Ubiquitin‐specific protease 7 accelerates p14ARF degradation by deubiquitinating thyroid hormone receptor‐interacting protein 12 and promotes hepatocellular carcinoma progression

Abstract

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 H epatocellular carcinoma (HCC) ranks as the fifth-most common cancer and the third cause of cancer-related mortality worldwide, mainly owing to its high rate of metastasis and recurrence.1 The recent identification of several oncogenes and tumor-suppressor genes has significantly deepened the understanding of the invasion and metastasis of HCC. 2 However, the effects of tumor progressionrelated genes often depend on the level of their protein products as well as their post-translational Abbreviations: 2D-LC-MS/MS, two-dimensional liquid chromatography coupled with tandem mass

Mortalin promotes cell proliferation and epithelial mesenchymal transition of intrahepatic cholangiocarcinoma cells in vitro

“…Western blot, immunofluorescence (IF) and quantitative real-time PCR (qRT-PCR) were performed as described previously 19 20. The antibodies used for Western blot and IF are listed in online supplementary table S1.…”

“…Matrigel invasion assay, wound-healing assay and proliferation assay were performed as described previously 20 21. Cell apoptosis was detected by FACSCalibur flow cytometry (FCM; Becton Dickinson, FranklinLakes, New Jersey, USA) as described previously 20 21…”

“…Cell apoptosis was detected by FACSCalibur flow cytometry (FCM; Becton Dickinson, FranklinLakes, New Jersey, USA) as described previously 20 21…”

The ubiquitin–proteasome system and its potential application in hepatocellular carcinoma therapy

“…USP7 is also proved to be the oncoprotein in HCC which stabilizes TRIP12 (thyroid hormone receptor-interacting protein 12) and constitutively inactivates p14 [76].…”

“…The Ub, which is 8.5 kDa and consists of 76 ] 20S is involved in the activations of receptor endocytosis, cell signaling, protein trafficking and DNA damage repair [27,28]. Several other proteins have also been identified as Ub-like proteins (UBLs) related to Ub in sequence and three-dimensional structure.…”