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Ubiquitin‐specific protease 7 accelerates p14 ARF degradation by deubiquitinating thyroid hormone receptor‐interacting protein 12 and promotes hepatocellular carcinoma progression
Author(s) -
Cai JiaBin,
Shi GuoMing,
Dong ZhaoRu,
Ke AiWu,
Ma HongHui,
Gao Qiang,
Shen ZaoZhuo,
Huang XiaoYong,
Chen Hao,
Yu DingDang,
Liu LiXin,
Zhang PengFei,
Zhang Chi,
Hu MeiYu,
Yang LiuXiao,
Shi YingHong,
Wang XiaoYing,
Ding ZhenBin,
Qiu ShuangJian,
Sun HuiChuan,
Zhou Jian,
Shi Yujiang G.,
Fan Jia
Publication year - 2015
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27682
Subject(s) - cancer research , deubiquitinating enzyme , ubiquitin , hepatocellular carcinoma , ectopic expression , tumor progression , biology , thyroid carcinoma , thyroid , medicine , pathology , endocrinology , cancer , cell culture , gene , biochemistry , genetics
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. (H epatology 2015;61:1603‐1614)