Ubiquitin-Specific Protease 7 Accelerates p14ARF Degradation by Deubiquitinating Thyroid Hormone Receptor-Interacting Protein 12 and Promotes Hepatocellular Carcinoma Progression
Ubiquitin-Specific Protease 7 Accelerates p14ARF Degradation by Deubiquitinating Thyroid Hormone Receptor-Interacting Protein 12 and Promotes Hepatocellular Carcinoma Progression
复制标题
泛素特异性蛋白酶 7 通过使甲状腺激素受体相互作用蛋白 12 去泛素化来加速 p14 (ARF) 降解，并促进肝细胞癌进展。
DOI：
10.1002/hep.27682
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发表时间：
2015-05-01
期刊：
影响因子：
13.5
通讯作者：
Fan, Jia
中科院分区：
文献类型：
--
作者：
Cai, Jia-Bin;Shi, Guo-Ming;Fan, Jia
就总生存期（OS）而言，肝细胞癌（HCC）的预后仍然不佳，其分子发病机制尚未完全明确。在这里，我们报告去泛素化酶泛素特异性蛋白酶 7 (USP7) 在人类 HCC 组织中的表达高于匹配的瘤周组织。 USP7 异位表达可促进体内和体外 HCC 细胞的生长。从机制上讲，USP7 过表达通过与甲状腺激素受体相互作用蛋白 12 (TRIP12) 形成复合物并稳定甲状腺激素受体相互作用蛋白 12 (TRIP12)，从而诱导组成型 p14(ARF) 泛素化，从而促进 HCC 细胞生长。临床上，USP7过表达与恶性表型显着相关，包括肿瘤体积较大、肿瘤多发、分化差、甲胎蛋白升高和微血管侵犯。此外，USP7和/或TRIP12的过度表达与较短的OS和较高的HCC累积复发率相关。结论：USP7通过去泛素化稳定TRIP12，从而组成性失活p14（ARF）并促进HCC进展。这代表了预测预后的新标志物和 HCC 的潜在治疗靶点。 （肝病学2015；61：1603-1614）
The prognosis for hepatocellular carcinoma (HCC) remains dismal in terms of overall survival (OS), and its molecular pathogenesis has not been completely defined. Here, we report that expression of deubiquitylase ubiquitin-specific protease 7 (USP7) is higher in human HCC tissues than in matched peritumoral tissues. Ectopic USP7 expression promotes growth of HCC cells in vivo and in vitro. Mechanistically, USP7 overexpression fosters HCC cell growth by forming a complex with and stabilizing thyroid hormone receptor-interacting protein 12 (TRIP12), which induces constitutive p14(ARF) ubiquitination. Clinically, USP7 overexpression is significantly correlated with a malignant phenotype, including larger tumor size, multiple tumor, poor differentiation, elevated alpha-fetoprotein, and microvascular invasion. Moreover, overexpression of USP7 and/or TRIP12 correlates with shorter OS and higher cumulative recurrence rates of HCC. Conclusion: USP7 stabilizes TRIP12 by deubiquitination, thus constitutively inactivating p14(ARF) and promoting HCC progression. This represents a novel marker for predicting prognosis and a potential therapeutic target for HCC. (Hepatology 2015;61:1603-1614)