Ubiquitin-specific protease 4 promotes metastasis of hepatocellular carcinoma by increasing TGF-β signaling-induced epithelial-mesenchymal transition.
Ubiquitin-specific protease 4 promotes metastasis of hepatocellular carcinoma by increasing TGF-β signaling-induced epithelial-mesenchymal transition.
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DOI：
10.18632/aging.101587
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发表时间：
2018-10-18
期刊：
影响因子：
--
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Qiu C;Liu Y;Mei Y;Zou M;Zhao Z;Ye M;Wu X
侵袭和转移是晚期肝细胞癌复发和死亡的主要原因。揭示肝细胞癌转移的机制对于开发新的治疗方法和降低患者死亡率具有重要意义。泛素特异性蛋白水解酶4(USP4)通过使一些重要的致癌蛋白去泛素化并影响其降解而参与肿瘤的发生。在目前的研究中，我们发现USP4在肝癌组织中显著上调，并且USP4的高表达与患者的远处转移和生存不良有关。通过基因干扰实验，我们发现USP4基因敲除显著抑制了肝癌细胞在体外的迁移和侵袭，而USP4过表达则产生了相反的结果。在体内，我们还发现USP4基因敲除明显阻断了肝癌细胞的转移。在机制上，我们揭示了USP4与转化生长因子-β受体I型(TGFR-1)直接相互作用并去泛素化，激活转化生长因子-β信号通路，进而诱导肝癌细胞上皮-间充质转化。综上所述，我们的研究结果表明，USP4在肝细胞癌中高表达，并促进肿瘤的侵袭和转移，其潜在机制是USP4直接与TGFR-1相互作用并使其去泛素化，从而增加转化生长因子-β信号诱导的内皮细胞转化。这些结果可能为肝癌的治疗提供新的治疗靶点。
Invasion and metastasis are the main cause of recurrence and death in advanced hepatocellular carcinoma (HCC). Revealing the mechanisms of HCC metastasis is important for developing new therapeutic approaches and reducing patient mortality. Ubiquitin specific protease 4 (USP4), is involved in tumorigenesis by deubiquitinating some important oncogenic proteins and impacting their degradation. In the present study, we found that USP4 was significantly upregulated in HCC tumor tissues and the high expression of USP4 was associated with distant metastasis and poor survival in patients. Using gene interference, we demonstrated that USP4 knockdown significantly inhibited HCC cell migration and invasion in vitro, and USP4 overexpression had the opposite results. In vivo, we also found that USP4 knockdown obviously blocked HCC cell metastasis. Mechanistically, we revealed that USP4 interacted directly with and deubiquitinated TGF-β receptor type I (TGFR-1) to activate the TGF-β signaling pathway, and subsequently induced the Epithelial-Mesenchymal Transition (EMT) in HCC cells. Taken together, our results elucidate that USP4 is highly expressed in HCC and promotes the tumor invasion and metastasis, the underlying mechanism is that USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-β signaling-Induced EMT. These results could provide a new therapeutic target for the treatment of HCC.
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影响因子：
4.6
作者：
Hwang SJ;Lee HW;Kim HR;Lee H;Shin CH;Yun SI;Lee DH;Kim DH;Kim KK;Joo KM;Kim HH
通讯作者：
Kim HH
DOI：
10.1038/nrd.2017.152
发表时间：
2018-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Harrigan JA;Jacq X;Martin NM;Jackson SP
通讯作者：
Jackson SP
上调去泛素酶 USP4 在黑色素瘤中发挥致癌作用
影响因子：
5.3
作者：
Guo W;Ma J;Pei T;Zhao T;Guo S;Yi X;Liu Y;Wang S;Zhu G;Jian Z;Gao T;Li C;Liao W;Shi Q
通讯作者：
Shi Q
影响因子：
13.5
作者：
Altekruse, Sean F.;McGlynn, Katherine A.;Dickie, Lois A.;Kleiner, David E.
通讯作者：
Kleiner, David E.
影响因子：
254.7
作者：
Chen, Wanqing;Zheng, Rongshou;He, Jie
通讯作者：
He, Jie