miR-146a is directly regulated by STAT3 in human hepatocellular carcinoma cells and involved in anti-tumor immune suppression

STAT3 signaling, a key pathway mediating immune suppression in the tumor microenvironment, is responsible for the transcription of several important miRNAs. In this study, we observed that miR-146a, a known important regulator of immune responses, was downregulated by blocking activated STAT3 in hepatocellular carcinoma (HCC) cells.

Furthermore, miR-146a inhibition in HCC cells not only altered the STAT3 activation–associated cytokine profile but also reversed HCC-induced NK cell dysfunction in vitro and improved the anti-tumor effect of lymphocytes in vivo. Importantly, ChIP and luciferase reporter assays confirmed that STAT3 directly bound to the miR-146a promoter and induced miR-146a expression. These findings indicated that miR-146a expression was regulated by aberrantly activated STAT3 in HCC cells and exerted negative effects on anti-tumor immune response, which resulted in the upregulation of cytokines such as TGF-β, IL-17, VEGF and downregulation of type I IFN to create an immunosuppressive microenvironment.