Loss of p190A RhoGAP induces aneuploidy and enhances bladder cancer cell migration and invasion by modulating actin dynamics

TL;DR

Loss of p190A protein leads to abnormal cell division and increased bladder cancer cell movement, suggesting it acts as a tumor suppressor.

Contribution

This study identifies p190A as a tumor suppressor in bladder cancer through its role in ploidy control and actin regulation.

Findings

p190A mutations are present in up to 8% of bladder cancer cases.

Lower p190A expression correlates with increased cancer invasiveness and worse survival.

Loss of p190A disrupts actin dynamics and promotes cancer cell migration and invasion.

Abstract

p190A has been studied across various cancer types, and mutation rates of up to 20% were observed in some cancers, supporting the significance of p190A in carcinogenesis. Since the relevance of p190A in bladder cancer has not been addressed so far, we attempted to explore it. Evaluation of TCGA high-throughput sequencing datasets revealed p190A mutations in up to 8% of bladder cancer samples across several studies. Employing immunohistochemistry on tissue microarray that included 202 BC patient samples, we observed that lower p190A expression correlates with increased invasiveness and poorer survival outcomes. These findings suggested that p190A may have a tumor suppressor function in bladder tissue, consistent with its anticipated function in ploidy-control. p190A knockdown resulted in chromosomal instability in ureter-derived epithelial cells with otherwise normal karyotype, supporting its potential involvement in tumorigenesis. Loss-of-function studies in low-invasive bladder RT4 cell line and gain-of-function experiments in two highly invasive bladder cancer cell lines (T24 and BFTC) demonstrated that p190A influences cell migration and invasion in vitro, as determined by scratch assay and Boyden chamber approaches. This conclusion was further validated by ex vivo porcine bladder invasion approach, invadopodia formation, and gelatin degradation assays. Pathway analysis revealed that altered p190A expression influences both the Rho-ROCK-dependent LIMK1-cofilin pathway and the phosphorylation of cortactin by focal adhesion kinase, both of which regulate critical cellular processes such as actin network organization and polarization to facilitate efficient, coordinated cell migration and division. In summary, our results indicate that p190A has a genuine role in controlling cell-ploidy and regulates actin dynamics in the bladder urothelium, while loss of p190A results in genome instability and drives bladder cancer initiation and progression through deregulated actin dynamics.

The online version contains supplementary material available at 10.1038/s41598-025-23687-4.

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