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

Xiang, Michael and Birkbak, Nicolai J. and Vafaizadeh, Vida and Walker, Sarah R. and Yeh, Jennifer E. and Liu, Suhu and Kroll, Yasmin and Boldin, Mark and Taganov, Konstantin and Groner, Bernd and Richardson , Andrea L. and Frank, David A. (2014) STAT3 Induction of miR-146b Forms a Feedback Loop to Inhibit the NF-kB to IL-6 Signaling Axis and STAT3-Driven Cancer Phenotypes. Science Signaling, 7 (310). Art. No. ra11. ISSN 1945-0877. PMCID PMC4233120.

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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 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 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-kB relevant to constitutive STAT3 activation in malignancy and the role of inflammation in oncogenesis.

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URLURL TypeDescription;7/310/ra11PublisherArticle CentralArticle
Additional Information:© 2014 American Association for the Advancement of Science. Submitted 8 July 2013. Accepted 29 December 2013. Final Publication 28 January 2014. We thank D. Baltimore for scientific input. Funding: This work was supported by a grant from the National Cancer Institute (R01-CA160979), the Brent Leahey Fund, and a Breast Cancer Research Foundation–American Association for Cancer Research grant for Translational Breast Cancer Research. This work was also supported by award numbers T32GM007753 and F30 CA165740-01 from the National Institute of General Medical Sciences. Author contributions: M.X. designed and performed the experiments, analyzed the data, and wrote the paper. N.J.B. and A.L.R. provided data and analyses pertaining to the human invasive breast cancer cohort. V.V. and B.G. performed the experiments relating to mouse mammary tissue. S.R.W., J.E.Y., S.L., Y.K., M.B., and K.T. performed the experiments and analyzed the data. D.A.F. designed the experiments, analyzed the data, and provided editorial input. Competing interests: The authors declare that they have no competing interests. Data and materials availability: Data from the miRNA screen are deposited in the Gene Expression Omnibus database under accession number GSE44089.
Funding AgencyGrant Number
Brent Leahey FundUNSPECIFIED
Breast Cancer Research FoundationUNSPECIFIED
NIH Predoctoral FellowshipT32GM007753
NIH Postdoctoral FellowshipF30 CA165740-01
National Cancer InstituteUNSPECIFIED
American Association for Cancer Research (AACR)UNSPECIFIED
Issue or Number:310
PubMed Central ID:PMC4233120
Record Number:CaltechAUTHORS:20140319-105046118
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Official 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-kB to IL-6 signaling axis and STAT3- driven cancer phenotypes. Sci. Signal. 7, ra11 (2014).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:44393
Deposited By: Ruth Sustaita
Deposited On:19 Mar 2014 20:08
Last Modified:03 Oct 2019 06:17

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