β-Catenin signaling in hepatocellular cancer: Implications in inflammation, fibrosis, and proliferation.
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.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Jung Min
JM
Lee
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Jing
J
Yang
Hepatobiliary and Pancreatic Surgery Program, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
Pippa
P
Newell
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Sucha
S
Singh
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Anil
A
Parwani
Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Scott L
SL
Friedman
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Kari Nichole
KN
Nejak-Bowen
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: smonga@pitt.edu.
Satdarshan P
SP
Monga
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D005355:Fibrosis / Q000473:pathology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*
D051176:beta Catenin; D005974:Glutamate-Ammonia Ligase
Fibrosis; Glutamine synthetase; Hepatocellular carcinoma; Inflammation; Proliferation; β-Catenin