Chan David W, Lee Joyce M F, Chan Patrick C Y, Ng Irene O L
Liver Cancer and Hepatitis Research Laboratory and SH Ho Foundation Research Laboratories, Department of Pathology, The University of Hong Kong, Hong Kong, China.
Int J Cancer. 2008 Sep 1;123(5):1043-52. 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 G(2)/M cell cycle arrest, reduced cell proliferation in low serum medium, suppressed anchorage-independent growth in soft agar and increased sensitivity to TNFalpha-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.
T-钙黏蛋白是一种非典型钙黏蛋白，越来越多的证据表明，T-钙黏蛋白对上皮细胞类型的癌症具有肿瘤抑制作用，并且对肿瘤血管生成也有积极影响。人类肝细胞癌（HCC）是一种血管丰富的肿瘤，T-钙黏蛋白已被证明在HCC的瘤内内皮细胞中过表达。然而，T-钙黏蛋白在肝细胞或HCC细胞中的表达状态和功能仍不清楚。在此，我们证明T-钙黏蛋白在HCC细胞中表达下调（26.5%，13/49例），但在瘤内内皮细胞中免疫组化显示经常过表达（77.6%，38/49）。半定量RT-PCR分析还表明，11种HCC细胞系中有7种T-钙黏蛋白基因表达下调。杂合性缺失分析显示，42例人类HCC样本中有32 - 38%在该位点存在等位基因缺失。在用去甲基化剂5-氮杂-2'-脱氧胞苷或组蛋白脱乙酰酶抑制剂曲古抑菌素A进行药物处理后，在HCC样本和细胞系中经常观察到T-钙黏蛋白启动子高甲基化和/或组蛋白去乙酰化。在功能上，T-钙黏蛋白的强制表达诱导G(2)/M期细胞周期阻滞，降低低血清培养基中的细胞增殖，抑制软琼脂中不依赖贴壁的生长，并增加HCC细胞对TNFα介导的凋亡的敏感性。有趣的是，我们发现T-钙黏蛋白显著抑制c-Jun的活性，c-Jun是一种在HCC细胞中持续激活的关键癌蛋白。总之，T-钙黏蛋白在人类HCC中存在差异表达。T-钙黏蛋白在HCC细胞中的低表达表明，它可能是HCC发生过程中除T-钙黏蛋白介导的血管生成之外的另一个关键事件。
