The E3 ubiquitin ligase TRIM7 suppressed hepatocellular carcinoma progression by directly targeting Src protein
The E3 ubiquitin ligase TRIM7 suppressed hepatocellular carcinoma progression by directly targeting Src protein
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E3 泛素连接酶 TRIM7 通过直接靶向 Src 蛋白来抑制肝细胞癌的进展。
DOI：
10.1038/s41418-019-0464-9
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发表时间：
2020-06-01
影响因子：
12.4
通讯作者：
Han, Lihui
中科院分区：
文献类型：
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作者：
Zhu, Lihui;Qin, Chengyong;Han, Lihui
已知异常Src激酶活性与多种人类恶性肿瘤有关，而Src的调节机制尚未完全阐明。在这里，我们证明了三重基序包含7（TRIM 7）直接与Src相互作用，诱导Lys 48连接的多泛素化的Src和减少的肝癌（HCC）细胞中的Src蛋白的丰度。我们通过在几种HCC模型中的体内和体外对Src-mTORC 1-S6 K1轴的负调节，进一步将TRIM 7鉴定为HCC细胞中的肿瘤抑制因子。此外，我们证实了TRIM 7在临床肝癌组织中的异常表达及其与临床HCC标本中Src蛋白的负相关性。总的来说，我们证明了TRIM 7通过其直接负调控Src和调节Src-mTORC 1-S6 K1轴来抑制HCC进展;因此，我们提供了对HCC发展的新见解，并通过调节TRIM 7来定义具有过度活性Src的癌症的有希望的治疗策略。
Aberrant Src kinase activity is known to be involved in a variety of human malignancies, whereas the regulatory mechanism of Src has not been completely clarified. Here, we demonstrated that tripartite motif containing 7 (TRIM7) directly interacted with Src, induced Lys48-linked polyubiquitination of Src and reduced the abundance of Src protein in hepatocellular carcinoma (HCC) cells. We further identified TRIM7 as a tumor suppressor in HCC cells through its negative modulation of the Src-mTORC1-S6K1 axis in vivo and in vitro in several HCC models. Moreover, we verified the dysregulated expression of TRIM7 in clinical liver cancer tissues and its negative correlation with Src protein in clinical HCC specimens. Overall, we demonstrated that TRIM7 suppressed HCC progression through its direct negative regulation of Src and modulation of the Src-mTORC1-S6K1 axis; thus, we provided a novel insight into the development of HCC and defined a promising therapeutic strategy for cancers with overactive Src by modulating TRIM7.