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Cancer Lett. 2014 Feb 1;343(1):90-7. doi: 10.1016/j.canlet.2013.09.020. Epub 2013 Sep 23.

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

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  • 1Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 2Hepatobiliary and Pancreatic Surgery Program, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
  • 3Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
  • 4Department 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.

Abstract

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.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

KEYWORDS:

Fibrosis; Glutamine synthetase; Hepatocellular carcinoma; Inflammation; Proliferation; β-Catenin

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