USP16 Downregulation by Carboxyl-terminal Truncated HBx Promotes the Growth of Hepatocellular Carcinoma Cells.
USP16 Downregulation by Carboxyl-terminal Truncated HBx Promotes the Growth of Hepatocellular Carcinoma Cells.
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羧基末端截短的 HBx 下调 USP16 促进肝细胞癌细胞的生长
DOI：
10.1038/srep33039
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发表时间：
2016-09-16
影响因子：
4.6
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Qian Y;Wang B;Ma A;Zhang L;Xu G;Ding Q;Jing T;Wu L;Liu Y;Yang Z;Liu Y
B型肝炎病毒（HBV）感染是导致肝细胞癌（HCC）发生的主要因素。HBV X蛋白（HBx）已被证明通过促进肿瘤生长和转移加速HCC进展。在临床上，羧基端截短的HBx（Ct-HBx）蛋白经常存在于HCC肿瘤组织中，但不存在于非肿瘤组织中。在这项研究中，我们分析了去泛素化酶的表达谱在细胞中有或没有异位表达的Ct-HBx蛋白，并观察到泛素特异性肽酶16（USP 16）的表达基本上抑制Ct-HBx蛋白。强制下调USP 16的肝肿瘤细胞表现出体内集落形成和肿瘤生长的能力增加。此外，USP 16抑制促进肿瘤细胞中的干细胞样特性，如其球状体形成和化学反应性所证明。此外，USP 16在肿瘤细胞中的异位表达显著消除了Ct-HBx蛋白（HBxΔ35）的促肿瘤活性，导致肿瘤细胞活力和肿瘤生长降低。在人类HCC中，USP 16经常下调，并且USP 16的表达降低与高肿瘤分期和低分化状态相关。综上所述，我们的研究表明，USP 16下调是Ct-HBx介导的促进HCC致瘤性和恶性的关键事件。
Hepatitis B virus (HBV) infection is a major factor that contributes to the development of hepatocellular carcinoma (HCC). HBV X protein (HBx) has been shown to accelerate HCC progression by promoting tumour growth and metastasis. In the clinic, carboxyl-terminal truncated HBx (Ct-HBx) proteins are frequently present in HCC tumour tissues, but not in non-tumorous tissues. In this study, we analysed deubiquitinase expression profiles in cells with or without ectopic expression of the Ct-HBx proteins and observed that the expression of ubiquitin specific peptidase 16 (USP16) was substantially inhibited by Ct-HBx proteins. Liver tumour cells with forced down-regulation of USP16 exhibited increased capabilities for colony formation and tumour growthin vivo. In addition, USP16 inhibition promoted stem-like properties in tumour cells, as evidenced by their spheroid formation and chemo-responsiveness. Furthermore, ectopic expression of USP16 in tumour cells significantly abrogated the tumour promoting activities of the Ct-HBx proteins (HBxΔ35), leading to decreased tumour cell viability and tumour growth. In human HCCs, USP16 was frequently downregulated, and the decreased expression of USP16 was correlated with high tumour stages and poor differentiation status. Taken together, our study suggests that USP16 downregulation is a critical event in Ct-HBx-mediated promotion of HCC tumorigenicity and malignancy.