NFATc3 inhibits hepatocarcinogenesis and HBV replication via positively regulating RIG-I-mediated interferon transcription

Nuclear factor of activated T cells 3 (NFATc3) has been reported to upregulate type I interferons (IFNs) expression, and the abnormal expression and activation of NFATc3 were closely related to tumorigenesis. However, the potential function of NFATc3 in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains to be elucidated. In this study, we found that NFATc3 gene was frequently deleted and downregulated in HCC tumor tissues, and that the downregulation of NFATc3 was associated with poor prognosis of HCC patients. The gain- and loss-of-function experiments demonstrated that NFATc3 inhibited HCC cell proliferation and invasion, as well as HBV replication. Mechanistically, NFATc3 could bind to the promoters of IFNL1 and IFNB1 genes and prompt the production of IFNs and interferon-stimulated genes. Furthermore, retinoic acid-inducible gene-I (RIG-I) pathway activation increased NFATc3 expression and nuclear localization, and activated NFATc3 further enhanced RIG-I-mediated IFN responses. Collectively, our findings reveal a novel regulatory signaling cascade, the RIG-I/NFATc3/IFNs axis, which inhibits hepatocarcinogenesis and HBV replication by enhancing the immune response in hepatocytes, and this functional axis might potentially be exploited for therapeutic benefits in the clinical treatment of HBV-related HCC.