhu Liu, Yasmin Kroll, Mark Boldin, Konstantin Taganov, Bernd Groner, Andrea L. Richardson, David A. Frank

Research output: Contribution to journalArticle

Abstract

Interleukin-6 (IL-6)-mediated activation of signal transducer and activator of transcription 3 (STAT3) is a mechanism by which chronic inflammation can contribute to cancer and is a common oncogenic event. We discovered a pathway, the loss of which is associated with persistent STAT3 activation in human cancer. We found that the gene encoding the tumor suppressor microRNA miR-146b is a direct STAT3 target gene, and its expression was increased in normal breast epithelial cells but decreased in tumor cells. Methylation of the miR-146b promoter, which inhibited STAT3-mediated induction of expression, was increased in primary breast cancers. Moreover, we found that miR-146b inhibited nuclear factor κB (NF-κB)-dependent production of IL-6, subsequent STAT3 activation, and IL-6/STAT3-driven migration and invasion in breast cancer cells, thereby establishing a negative feedback loop. In addition, higher expression of miR-146b was positively correlated with patient survival in breast cancer subtypes with increased IL6 expression and STAT3 phosphorylation. Our results identify an epigenetic mechanism of crosstalk between STAT3 and NF-κB relevant to constitutive STAT3 activation in malignancy and the role of inflammation in oncogenesis.

Original languageEnglish (US)
Article numberra11
JournalScience signaling
Volume7
Issue number310
DOIs
StatePublished - Jan 28 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Xiang, M., Birkbak, N. J., Vafaizadeh, V., Walker, S. R., Yeh, J. E., Liu, S., Kroll, Y., Boldin, M., Taganov, K., Groner, B., Richardson, A. L., & Frank, D. A. (2014). STAT3 induction of miR-146b forms a feedback loop to inhibit the NF-κB to IL-6 signaling axis and STAT3-driven cancer phenotypes. Science signaling, 7(310), [ra11]. https://doi.org/10.1126/scisignal.2004497