Abstract
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, TAp63γ. In contrast, NMIBC cells are hyperactive in DNA repair and exhibit upregulated DNA repair genes and TAp63γ. A parallel exists in human tumors, as MIBC tissues have markedly lower DNA repair activity, and lower expression of DNA repair genes and TAp63γ compared to NMIBC tissues. Forced TAp63γ expression in MIBC significantly mitigates DNA repair deficiencies and reduces mutational susceptibility. Knockdown of TAp63γ in NMIBC greatly reduces DNA repair capacity and enhances mutational susceptibility. Manipulated TAp63γ expression or knockdown of p53m reduce the invasion of MIBC by 40-60%. However, the combination of p53m knockdown with forced TAp63γ expression reduce the invasion ability to nil suggesting that p53m contributes to invasion phenotype independent from TAp63γ. These results indicate that in BC, TAp63γ regulates DNA repair capacities, mutational susceptibility and invasion, and that p53m contribute to the invasion phenotype. We conclude that concurrent TAp63γ suppression and acquisition of p53m are a major cause for MIBC development.
Highlights
Bladder cancer (BC) is the fifth most frequently occurring cancer in the US; in 2018, there were 81,400 new BC cases and 17,980 BC deaths (Patel et al, 2014)
We found that MIBC cells are more susceptible than non-m uscle-invasive bladder cancer (NMIBC) cells to bulky- and oxidative-D NA-d amage-induced mutagenesis, and that MIBC cells are deficient in nucleotide excision repair (NER) and base excision repair (BER), NMIBC cells are proficient in both repair mechanisms
Since it is well established that the major repair pathways for bulky cyclobutane pyrimidine dimers (CPDs) and oxidative DNA damage (ODD) are NER and BER mechanisms, these results indicate that NMIBC cells are proficient in NER and BER, whereas MIBC cells are deficient in NER and BER
Summary
Bladder cancer (BC) is the fifth most frequently occurring cancer in the US; in 2018, there were 81,400 new BC cases and 17,980 BC deaths (Patel et al, 2014). Cancer Biology types that are well- to moderately-d ifferentiated and do not penetrate the lamina propria of the bladder wall (non-muscle-invasive BC, NMIBC), and the muscle-invasive types (MIBC) that are much more poorly differentiated (Wu, 2005; Van Batavia et al, 2014). While the former is much less malignant and less lethal than the latter, it frequently recurs after surgery. The molecular paths that lead to these two types of BC are unclear (Wu, 2005)
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