TP53INP2 Modulates Epithelial-to-Mesenchymal Transition via the GSK-3β/β-Catenin/Snail1 Pathway in Bladder Cancer Cells

Zhengtao Zhou; Xiaoqiang Liu; Yulei Li; Junhua Li; Wen Deng; Jian Zhong; Luyao Chen; Yu Li; Xiantao Zeng; Gongxian Wang; Jingyu Zhu; Bin Fu

doi:10.2147/OTT.S251830

TP53INP2 Modulates Epithelial-to-Mesenchymal Transition via the GSK-3β/β-Catenin/Snail1 Pathway in Bladder Cancer Cells

Onco Targets Ther. 2020 Sep 28:13:9587-9597. doi: 10.2147/OTT.S251830. eCollection 2020.

Authors

Zhengtao Zhou^#^{1

2}, Xiaoqiang Liu^#^{1

2}, Yulei Li¹, Junhua Li³, Wen Deng¹, Jian Zhong⁴, Luyao Chen¹, Yu Li¹, Xiantao Zeng⁵, Gongxian Wang^{1

2}, Jingyu Zhu³, Bin Fu^{1

2}

Affiliations

¹ Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China.
² Jiangxi Institute of Urology, Nanchang, People's Republic of China.
³ Department of Urology, Third Hospital of Hangzhou, Hangzhou, People's Republic of China.
⁴ Department of Surgery, Nankang District Chinese Medicine Hospital, Ganzhou, People's Republic of China.
⁵ Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China.

^# Contributed equally.

Abstract

Background: The tumor protein p53-inducible nuclear protein 2 (TP53INP2), an autophagy protein, is essential for autophagosome formation. The deregulation of autophagy is associated with multiple human diseases, including cancer. The present study aims to explore the role of TP53INP2 in bladder cancer.

Materials and methods: Quantitative real-time polymerase chain reaction was used to detect the mRNA level. Relative TP53INP2 protein expression was detected by immunohistochemistry and Western blot. The effect of TP53INP2 silencing on the proliferation, migration, and invasion of bladder cancer cells was investigated by CCK-8 detection kit and transwell assay. In addition, transfection and immunofluorescence were performed.

Results: In this study, we report that high expression of TP53INP2 is correlated with poor patient survival in bladder cancer. Results demonstrate that the depletion of TP53INP2 inhibits the migration, invasion, and epithelial-to-mesenchymal transition (EMT) of bladder cancer cells. The underlying mechanism was explored. Results show that the TP53INP2 knockdown suppresses EMT by inhibiting the active non-phosphorylated β-catenin and decreasing the Snail1 levels. Furthermore, the glycogen synthase kinase-3 beta (GSK-3β) inhibitor IM-12 abrogates the effect of TP53INP2 silencing. Interestingly, the induction of autophagy partially abrogates the TP53INP2 knockdown-induced decrease in active β-catenin and inhibition of migration and invasion in bladder cancer cells.

Conclusion: In summary, our results show that the downregulation of TP53INP2 inhibits EMT via the GSK-3β/β-catenin/Snail1 pathway in bladder cancer. The findings of this study uncover the novel role of TP53INP2 and offer new insights into bladder cancer clinical therapy.

Keywords: EMT; Snail1; TP53INP2; bladder cancer; β-catenin.

Grants and funding

This study was supported by the National Natural Science Foundation of P.R. China (grant no. 81560419 and no. 81960512), the Natural Science Foundation of Jiangxi (grant no. 20151BAB205047 and 20202BAB216006) and the Jiangxi Province Infrastructure Facilities for Scientific Research Institutes (grant no. 20142BBA13038 and 20151BBA13047).