Genetic and epigenetic inactivation of T‐cadherin in human hepatocellular carcinoma cells

• Published in: International journal of cancer Vol. 123; no. 5; pp. 1043 - 1052
• Main Authors: Chan, David W., Lee, Joyce M.F., Chan, Patrick C.Y., Ng, Irene O.L.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-09-2008; Wiley-Liss
• Subjects: Acetylation - drug effects; Adult; Aged; Anticarcinogenic Agents - metabolism; Antimetabolites, Antineoplastic - pharmacology; Apoptosis - drug effects; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Biological and medical sciences; Blotting, Western; Cadherins - drug effects; Cadherins - genetics; Cadherins - metabolism; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Cell Cycle - drug effects; Cell Proliferation - drug effects; c‐Jun; DNA Methylation - drug effects; DNA Modification Methylases - antagonists & inhibitors; Down-Regulation; endothelial cells; Epigenesis, Genetic - drug effects; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic - drug effects; Gene Silencing - drug effects; HCC; hepatocellular carcinoma cells; Histone Deacetylase Inhibitors; Histones - metabolism; Humans; Hydroxamic Acids - pharmacology; hypermethylation; Immunohistochemistry; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; LOH; Loss of Heterozygosity; Male; Medical sciences; Middle Aged; Promoter Regions, Genetic; Proto-Oncogene Proteins c-jun - drug effects; Proto-Oncogene Proteins c-jun - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Tumors; T‐cadherin; underexpression; Up-Regulation; Endothelial cell; endothelial cells; hypermethylation; Hepatic disease; Hepatocellular carcinoma; Inactivation; Liver cancer; Cancerology; Genetics; hepatocellular carcinoma cells; underexpression; Protooncogene; Human; LOH; HCC; Malignant tumor; Cadherin; c-Jun; T-cadherin; C-Onc gene; Loss of heterozygosity; Epigenetics; Digestive diseases; Methylation; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.23634

T‐cadherin is an atypical cadherin and growing evidence has indicated that T‐cadherin exerts tumor‐suppressive effects on cancers of epithelial cell type and also causes positive effects on tumor angiogenesis. Human hepatocellular carcinoma (HCC) is a hypervascular tumor and T‐cadherin has been shown to be overexpressed in intratumoral endothelial cells of HCCs. However, the expression status and functions of T‐cadherin in hepatocytes or HCC cells remain unclear. Here, we demonstrated that T‐cadherin was underexpressed in HCC cells (26.5%, 13/49 cases), but was frequently (77.6%, 38/49) overexpressed in intratumoral endothelial cells immunohistochemically. Semiquantitative RT‐PCR analysis also showed that the T‐cadherin gene was underexpressed in 7 of 11 HCC cell lines. Loss of heterozygosity analysis revealed that 32–38% of the 42 human HCC samples had allelic losses at this locus. Upon pharmacological treatment with demethylating agent 5‐aza‐2′‐deoxycytidine or histone deacetylase inhibitor trichostatin A, T‐cadherin promoter hypermethylation and/or histone deacetylation was frequently observed in HCC samples and cell lines. Functionally, enforced expression of T‐cadherin induced G2/M cell cycle arrest, reduced cell proliferation in low serum medium, suppressed anchorage‐independent growth in soft agar and increased sensitivity to TNFα‐mediated apoptosis in HCC cells. Intriguingly, we found that T‐cadherin significantly suppressed the activity of c‐Jun, a crucial oncoprotein constitutively activated in HCC cells. To conclude, T‐cadherin was differentially expressed in human HCCs. The underexpression of T‐cadherin in HCC cells suggests it may be another critical event in addition to T‐cadherin‐mediated angiogenesis during HCC development. © 2008 Wiley‐Liss, Inc.