The Matricellular Protein CCN1 Suppresses Hepatocarcinogenesis by Inhibiting Compensatory Proliferation

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and is on the rise in the United States. Previous studies showed that the matricellular protein CCN1 (CYR61) is induced during hepatic injuries and functions to restrict and resolve liver fibrosis. Here we show that CCN1 suppresses hepatocarcinogenesis by inhibiting carcinogen-induced compensatory hepatocyte proliferation, thus limiting the expansion of damaged and potentially oncogenic hepatocytes. Consistent with tumor suppression, CCN1 expression is down-regulated in human HCC. Ccn1(ΔHep) mice with hepatocyte-specific deletion of Ccn1 suffer increased HCC tumor multiplicity induced by the hepatocarcinogen diethylnitrosoamine (DEN). Knockin mice (Ccn1(dm/dm)) that express an integrin α(6)β(1)-binding defective CCN1 phenocopied Ccn1(ΔHep) mice, indicating that CCN1 acts through its α(6)β(1) binding sites in this context. CCN1 effectively inhibits EGFR-dependent hepatocyte proliferation through integrin α(6)-mediated accumulation of reaction oxygen species (ROS), thereby triggering p53 activation and cell cycle block. Consequently, Ccn1(dm/dm) mice exhibit diminished p53 activation and elevated compensatory hepatocyte proliferation, resulting in increased HCC. Furthermore, we show that a single dose of the EGFR inhibitor erlotinib delivered prior to DEN-induced injury was sufficient to block compensatory proliferation and annihilate development of HCC nodules observed 8 months later, suggesting potential chemoprevention by targeting CCN1-inhibitable EGFR-dependent hepatocyte proliferation. Together, these results show that CCN1 is an injury response protein that functions not only to restrict fibrosis in the liver, but also to suppress hepatocarcinogenesis by inhibiting EGFR-dependent hepatocyte compensatory proliferation.