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Disregulation of E-cadherin in transgenic mouse models of liver cancer

Calvisi, Diego Francesco and Ladu, Sara and Conner, Elizabeth A. and Factor, Valentina M. and Thorgeirsson, Snorri S. (2004) Disregulation of E-cadherin in transgenic mouse models of liver cancer. Laboratory Investigation, Vol. 84 , p. 1137-1147. eISSN 1530-0307. Article.

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DOI: 10.1038/labinvest.3700147

Abstract

E-cadherin is a cell–cell adhesion molecule that plays a pivotal role in the development and maintenance of cell polarity. Disruption of E-cadherin-mediated adhesion represents a key step toward the invasive phenotype in a variety of solid tumors, including hepatocellular carcinoma (HCC). Here, we investigate whether deregulation of E-cadherin occurs along the multistep process of hepatocarcinogenesis in transgenic mouse models, including c-Myc, E2F1, c-Myc/TGF-α and c-Myc/E2F1 mice. Liver tumors from the transgenic mouse lines could be divided into two categories based on E-cadherin levels. Of 28, 20 (71.4%) c-Myc HCCs showed marked reduction of E-cadherin expression when compared with wild-type livers. In contrast, all of c-Myc/TGF-α and the majority of E2F1 and c-myc/E2F1 preneoplastic and neoplastic lesions exhibited overexpression of E-cadherin. Downregulation of E-cadherin was associated with promoter hypermethylation in seven of 20 c-Myc HCCs (35%), while no loss of heterozygosity at the E-cadherin locus was detected. Nuclear accumulation of β-catenin did not correlate with E-cadherin downregulation. Furthermore, c-Myc HCCs with reduced E-cadherin displayed upregulation of hypoxia-inducible factor-1α and vascular endothelial growth factor proteins. Importantly, loss of E-cadherin was associated with increased cell proliferation and higher microvessel density in c-Myc tumors. Taken together, these data suggest that loss of E-cadherin might favor tumor progression in relatively more benign HCC from c-Myc transgenic mice by stimulating neoplastic proliferation and angiogenesis under hypoxic conditions.

Item Type:Article
ID Code:1264
Status:Published
Refereed:Yes
Uncontrolled Keywords:Angiogenesis, β-catenin, E-cadherin, HCC, hypoxia, transgenic mice
Subjects:Area 06 - Scienze mediche > MED/04 Patologia generale
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Nature Publishing Group
eISSN:1530-0307
Copyright Holders:© 2004 USCAP
Additional Information:Pubblicato online il 28 giugno 2004.
Deposited On:18 Aug 2009 10:04

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