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

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.
AuthorsJung Min Lee, Jing Yang, Pippa Newell, Sucha Singh, Anil Parwani, Scott L Friedman, Kari Nichole Nejak-Bowen, Satdarshan P Monga
JournalCancer letters (Cancer Lett) Vol. 343 Issue 1 Pg. 90-7 (Feb 01 2014) ISSN: 1872-7980 [Electronic] Ireland
PMID24071572 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • beta Catenin
  • Glutamate-Ammonia Ligase
Topics
  • Animals
  • Carcinoma, Hepatocellular (metabolism)
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytoplasm (metabolism)
  • DNA Methylation
  • Female
  • Fibrosis (pathology)
  • Glutamate-Ammonia Ligase (metabolism)
  • Humans
  • Immunohistochemistry
  • Inflammation
  • Liver Neoplasms (metabolism)
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation
  • Signal Transduction
  • beta Catenin (metabolism)

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