Department of General Surgery, Zhujiang Hospital of Southern Medical University, NO. 253 Guangzhou Industrial Avenue, Guangzhou 510282, Guangdong Province, China; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, NO. 78 Hengzhigang Road, Guangzhou 510095, Guangdong, China.
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, NO. 78 Hengzhigang Road, Guangzhou 510095, Guangdong, China.
Exp Cell Res. 2018 Feb 15;363(2):218-226. doi: 10.1016/j.yexcr.2018.01.011. Epub 2018 Jan 10.
The poor outcome of hepatocellular carcinoma (HCC) is mainly due to the development of fast growth, invasion and metastasis. The role of TET2 has been implicated in some cancer types, but its role and mechanisms in HCC remains elusive. In this study, our findings indicated that TET2 expression frequently increased in HCC and that TET2 expressional upregulation correlated with HCC progression. TET2 knockdown inhibited HCC cells proliferation in vitro and growth in vivo, and inhibited the invasion potential of HCC cells. Mechanically, TET2 knockdown upregulated E-cadherin expression and then attenuated β-catenin transactivation in HCC cells. TET2 repressed E-cadherin expression via recruited HDAC1 to E-cadherin promoter to reduce the H3K9Ac and H4K16Ac levels. Moreover, β-catenin signaling transcriptionally regulated TET2 expression to form a positive feedback in HCC cells. These findings indicate that the dysregulation of TET2/E-cadherin/β-catenin regulatory loop is a critical oncogenic event in HCC progression.
肝细胞癌（HCC）预后较差，主要是由于其生长迅速、侵袭和转移。TET2 在一些癌症类型中发挥作用，但它在 HCC 中的作用和机制仍不清楚。在这项研究中，我们的研究结果表明，TET2 在 HCC 中频繁表达增加，并且 TET2 的表达上调与 HCC 的进展相关。TET2 敲低抑制 HCC 细胞在体外的增殖和体内的生长，并抑制 HCC 细胞的侵袭潜力。机制上，TET2 敲低通过募集 HDAC1 到 E-钙黏蛋白启动子来抑制 HCC 细胞中 E-钙黏蛋白的表达，从而降低 H3K9Ac 和 H4K16Ac 水平。此外，β-连环蛋白信号转导转录调控 TET2 的表达，在 HCC 细胞中形成正反馈。这些发现表明，TET2/E-钙黏蛋白/β-连环蛋白调节环的失调是 HCC 进展中的一个关键致癌事件。
