Sci. Signal., 28 January 2014
Micro-Mediated FeedbackChronic inflammation and interleukin-6 (IL-6), which is produced in response to nuclear factor B (NF-B) signaling, is a proinflammatory cytokine associated with cancer. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor stimulated in response to IL-6 and its receptor-bound kinases from the Janus kinase (JAK) family. Xiang et al. found that STAT3 stimulated expression of the gene encoding the microRNA miR-146b, which inhibited NF-B–mediated induction of IL-6 to prevent a proinflammatory response in normal breast epithelial cells. However, promoter methylation reduced miR-146b expression in breast cancer cell lines and patient tissue, and its expression correlated with survival in patients with estrogen receptor– or triple-negative breast cancer. In addition to inhibiting STAT3 activity and cell migration and invasion, introduction of a miR-146b mimic was as cytotoxic as pharmacological inhibition of JAK to triple-negative breast cancer cells in culture, and combination therapy in cells was additive. The findings suggest that therapies reintroducing or stimulating miR-146b production may be beneficial to patients with tumors with high STAT3 activity.
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-B to IL-6 Signaling Axis and STAT3-Driven Cancer Phenotypes. Sci. Signal. 7, ra11 (2014).
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