STAT3 induction of miR-146b forms a feedback loop to inhibit the NF-κB to IL-6 signaling axis and STAT3-driven cancer phenotypes.
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.
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Michael
M
Xiang
Nicolai J
NJ
Birkbak
Vida
V
Vafaizadeh
Sarah R
SR
Walker
Jennifer E
JE
Yeh
Suhu
S
Liu
Yasmin
Y
Kroll
Mark
M
Boldin
Konstantin
K
Taganov
Bernd
B
Groner
Andrea L
AL
Richardson
David A
DA
Frank
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
C508600:IL6 protein, human; D015850:Interleukin-6; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human