Deubiquitinase PSMD14 enhances hepatocellular carcinoma growth and metastasis by stabilizing GRB2
Deubiquitinase PSMD14 enhances hepatocellular carcinoma growth and metastasis by stabilizing GRB2
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去泛素酶 PSMD14 通过稳定 GRB2 增强肝细胞癌的生长和转移
DOI：
10.1016/j.canlet.2019.10.025
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发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Yin, Zhenyu
中科院分区：
文献类型：
--
作者：
Lv, Jie;Zhang, Sheng;Yin, Zhenyu
肝细胞癌（HCC）已成为全球最常见的恶性肿瘤之一。它与高死亡率相关，这也可以明显看出其发病率和预后极差。据报道，去泛素化酶26S蛋白酶体非ATP酶调节亚基14（PSMD14）在几种人类癌症中充当癌基因。本研究旨在揭示PSMD14在HCC进展和潜在机制中的功能意义。我们发现在HCC组织中PSMD14显着上调。 PSMD14的过表达与血管浸润，肿瘤数量，肿瘤复发以及无肿瘤不良以及HCC患者的总体存活相关。敲低和过表达的实验表明，PSMD14在体外促进了HCC细胞中的增殖，迁移和侵袭，并促进了肿瘤的生长和体内转移。从机械上讲，我们将PSMD14确定为GRB2的新型翻译后调节剂。 PSMD14通过在HCC细胞中的这种癌蛋白去泛素化抑制GRB2的降解。此外，用O-苯磺烷（OPA）对PSMD14的药理抑制抑制了体外和体内HCC细胞的恶性行为。总之，我们的发现表明，PSMD14可以成为HCC的新型有前途的治疗候选者。
Hepatocellular carcinoma (HCC) has emerged as one of the most common malignancies worldwide. It is associated with a high mortality rate, as evident from its increasing incidence and extremely poor prognosis. The deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) has been reported to act as an oncogene in several human cancers. The present study aimed to reveal the functional significance of PSMD14 in HCC progression and the underlying mechanisms. We found that PSMD14 was significantly upregulated in HCC tissues. Overexpression of PSMD14 correlated with vascular invasion, tumor number, tumor recurrence, and poor tumor-free and overall survival of patients with HCC. Knockdown and overexpression experiments demonstrated that PSMD14 promoted proliferation, migration, and invasion in HCC cells in vitro, and facilitated tumor growth and metastasis in vivo. Mechanistically, we identified PSMD14 as a novel post-translational regulator of GRB2. PSMD14 inhibits degradation of GRB2 via deubiquitinating this oncoprotein in HCC cells. Furthermore, pharmacological inhibition of PSMD14 with O-phenanthroline (OPA) suppressed the malignant behavior of HCC cells in vitro and in vivo. In conclusion, our findings suggest that PSMD14 could serve as a novel promising therapeutic candidate for HCC.