Loss of polarity protein Par3, via transcription factor Snail, promotes bladder cancer metastasis

Bladder cancer (BLCA) remains the leading cause of cancer-related mortality among genitourinary malignancies worldwide. BLCA metastasis represents the primary reason for its poor prognosis. In this study, we report that decreased expression of partitioning defective 3 (Par3), a polarity protein (encoded by PARD3), is associated with tumor aggressive phenotypes and poor prognosis in BLCA patients. Consistently, ablation of Par3 promotes the metastasis and invasion of BLCA cells in vitro and in vivo. Further studies reveal that zinc finger protein Snail represses the expression of Par3 by binding to E2-box (CAGGTG) of PARD3 promoter-proximal. Inhibition of GSK-3 beta promotes the expression and nuclear localization of Snail and then reduces the expression of Par3, resulting in the metastasis and invasion of BLCA cells. Moreover, we detected the interaction between Par3 (936-1356 aa) and ZO-1 (1372-1748 aa), which is involved in the maintenance of tight junction. Together, our results demonstrate that the GSK-3 beta/Snail/Par3/ZO-1 axis regulates BLCA metastasis, and Snail is a major regulator for Par3 protein expression in BLCA.

Automated summary

The study identified that decreased expression of Par3 is associated with aggressive phenotypes and poor prognosis in BLCA patients. Inhibition of GSK-3 beta promotes Snail expression and nuclear localization, leading to reduced Par3 expression and metastasis of BLCA cells. Additionally, an interaction between Par3 and ZO-1 was detected, which is involved in maintaining tight junctions in BLCA cells.