%0 Journal Article
%T NF-¦ÊB p65 Overexpression Promotes Bladder Cancer Cell Migration via FBW7-Mediated Degradation of RhoGDI¦Á Protein
%A Caiyi Chen
%A Chuanshu Huang
%A Claire S Liu
%A Dongyun Zhang
%A Haishan Huang
%A Jiheng Xu
%A Jingxia Li
%A Jiugao Ma
%A Junlan Zhu
%A Wenrui Sun
%A Yang Li
%A Zhongxian Tian
%J Archive of "Neoplasia (New York, N.Y.)".
%D 2017
%R 10.1016/j.neo.2017.06.002
%X 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-¦ÊBp65 expression was evaluated in N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)¨Cinduced high invasive BCs by immunohistochemistry staining and in human BC cell lines demonstrated by Western Blot. The effects of NF-¦ÊBp65 knockdown on BC cell migration and invasion, as well as its regulated RhoGDI¦Á and FBW7, were also evaluated in T24T cells by using loss- and gain-function approaches. Moreover, the interaction of FBW7 with RhoGDI¦Á was determined with immunoprecipitation assay, while critical role of ubiquitination of RhoGDI¦Á 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 RhoGDI¦Á expression. The regulatory effect of p65 on RhoGDI¦Á expression is mediated by its upregulation of FBW7, which specifically interacted with RhoGDI¦Á and promoted RhoGDI¦Á 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 RhoGDI¦Á protein and finally promoting human BC migration. The novel identification of p65/PTEN/FBW7/RhoGDI¦Á axis provides a significant insight into understanding the nature of BC migration, further offering a new theoretical support for cancer therapy
%K BC
%K bladder cancer
%K BBN
%K N-butyl-N-(4-hydroxybutyl)-nitrosamine
%K CHX
%K cycloheximide
%K RT-PCR
%K reverse transcription-polymerase chain reaction
%K NF-¦ÊB
%K transcription factors of the nuclear factor kappa B
%K RhoGDI
%K RHO guanosine diphosphate dissociation inhibitors
%K FBW7
%K F-box and WD repeat domain-containing 7
%K PTEN
%K phosphatase and tensin homolog
%K GFP
%K green fluorescent protein
%K MEF
%K murine embryonic fibroblasts
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540704/