RIG-I inhibits HCC carcinogenesis and enhances patient survival and IFN-α treatment response.
Major Finding: RIG-I inhibits HCC carcinogenesis and enhances patient survival and IFN-α treatment response.
Concept: Downstream of IFN-α, RIG-I increases STAT1 activity, leading to proapoptotic gene expression.
Impact: HCC patients harboring tumors with high RIG-I levels may benefit from IFN-α treatment.
Hepatocellular carcinoma (HCC) is highly intractable and characterized by gender disparity, with higher incidence and lower survival rates in men. Therapeutic options for HCC are limited, as treatment with interferon-α (IFN-α), an immunotherapy that activates the Janus kinase (JAK)/STAT signaling cascade, is only efficacious in a subset of patients. To discover potential biomarkers for predicting survival and IFN-α clinical response, Hou and colleagues analyzed samples from 443 Chinese patients with HCC, the majority of whom presented with chronic hepatitis B infection. Retinoic acid-inducible gene-I (RIG-I), an IFN-stimulated gene (ISG), was significantly reduced in primary HCC samples compared with matched nontumor tissues. RIG-I reduction could be attributed, at least in part, to altered histone modifications at the RIG1 gene locus. Importantly, low RIG-I expression was correlated with decreased disease-free and overall survival, as well as diminished IFN-α clinical response. RIG-I altered IFN-α efficacy via increased STAT1 activation and subsequent upregulation of downstream proapoptotic ISGs in vitro and in vivo; RIG-I interacted with STAT1 and impeded the binding of the phosphatase SHP1, leading to increased STAT1 tyrosine phosphorylation and activity. Genetic deletion of RIGI enhanced the incidence and growth of liver tumors in an inducible HCC mouse model system, suggesting that RIG-I suppresses HCC initiation and progression. In addition, RIG-I expression was lower in normal male liver tissue compared with female livers in mice and humans, and thus may contribute to the increased HCC carcinogenesis and poor prognosis seen in male patients. Taken together, these results indicate that RIG-I is a potential tumor suppressor in HCC and should be examined in more diverse patient cohorts as a potential predictive biomarker for IFN-α treatment efficacy.