Abstract
Bladder cancer (BC) is the sixth most common cancer in the United States and is the number one cause of death among patients with urinary system malignancies. This makes the identification of invasive regulator(s)/effector(s) as the potential therapeutic targets for managing BC a high priority. p63 is a member of the p53 family of tumor suppressor genes/proteins, plays a role in the differentiation of epithelial tissues, and is believed to function as a tumor suppressor. However, it remains unclear whether and how p63 functions in BC cell invasion after tumorigenesis. Here, we show that p63α protein levels were much higher in mouse high-invasive BC tissues than in normal tissues. Our results also revealed that p63α is crucial for heat shock protein 70 (Hsp70) expression and subsequently increases the ability of BC invasion. Mechanistic experiments demonstrated that p63α can transcriptionally up-regulate Hsp70 expression, thereby promoting BC cell invasion via the Hsp70/Wasf3/Wave3/MMP-9 axis. We further show that E2F transcription factor 1 (E2F1) mediates p63α overexpression-induced Hsp70 transcription. We also found that p63α overexpression activates E2F1 transcription, which appears to be stimulated by p63α together with E2F1. Collectively, our results demonstrate that p63α is a positive regulator of BC cell invasion after tumorigenesis, providing significant insights into the biological function of p63α in BC and supporting the notion that p63α might be a potential target for invasive BC therapy.
Highlights
Bladder cancer (BC) is the sixth most common cancer in the United States and is the number one cause of death among patients with urinary system malignancies
We demonstrated that p63␣ overexpression initiated E2F transcription factor 1 (E2F1) mRNA transcription/protein expression through E2F1 self-promoting mechanisms, which promoted heat shock protein 70 (Hsp70) transcription and in turn stabilized Wasf3/Wave3 protein, leading to mmp-9 transcription and BC cell invasion (Fig. 8G)
In this study we found that p63␣ was overexpressed in mouse invasive BC tissues as compared with normal bladder tissues and that overexpressed p63␣ could promote BC cell invasion
Summary
Previous studies have revealed that p63␣ can serve as a tumor suppressor (19 –23). its function in invasion after tumorigenesis remains elusive. The results showed that knockdown of Hsp led to a dramatic decrease in Wasf protein in T24 and T24T cells as compared with their nonsense scramble transfectants (Fig. 4, A and B), suggesting that Wasf might be a downstream effector of Hsp responsible for BC invasion. E–G, Sp1 and E2F1 proteins were consistently elevated in TAp63␣-overexpressed BC cells as compared with their scramble vector transfectants, whereas the effect of ectopic expression of Tap on expression/phosphorylation of C-Jun, CREB, and HSF1 was not consistent in three type BC cell lines, including T24, T24T, and UMUC3, revealing that Sp1 and E2F1 is modulated by TAp63␣ and may participate in hsp transcriptional regulation by p63␣. We demonstrated that p63␣ overexpression initiated E2F1 mRNA transcription/protein expression through E2F1 self-promoting mechanisms, which promoted Hsp transcription and in turn stabilized Wasf3/Wave protein, leading to mmp-9 transcription and BC cell invasion (Fig. 8G)
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