β‐Catenin and HCC phenotype in mice and men

Abstract

Aberrant activation of β‐catenin is evident in subset of hepatocellular carcinomas (HCCs). Biomax HCC tissue‐array of 89 cases was assessed for β‐catenin, glutamine synthetase (GS), PCNA, CD45, and Sirius Red staining. Hepatocyte‐specific‐ser45‐mutated β‐catenin transgenic (TG) mice were used to study the impact of β‐catenin mutation on thioacetamide (TAA) induced hepatic fibrosis and tumorigenesis. We identified a significant correlation between inflammation, fibrosis and proliferation in HCC. Aberrant nuclear/cytoplasmic localization of β‐catenin was associated with increased inflammation (p=0.03) and GS immunoreactivity (p=0.02). Cytoplasmic β‐catenin was only marginally associated with GS and fibrosis, but significantly with inflammation (p=0.03). Nuclear β‐catenin was associated with reduced fibrosis (p=0.04) and GS (p<0.01). TG mice exposed to TAA showed no early or enhanced HCC. We also observed 15.5% of HCCs lacking β‐catenin staining displaying low inflammation and fibrosis (p<0.05). Thus, nuclear β‐catenin is associated with decreased fibrosis and β‐catenin mutations do not promote fibrosis‐induced HCC in mice. β‐Catenin mutations and fibrosis may be two independent mechanisms of HCC. Increased inflammation associated with cytoplasmic but not nuclear β‐catenin implicates inflammation as a cause of β‐catenin mislocalization.