E3 ubiquitin ligase TRIM7 negatively regulates NF-kappa B signaling pathway by degrading p65 in lung cancer
E3 ubiquitin ligase TRIM7 negatively regulates NF-kappa B signaling pathway by degrading p65 in lung cancer
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E3泛素连接酶TRIM7通过降解肺癌中的p65负向调节NF-κB信号通路
DOI：
10.1016/j.cellsig.2020.109543
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发表时间：
2020-05-01
影响因子：
4.8
通讯作者：
Yu, Bentong
中科院分区：
文献类型：
--
作者：
Jin, Jiangbo;Lu, Zhuo;Yu, Bentong
trim7基因编码至少4种糖原蛋白相互作用蛋白1 （GNIP1）、GNIP2、GNIP3和trim7。据报道，最长的同种异构体GNIP1是一种致癌基因。然而，非常有趣的是，在我们的研究中，最短的同工异构体TRIM7与GNIP1在c端仅相差15个氨基酸，其作用方式与GNIP1完全不同。94例肺癌患者肿瘤中TRIM7表达较邻近正常组织降低，且TRIM7水平与临床分期呈负相关。在体外实验中，TRIM7显著抑制肿瘤细胞的增殖和迁移，促进细胞凋亡。进一步的研究表明，TRIM7与p65通过c端相互作用，这与GNIP1不同。TRIM7与p65相互作用促进p65泛素化，最终通过26S蛋白酶体加速p65的降解。在体内，稳定表达TRIM7可使肿瘤体积和重量减小。同时，TRIM7过表达组异种移植瘤模型中Ki67下调，甲状腺转录因子1 （TTF-1）和Caspase 3上调。令人印象深刻的是，TRIM7t（与GNIP1不同的没有c端序列的截断TRIM7）在体内对肿瘤生长的影响很小。这些发现突出了TRIM7对NF-kappa B信号通路负调控的奇特机制，并表明TRIM7可能是肺癌的潜在治疗靶点。
The gene trim7 encodes at least four isoforms Glycogenin-interacting protein 1 (GNIP1), GNIP2, GNIP3 and Tripartite motif containing 7 (TRIM7). GNIP1, the longest isoform, has been reported acting as an oncogene. However, it is very interesting that TRIM7, the shortest isoform, only 15 amino acids different from GNIP1 in C-terminal, acts in a completely different way from that of GNIP1 in our present study. TRIM7 expression was decreased in tumor compared with adjacent normal tissues, and the level of TRIM7 was negatively correlated with clinical stage of 94 patients with lung cancer. In vitro, TRIM7 dramatically inhibited the proliferation and migration of tumor cells, and promoted cell apoptosis. Further study showed that TRIM7 interacted with p65 via its C-terminal which is different from GNIP1. The interaction between TRIM7 and p65 promoted the ubiquitination of p65 and finally accelerated the degradation of p65 via 26S proteasome. In vivo, the tumor volume and weight were decreased by TRIM7 stable expression. Meanwhile, Ki67 was down-regulated, thyroid transcription factor 1 (TTF-1) and Caspase 3 were up-regulated in TRIM7 overexpression group in xenograft model. It is very impressive that TRIM7t (a truncated TRIM7 without C-terminal sequence that different with GNIP1) had little effect on the tumor growth in vivo. These findings highlight a curious mechanism for negative regulation of NF-kappa B signaling pathway by TRIM7 and demonstrate that TRIM7 would be a potential therapeutic target for lung cancer.