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

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.

miR-146b-5p within BCR-ABL1–Positive Microvesicles Promotes Leukemic Transformation of Hematopoietic Cells

“…MiR-146a plays functional roles in hematopoiesis and innate immune responses, as a tumor suppressor in many solid tumors (44,45). MiR-146b was found to function in thyroid cancer and glioma by targeting the TGFb pathway and NFkB, and also targeted by TF STATs (41,46,47). Our work demonstrated that increasing miR-146b-5p in K562-MVs could accelerate the transformation (Table 1).…”

Pyruvate kinase M2 accelerates pro-inflammatory cytokine secretion and cell proliferation induced by lipopolysaccharide in colorectal cancer

“…The importance of STAT3 activation in regulation of inflammatory cytokines has also been demonstrated in various cancers [38,39]. Our previous studies showed that PKM2 overexpression increased STAT3 gene transcription and STAT3 was required for the regulation of migration and adhesion associated signallings [16].…”

Exogenous oxytocin modulates human myometrial microRNAs

“…32 In this context, hsa-miR-146b-3p is thought to function in a negative feedback loop, whereby its induction by both interleukin-6 and signal transducer and activator of transcription 3 result in the inhibition of both NF-kB-dependent IL6 expression and downstream activation of signal transducer and activator of transcription 3. 33 Interleukin-6 is a key inflammatory mediator in parturition and stimulates cervical and fetal membrane remodeling. Thus, increased expression of hsa-miR-146b-3p in response to labor may represent a homeostatic response to the raised inflammatory mediators accompanying labor, such as interleukin-6.…”