IGF-II induced by hepatitis B virus X protein regulates EMT via SUMO mediated loss of E-cadherin in mice.
IGF-II induced by hepatitis B virus X protein regulates EMT via SUMO mediated loss of E-cadherin in mice.
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DOI：
10.18632/oncotarget.10922
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发表时间：
2016-08-30
期刊：
影响因子：
--
通讯作者：
Yu DY
中科院分区：
文献类型：
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作者：
Ha HL;Kwon T;Bak IS;Erikson RL;Kim BY;Yu DY
肝细胞癌（HCC）是最常见的癌症之一，也是癌症死亡的主要原因。这种疾病的预后很大程度上取决于其阶段。由于发育不良而导致的肝脏肿大可能是多步进展为 HCC 的关键点。人类和小鼠模型中肝肿大的机制尚不清楚。我们之前报道过，我们在表达乙型肝炎病毒 X 蛋白 (HBx) 的小鼠（HBx 小鼠）中观察到肝脏肿大。在这里，我们确定了 HBx 诱导的 IGF-II 在小鼠肝肿大和人肝癌细胞异常细胞生长中的关键作用。我们发现 HBx 诱导的 IGF-II 对于通过 E-钙粘蛋白的损失诱导上皮间质转化 (EMT) 至关重要。在小鼠肝脏中，E-钙粘蛋白的丢失是由翻译后调节介导的，至少部分是由蛋白酶和 SUMO 化介导的，而不是由转录调节介导的。相反，在肝癌细胞系（HepG2细胞）中，Akt信号通路除了通过SUMO化进行翻译后修饰外，还控制EMT相关转录因子（尤其是Twist）的mRNA表达水平。因此，IGF-II介导的E-钙粘蛋白缺失是小鼠肝肿大和肝癌细胞系异常细胞生长的核心。 HBx 诱导的 IGF-II 是一种潜在的生物标志物，也是 HCC 的治疗靶点。
Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of cancer mortality. Prognosis of this disease largely depends on its stage. An Enlarged liver, due to dysplasia, may be a critical point in the multi-step progression to HCC. The mechanism underlying hepatomegaly in human and mouse models are poorly understood. We previously reported we observed enlarged liver in hepatitis B virus X protein (HBx) expressing mice (HBx mice). Here we identify the critical role of HBx induced IGF-II in hepatomegaly in mice and abnormal cell growth in human hepatoma cells. We found that HBx induced IGF-II is essential to induce epithelial-mesenchymal transition (EMT) through loss of E-cadherin. In mouse liver, loss of E-cadherin was mediated by post-translational regulation, at least in part, by protease and SUMOylation not by transcriptional regulation. In contrast, in hepatoma cell line (HepG2 cells) Akt signal pathway controls the mRNA expression level of EMT-related transcription factors, especially Twist, in addition to post- translational modification through SUMOylation. Thus, IGF-II-mediated loss of E-cadherin is central in developing hepatomegaly in mice and abnormal cell growth in the hepatoma cell line. HBx induced IGF-II represents a potential biomarker, which is also a therapeutic target in HCC.