TRIM31 is upregulated in hepatocellular carcinoma and promotes disease progression by inducing ubiquitination of TSC1-TSC2 complex
TRIM31 is upregulated in hepatocellular carcinoma and promotes disease progression by inducing ubiquitination of TSC1-TSC2 complex
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TRIM31 在肝细胞癌中表达上调，并通过诱导 TSC1-TSC2 复合物泛素化促进疾病进展
DOI：
10.1038/onc.2017.349
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发表时间：
2018-01-25
期刊：
影响因子：
8
通讯作者：
Han, L.
中科院分区：
文献类型：
--
作者：
Guo, P.;Ma, X.;Han, L.
三方基序(Triartite Motif，TRIM)31是含三方基序的蛋白质家族中的一员，TRIM家族蛋白参与了广泛的生物学和病理过程。然而，TRIM31在肝细胞癌进展中的作用尚不清楚。在此，我们证明了TRIM31在肝癌组织中的表达显著高于配对的远端非癌肝组织，并且其过度表达与疾病进展密切相关。功能获得和功能丧失实验证实，TRIM31通过过度激活哺乳动物靶基因雷帕霉素复合体1(MTORC1)途径促进肝癌细胞的恶性行为。我们进一步证明，TRIM31通过直接与结节性硬化症复合体(TSC)1和mTORC1途径的上游抑制因子TSC2复合体相互作用，促进E3连接酶介导的K48连接的泛素化和该复合体的降解，从而发挥其致癌作用。综上所述，本研究证实TRIM31可以通过靶向TSC1-TSC2复合体的降解和进一步过度激活mTORC1通路来促进肝癌的进展。因此，它揭示了一种新的肝癌进展的分子机制，并提示了通过靶向TRIM31来治疗肝癌的潜在策略。
Tripartite motif (TRIM) 31 is a member of the tripartite motif-containing protein family, and TRIM family proteins are involved in a broad range of biological and pathological processes. However, the role of TRIM31 in hepatocellular carcinoma (HCC) progression is not known. Here we demonstrated that TRIM31 expression was significantly upregulated in liver cancer tissues compared with paired distal non-cancerous liver tissues from HCC patients, and its overexpression was significantly correlated with advanced disease status. Both gain and loss of function assay verified that TRIM31 promoted the malignant behaviors of HCC cells through overactivation of mammalian target of rapamycin complex1 (mTORC1) pathway. We further demonstrated that TRIM31 exerted its oncogenic effect by directly interacting with the tuberous sclerosis complex (TSC) 1 and TSC2 complex, the upstream suppressor of mTORC1 pathway, and promoting the E3 ligase-mediated K48-linked ubiquitination and degradation of this complex. In conclusion, this study demonstrated TRIM31 could promote HCC progression by targeting TSC1-TSC2 complex for degradation and further overactivating mTORC1 pathway. Thus, it revealed a novel molecular mechanism of HCC progression and indicated a potential therapeutic strategy against HCC by targeting TRIM31.