Characterization of H-cadherin expression in human hepatocellular carcinoma

Abstract

Cadherins are a superfamily of adhesion molecules that mediate Ca2+-dependent cell-cell adhesion in all solid tissues and tumors and are now known to be involved in many biological processes. H-cadherin, located on 16q24.2-3, is different from all the other known cadherins as it lacks the conventional transmembrane and cytoplasmic domains and is anchored to the membrane by a glycosylphosphatidylinositol anchor. Hepatocellular carcinoma (HCC) is a prevalent cancer worldwide and also in Southeast Asia and Hong Kong. In HCC, frequent chromosomal loss has been reported on 16q. In this study, we aimed to investigate the role of H-cadherin in hepatocarcinogenesis. We evaluated its expression and localization patterns, and investigated the factors that may induce the expression of H-cadherin in HCC. Results: Seven of the eleven HCC cell lines tested showed loss or weak mRNA expression of H-cadherin. However, in human HCCs, the tumors showed frequent (52%) higher levels of the H-cadherin mRNA expression (≥ 2 folds) as compared with those in the corresponding nontumorous livers. Using immunohistochemical method, we observed that the majority (65%) of human HCCs stained negative for H-cadherin. Even in those cases which were positive, the staining was very patchy. Instead, the endothelial cells of the microvessels within the tumors showed frequent expression of H-cadherin immunohistochemically. This was in contrast to the rare expression of H-cadherin in the sinusoidal endothelial cells in the corresponding nontumorous livers. Thus, while the HCC cells showed an underexpression of H-cadherin, the increased expression of H-cadherin in the microvessels within the tumors likely accounted for the frequent overexpression H-cadherin mRNA overall observed in the HCC samples. Furthermore, treatment with a DNA methyltransferase inhibitor, 5-aza-2’ deoxycytidine (5-Aza-dC), induced H-cadherin expression in the HCC cell lines that underexpressed H-cadherin. This suggests that hypermethylation partly contributes to gene silencing, in keeping with frequent silencing of the gene by aberrant methylation in other cancers such as the breast, colon, ovary and lung. In conclusion, H-cadherin is underexpressed in HCC cell lines and human HCC, and hypermethylation is a factor contributing to this underexpression. In addition, in view of the differential expression in intratumoral microvessels of HCC, elucidation of the function of H-cadherin may give important insights into the mechanism of angiogenesis.