The role of TAp63γ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells

It has long been recognized that non-muscle-invasive bladder cancer (NMIBC) has a low propensity (20%) of becoming muscle-invasive (MIBC), and that MIBC carry many more p53 point mutations (p53m) than NMIBC (50% vs 10%). MIBC also has a higher mutation burden than NMIBC. These results suggest that DNA repair capacities, mutational susceptibility and p53m are crucial for MIBC development. We found MIBC cells are hypermutable, deficient in DNA repair and have markedly downregulated DNA repair genes, XPC, hOGG1/2 and Ref1, and the tumor suppressor, TAp63 gamma. In contrast, NMIBC cells are hyperactive in DNA repair and exhibit upregulated DNA repair genes and TAp63 gamma. A parallel exists in human tumors, as MIBC tissues have markedly lower DNA repair activity, and lower expression of DNA repair genes and TAp63 gamma compared to NMIBC tissues. Forced TAp63 gamma expression in MIBC significantly mitigates DNA repair deficiencies and reduces mutational susceptibility. Knockdown of TAp63 gamma in NMIBC greatly reduces DNA repair capacity and enhances mutational susceptibility. Manipulated TAp63 gamma expression or knockdown of p53m reduce the invasion of MIBC by 40-60%. However, the combination of p53m knockdown with forced TAp63 gamma expression reduce the invasion ability to nil suggesting that p53m contributes to invasion phenotype independent from TAp63 gamma. These results indicate that in BC, TAp63 gamma regulates DNA repair capacities, mutational susceptibility and invasion, and that p53m contribute to the invasion phenotype. We conclude that concurrent TAp63 gamma suppression and acquisition of p53m are a major cause for MIBC development.

Automated summary

Research shows that MIBC cells have deficient DNA repair, high mutational susceptibility, and lower expression of DNA repair genes and TAp63 gamma, while NMIBC cells exhibit high DNA repair capacity, upregulated DNA repair genes, and higher TAp63 gamma expression. These findings suggest that TAp63 gamma plays a crucial role in regulating DNA repair capacities, mutational susceptibility, and invasion in bladder cancer, with p53m contributing to the invasion phenotype independently.