β-
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 β-
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-β-
catenin were evaluated for β-
catenin-
T cell factor transactivation by TOPFlash reporter activity and expression of certain targets. Hepatocyte-specific-serine-45-mutated β-
catenin transgenic mice (TG) and controls (Con) were used to study
thioacetamide (TAA)-induced hepatic
fibrosis and
tumorigenesis. Sustained β-
catenin activation was only observed in mutant-, not WT-β-
catenin transfected HCC cells. Aberrant intratumoral β-
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 β-
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 β-
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 β-
catenin,
inflammation,
fibrosis and HCC. GS staining is highly sensitive in identifying HCC with nuclear β-
catenin, which may in turn represent β-
catenin mutations, and does so with high negative predictive value. Also, β-
catenin mutations and
cirrhosis do not appear to cooperate in HCC pathogenesis in mice and men.