BRCC3 Promotes Tumorigenesis of Bladder Cancer by Activating the NF-κB Signaling Pathway Through Targeting TRAF2.
BRCC3 Promotes Tumorigenesis of Bladder Cancer by Activating the NF-κB Signaling Pathway Through Targeting TRAF2.
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BRCC3通过靶向TRAF2激活NF-κB信号通路促进膀胱癌肿瘤发生
DOI：
10.3389/fcell.2021.720349
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发表时间：
2021
影响因子：
5.5
通讯作者：
Liu T
中科院分区：
文献类型：
--
作者：
Tao H;Liao Y;Yan Y;He Z;Zhou J;Wang X;Peng J;Li S;Liu T
NF-κB信号在肿瘤中非常重要。然而，BRCC 3相关的NF-κB信号激活在膀胱癌中的作用仍有待研究。采用Western blotting和组织芯片免疫组化技术检测BRCC 3在膀胱癌组织中的异常表达。通过生长曲线、集落形成、软琼脂试验和异种移植模型分析BRCC 3过表达或敲除在膀胱癌中的作用。此外，使用RNA-Seq和荧光素酶报告基因测定来鉴定下游信号传导途径。最后，通过免疫共沉淀和荧光共聚焦实验验证BRCC 3的精确靶点。在这里，我们发现BRCC 3的高表达通过靶向TRAF 2蛋白促进肿瘤发生。BRCC 3在膀胱癌患者中表达上调，这表明预后不良。通过体外和体内试验，我们发现基因BRCC 3消融显著阻断膀胱癌细胞的增殖、活力和迁移。从机制上讲，RNA-Seq分析显示，NF-κB信号在BRCC 3缺陷细胞中下调。BRCC 3与TRAF 2结合并协同激活NF-κB信号传导。我们的研究结果表明BRCC 3高表达通过靶向TRAF 2激活NF-κB信号传导，这反过来促进膀胱癌的肿瘤发生。这一发现表明BRCC 3是膀胱癌患者的潜在靶点。
NF-κB signaling is very important in cancers. However, the role of BRCC3-associated NF-κB signaling activation in bladder cancer remains to be characterized. Western blotting and IHC of tissue microarray were used to confirm the abnormal expression of BRCC3 in bladder cancer. Growth curve, colony formation, soft agar assay and Xenograft model were performed to identify the role of BRCC3 over-expression or knock-out in bladder cancer. Further, RNA-Seq and luciferase reporter assays were used to identify the down-stream signaling pathway. Finally, co-immunoprecipitation and fluorescence confocal assay were performed to verify the precise target of BRCC3. Here, we found that high expression of BRCC3 promoted tumorigenesis through targeting the TRAF2 protein. BRCC3 expression is up-regulated in bladder cancer patients which indicates a negative prognosis. By in vitro and in vivo assays, we found genetic BRCC3 ablation markedly blocks proliferation, viability and migration of bladder cancer cells. Mechanistically, RNA-Seq analysis shows that NF-κB signaling is down-regulated in BRCC3-deficient cells. BRCC3 binds to and synergizes with TRAF2 to activate NF-κB signaling. Our results indicate that high BRCC3 expression activates NF-κB signaling by targeting TRAF2 for activation, which in turn facilitates tumorigenesis in bladder cancer. This finding points to BRCC3 as a potential target in bladder cancer patients.
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