β-Catenin signaling in hepatocellular cancer: Implications in inflammation, fibrosis, and proliferation

beta-Catenin signaling is implicated in hepatocellular carcinoma (HCC), although its role in inflammation, fibrosis, and proliferation is unclear. Commercially available HCC tissue microarray (TMA) of 89 cases was assessed for beta-catenin, one of its transcriptional targets glutamine synthetase (GS), proliferation (PCNA), inflammation (CD45), and fibrosis (Sirius Red). HCC cells transfected with wild-type (WT) or mutant-p-catenin were evaluated for beta-catenin-T cell factor transactivation by TOPFlash reporter activity and expression of certain targets. Hepatocyte-specific-serine-45-mutated beta-catenin transgenic mice (TG) and controls (Con) were used to study thioacetamide (TAA)-induced hepatic fibrosis and tumorigenesis. Sustained beta-catenin activation was only observed in mutant-, not WT-beta-catenin transfected HCC cells. Aberrant intratumoral beta-catenin stabilization was evident in 33% cases with 9% showing predominant nuclear with some cytoplasmic (N/C) localization and 24% displaying predominant cytoplasmic with occasional nuclear (C/N) localization. N/C beta-catenin was associated with reduced fibrosis (p = 0.017) and tumor-wide GS staining (p < 0.001) while C/N correlated with increased intratumoral inflammation (p = 0.064) and proliferation (p = 0.029). A small subset of HCC patients (15.5%) lacked beta-catenin staining and exhibited low inflammation and fibrosis (p < 0.05). TG and Con mice exposed to TAA showed comparable development of fibrosis and progression to cirrhosis and HCC. Taken together the data suggests a complex relationship of beta-catenin, inflammation, fibrosis and HCC. GS staining is highly sensitive in identifying HCC with nuclear beta-catenin, which may in turn represent beta-catenin mutations, and does so with high negative predictive value. Also, beta-catenin mutations and cirrhosis do not appear to cooperate in HCC pathogenesis in mice and men. (C) 2013 Elsevier Ireland Ltd. All rights reserved.