Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1
Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1
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DOI：
10.1038/sj.onc.1208827
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发表时间：
2005-10-06
期刊：
影响因子：
8
通讯作者：
Jang, KL
中科院分区：
文献类型：
--
作者：
Lee, JO;Kwun, HJ;Jang, KL
E-钙粘附素是一种关键的细胞黏附分子，被认为是一种肿瘤抑制因子，在肝细胞癌，尤其是与乙肝病毒相关的肿瘤中经常发生改变。在此，我们报道了HBx蛋白在转录水平上抑制E-钙粘蛋白的表达。基于HBx天然变异体的不同作用，我们确定HBx反式激活结构域中的Lys-130对E-钙粘附素的抑制是至关重要的。经DNA甲基转移酶抑制剂5‘-aza-2’DC处理后，HBx的抑制作用被取消。此外，甲基化特异性的聚合酶链式反应显示E-钙粘蛋白启动子的CpG岛1被HBx高甲基化。此外，HBx通过刺激DNA甲基转移酶1的转录来诱导其表达。因此，我们得出结论，HBx通过诱导甲基化介导的启动子失活来抑制E-钙粘素的表达。E-钙粘附素表达减少导致HBx表达细胞的形态发生显著变化。此外，表达HBx的细胞在悬浮培养中聚集得很差，反映了它们细胞间相互作用的变化。表达HBx的细胞具有更强的胶原侵袭能力，进一步证明了其生物学意义。因此，本研究提示，HBx在肝细胞癌的发生过程中，通过促进细胞与周围细胞的分离和向原发肿瘤部位以外的转移而发挥作用。
E-cadherin is a key cell adhesion molecule implicated as a tumor suppressor, which is frequently altered in hepatocellular carcinoma, especially in hepatitis B virus (HBV)-related tumors. Here, we report that HBV X protein (HBx) represses E-cadherin expression at the transcription level. Based on the differential effects of HBx natural variants, we determined that Lys-130 in the transactivation domain of HBx is critical for the E-cadherin repression. The repression effect of HBx was abolished after treatment with DNA methyltransferase inhibitor, 5'-Aza-2'dC. In addition, methylation-specific PCR analysis revealed that the CpG island 1 of E-cadherin promoter is hypermethylated by HBx. Furthermore, HBx induces DNA methyltransferase 1 expression by stimulating its transcription. Therefore, we conclude that HBx represses E-cadherin expression by inducing methylation-mediated promoter inactivation. The reduced E-cadherin expression results in dramatic morphological changes of the HBx-expressing cells. In addition, HBx-expressing cells aggregate poorly in suspension culture, reflecting their altered intercellular interactions. The biological significance was further demonstrated by the increased collagen invasion ability of HBx-expressing cells. Therefore, the present study suggests that HBx plays a role during hepatocellular carcinogenesis by favoring cell detachment from the surrounding cells and migration outside of the primary tumor site.