NF-κB p65 Overexpression Promotes Bladder Cancer Cell Migration via FBW7-Mediated Degradation of RhoGDIα Protein.
NF-κB p65 Overexpression Promotes Bladder Cancer Cell Migration via FBW7-Mediated Degradation of RhoGDIα Protein.
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NF-kappa B p65 过表达通过 FBW7 介导的 RhoGDIa 蛋白降解促进膀胱癌细胞迁移
DOI：
10.1016/j.neo.2017.06.002
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Zhu J;Li Y;Chen C;Ma J;Sun W;Tian Z;Li J;Xu J;Liu CS;Zhang D;Huang C;Huang H
背景技术背景：浸润性膀胱癌（invasive bladder cancer，BC）是世界范围内最致命的泌尿系统恶性肿瘤之一，了解BC迁移、侵袭和转移的分子机制对降低BC的死亡率具有重要意义。虽然RelA/p65是NF-κ B B转录因子家族的成员之一，但其对人膀胱癌运动的调节作用及其机制尚不清楚。方法：通过免疫组织化学染色和Western Blot检测NF-κ Bp 65在N-丁基-N-（4-羟丁基）-亚硝胺（BBN）诱导的高侵袭性BC中的表达。在T24 T细胞中，通过使用功能丧失和获得方法，评估NF-κ Bp 65敲低对BC细胞迁移和侵袭的影响，以及其调节的RhoGDIα和FBW 7。此外，还通过免疫沉淀法研究了FBW 7与RhoGDIα的相互作用，并证实了FBW 7对RhoGDIα的泛素化作用。结果：在BBN诱导的高侵袭性膀胱癌和人膀胱癌细胞系中，p65蛋白显著上调。我们还观察到p65过表达通过抑制RhoGDIα表达促进BC细胞迁移。p65对RhoGDIα表达的调节作用是通过上调FBW 7介导的，FBW 7特异性地与RhoGDIα相互作用，促进RhoGDIα的泛素化和降解。机制研究表明，p65稳定E3连接酶FBW 7蛋白介导的衰减pten mRNA转录。结论：我们证明p65过表达抑制pten mRNA的转录，从而稳定泛素E3连接酶FBW 7的蛋白表达，进而增加RhoGDIα蛋白的泛素化和降解，最终促进人BC迁移。p65/PTEN/FBW 7/RhoGDIα轴的新发现为理解BC迁移的本质提供了重要的见解，进一步为癌症治疗提供了新的理论支持。
BACKGROUND: Since invasive bladder cancer (BC) is one of the most lethal urological malignant tumors worldwide, understanding the molecular mechanisms that trigger the migration, invasion, and metastasis of BC has great significance in reducing the mortality of this disease. Although RelA/p65, a member of the NF-kappa B transcription factor family, has been reported to be upregulated in human BCs, its regulation of BC motility and mechanisms have not been explored yet. METHODS: NF-κBp65 expression was evaluated in N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)–induced high invasive BCs by immunohistochemistry staining and in human BC cell lines demonstrated by Western Blot. The effects of NF-κBp65 knockdown on BC cell migration and invasion, as well as its regulated RhoGDIα and FBW7, were also evaluated in T24T cells by using loss- and gain-function approaches. Moreover, the interaction of FBW7 with RhoGDIα was determined with immunoprecipitation assay, while critical role of ubiquitination of RhoGDIα by FBW7 was also demonstrated in the studies. RESULTS: p65 protein was remarkably upregulated in the BBN-induced high invasive BCs and in human BC cell lines. We also observed that p65 overexpression promoted BC cell migration by inhibiting RhoGDIα expression. The regulatory effect of p65 on RhoGDIα expression is mediated by its upregulation of FBW7, which specifically interacted with RhoGDIα and promoted RhoGDIα ubiquitination and degradation. Mechanistic studies revealed that p65 stabilizing the E3 ligase FBW7 protein was mediated by its attenuating pten mRNA transcription. CONCLUSIONS: We demonstrate that p65 overexpression inhibits pten mRNA transcription, which stabilizes the protein expression of ubiquitin E3 ligase FBW7, in turn increasing the ubiquitination and degradation of RhoGDIα protein and finally promoting human BC migration. The novel identification of p65/PTEN/FBW7/RhoGDIα axis provides a significant insight into understanding the nature of BC migration, further offering a new theoretical support for cancer therapy.
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影响因子：
--
作者：
Jin H;Yu Y;Hu Y;Lu C;Li J;Gu J;Zhang L;Huang H;Zhang D;Wu XR;Gao J;Huang C
通讯作者：
Huang C
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通讯作者：
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