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Sci. Signal., 28 January 2014
Vol. 7, Issue 310, p. ra11
[DOI: 10.1126/scisignal.2004497]

RESEARCH ARTICLES

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

Michael Xiang1, Nicolai J. Birkbak2*, Vida Vafaizadeh3, Sarah R. Walker1,4, Jennifer E. Yeh1, Suhu Liu1, Yasmin Kroll1, Mark Boldin5{dagger}, Konstantin Taganov5{ddagger}, Bernd Groner3, Andrea L. Richardson2, and David A. Frank1,4§

1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
2 Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02215, USA.
3 Georg-Speyer-Haus, Institute for Biomedical Research, D-60956 Frankfurt, Germany.
4 Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02215, USA.
5 Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.

* Present address: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.

{dagger} Present address: Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.

{ddagger} Present address: EMD Millipore, 28820 Single Oak Drive, Temecula, CA 92590, USA.

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 {kappa}B (NF-{kappa}B)–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-{kappa}B relevant to constitutive STAT3 activation in malignancy and the role of inflammation in oncogenesis.

§ Corresponding author. E-mail: david_frank{at}dfci.harvard.edu

Citation: M. Xiang, N. J. Birkbak, V. Vafaizadeh, S. R. Walker, J. E. Yeh, S. Liu, Y. Kroll, M. Boldin, K. Taganov, B. Groner, A. L. Richardson, D. A. Frank, STAT3 Induction of miR-146b Forms a Feedback Loop to Inhibit the NF-{kappa}B to IL-6 Signaling Axis and STAT3-Driven Cancer Phenotypes. Sci. Signal. 7, ra11 (2014).

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
MicroRNA Circuits Regulate the Cancer-Inflammation Link.
D. Iliopoulos (2014)
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