HBx protein-mediated ATOH1 downregulation suppresses ARID2 expression and promotes hepatocellular carcinoma.
HBx protein-mediated ATOH1 downregulation suppresses ARID2 expression and promotes hepatocellular carcinoma.
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HBx蛋白介导的ATOH1下调抑制ARID2表达并促进肝细胞癌
DOI：
10.1111/cas.13277
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发表时间：
2017-07
期刊：
影响因子：
5.7
通讯作者：
Tang N
中科院分区：
文献类型：
--
作者：
Gao Q;Wang K;Chen K;Liang L;Zheng Y;Zhang Y;Xiang J;Tang N
乙型肝炎病毒X蛋白在肝细胞癌的发病中起着至关重要的作用。我们之前发现肿瘤抑制因子ARID2抑制肝癌细胞周期进展和肿瘤生长。在这里，我们评估了乙型肝炎病毒X蛋白是否参与了ARID2表达的调节以及与乙型肝炎病毒感染相关的肝癌发生。在HBV -复制型肝癌细胞、HBV转基因小鼠和HBV -相关临床HCC组织中，ARID2表达下调。HBx在肝细胞癌组织中的表达水平与ARID2的表达水平呈负相关。此外，HBx在转录水平上抑制ARID2。机制上，被HBx抑制的ARID2基因的启动子区域位于nt‐1040/nt‐601，包含潜在的ATOH1结合元件。此外，ATOH1的异位表达或ARID2启动子内ATOH1结合位点的突变部分消除了HBx‐触发的ARID2转录抑制。功能上，ARID2消除了HBx增强的肝癌细胞迁移和增殖，而ATOH1的缺失增强了HCC细胞的致瘤性。因此，我们的研究结果表明，HBx通过ATOH1解除ARID2的调控可能参与了HBV相关肝细胞癌的发展。
Hepatitis B virus X protein plays a crucial role in the pathogenesis of hepatocellular carcinoma. We previously showed that the tumor suppressor ARID2 inhibits hepatoma cell cycle progression and tumor growth. Here, we evaluated whether hepatitis B virus X protein was involved in the modulation of ARID2 expression and hepatocarcinogenesis associated with hepatitis B virus infection. ARID2 expression was downregulated in HBV‐replicative hepatoma cells, HBV transgenic mice, and HBV‐related clinical HCC tissues. The expression levels of HBx were negatively associated with those of ARID2 in hepatocellular carcinoma tissues. Furthermore, HBx suppressed ARID2 at transcriptional level. Mechanistically, the promoter region of ARID2 gene inhibited by HBx was located at nt‐1040/nt‐601 and contained potential ATOH1 binding elements. In addition, ectopic expression of ATOH1 or mutation of ATOH1 binding sites within ARID2 promoter partially abolished HBx‐triggered ARID2 transcriptional repression. Functionally, ARID2 abrogated HBx‐enhanced migration and proliferation of hepatoma cells, whereas depletion of ATOH1 enhanced tumorigenecity of HCC cells. Therefore, our findings suggested that deregulation of ARID2 by HBx through ATOH1 may be involved in HBV‐related hepatocellular carcinoma development.