Tripartite motif-containing 37 (TRIM37) promotes the aggressiveness of non-small-cell lung cancer cells by activating the NF-κB pathway
Tripartite motif-containing 37 (TRIM37) promotes the aggressiveness of non-small-cell lung cancer cells by activating the NF-κB pathway
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含有三联基序的 37 (TRIM37) 通过激活 NF-B 通路促进非小细胞肺癌细胞的侵袭性
DOI：
10.1002/path.5144
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发表时间：
2018-11-01
影响因子：
7.3
通讯作者：
Dai, Ting
中科院分区：
文献类型：
--
作者：
Li, Yun;Deng, Liwen;Dai, Ting
非小细胞肺癌（NSCLC）是最常见的恶性肿瘤之一，其中NF-B通路被组成性激活。在此，我们确定了E3泛素连接酶，三重基序包含37（TRIM 37），参与TRAF 2的K63多聚泛素化，这是NF-B信号转导激活的重要步骤。TRIM 37在NSCLC细胞系和组织中的mRNA和蛋白表达水平均显著高于正常支气管上皮细胞和匹配的癌旁非肿瘤组织。TRIM 37的表达与NSCLC的临床分期和不良生存率密切相关。TRIM 37的过表达拮抗顺铂诱导的细胞凋亡，诱导血管生成和增殖，并增加体外和体内NSCLC细胞的侵袭性，而抑制TRIM 37则导致相反的效果。基因集富集分析（GSEA）显示TRIM 37表达与NF-B信号传导显著相关。此外，我们发现TRIM 37与TRAF 2结合并促进K63连接的TRAF 2遍在蛋白化，维持NF-B途径的最终激活。TRIM 37环指结构域的突变，E3泛素连接酶的标志，导致丧失促进TRAF 2的K63多聚泛素化和激活NF-B信号传导的能力。总之，我们的研究结果提供了证据表明TRIM 37在组成性NF-B通路活化中起重要作用，并可作为NSCLC的预后因子和治疗靶点。版权所有（c）2018大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Non-small-cell lung cancer (NSCLC), in which the NF-B pathway is constitutively activated, is one of the most common malignancies. Herein, we identify an E3 ubiquitin ligase, tripartite motif-containing 37 (TRIM37), participating in the K63 polyubiquitination of TRAF2, which is a significant step in the activation of NF-B signaling. Both the mRNA and the protein expression levels of TRIM37 were much higher in NSCLC cell lines and tissues than in normal bronchial epithelial cells and matched adjacent non-tumor tissues. TRIM37 expression correlated closely with clinical stage and poor survival in NSCLC. Overexpression of TRIM37 antagonized cisplatin-induced apoptosis, induced angiogenesis and proliferation, and increased the aggressiveness of NSCLC cells in vitro and in vivo, whereas inhibition of TRIM37 led to the opposite effects. Gene set enrichment analysis (GSEA) showed that TRIM37 expression significantly correlated with NF-B signaling. Furthermore, we found that TRIM37 bound to TRAF2 and promoted K63-linked ubiquitination of TRAF2, sustaining the eventual activation of the NF-B pathway. Mutation in the ring finger domain of TRIM37, a hallmark of E3 ubiquitin ligases, led to loss of the ability to promote K63 polyubiquitination of TRAF2 and activate NF-B signaling. Taken together, our findings provide evidence that TRIM37 plays an important role in constitutive NF-B pathway activation and could serve as a prognostic factor and therapeutic target in NSCLC. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.