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

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

SUBMITTER: Lee JM

PROVIDER: S-EPMC3874258 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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

Lee Jung Min JM Yang Jing J Newell Pippa P Singh Sucha S Parwani Anil A Friedman Scott L SL Nejak-Bowen Kari Nichole KN Monga Satdarshan P SP

Cancer letters 20130923 1

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 ...[more]

PMID: 24071572

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Dataset Information

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

Publications

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

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