STAT3 Induction of miR-146b Forms a Feedback Loop to Inhibit the NF-κB to IL-6 Signaling Axis and STAT3-Driven Cancer Phenotypes

Research output: Contribution to journalJournal article – Annual report year: 2014Researchpeer-review

Without internal affiliation

  • Author: Xiang, Michael

  • Author: Birkbak, Nicolai Juul

    Harvard Medical School, Denmark

  • Author: Vafaizadeh, Vida

  • Author: Walker, Sarah R.

  • Author: Yeh, Jennifer E.

  • Author: Liu, Suhu

  • Author: Kroll, Yasmin

  • Author: Boldin, Mark

  • Author: Taganov, Konstantin

  • Author: Groner, Bernd

  • Author: Richardson, Andrea L.

  • Author: Frank, David A.

View graph of relations

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 ofwhich is associated with persistent STAT3 activation in human cancer. We found that the gene encoding the tumor suppressormicroRNA 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 kB (NF-kB)–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 ofmiR-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-kB relevant to constitutive STAT3 activation inmalignancy and the role of inflammation in oncogenesis.
Original languageEnglish
JournalScience Signaling
Issue number310
Number of pages14
Publication statusPublished - 2014
Externally publishedYes
CitationsWeb of Science® Times Cited: No match on DOI

ID: 97086854