title: miR-146a is directly regulated by STAT3 in human hepatocellular carcinoma cells and involved in anti-tumor immune suppression.
abstract: MicroRNAs (miRNAs) play an important role in tumorigenesis, but their role in tumor-induced immune suppression is largely unknown. 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. This further insight into understanding the mechanism responsible for tumor-induced immune suppression highlights the potential application of miR-146a as a novel immunotherapeutic target for HCC.
authors.affiliation: a Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences ; Shandong University ; Jinan , Shandong Province , China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Sun
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Hou
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Han
authors.forename: Cai
authors.initials: C
authors.lastname: Zhang
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002470:Cell Survival; D056945:Hep G2 Cells; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology / Q000628:therapy; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D020381:Interleukin-17; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A
keywords: HCC; STAT3; anti-tumor immune suppression; miR-146a; miRNA