Loss of ΔNp63α Promotes Invasion of Urothelial Carcinomas via N-Cadherin/Src Homology and Collagen/Extracellular Signal-Regulated Kinase Pathway

p63 plays a critical role in normal development and maintenance of stratified epithelia, including the urothelium. In the normal urothelium, urothelial cells in the basal layers abundantly express the predominant p63 isoform Delta Np63 alpha. We previously showed that (a) Delta Np63 alpha expression at the similar level to the normal urothelium is retained in most low-grade papillary noninvasive (LPN) tumors, whereas frequently lost in high-grade invasive carcinomas, and that (b) loss of Delta Np63 alpha is associated with poor prognosis of invasive bladder urothelial carcinoma patients. However, a functional role of Delta Np63 alpha in progression of urothelial carcinomas remains to be elucidated. Here, we show that loss of Delta Np63 alpha expression promotes invasion of urothelial carcinoma cells. In 5637 cells substantially expressing only Delta Np63 alpha isoform at the protein level, knockdown of endogenous p63 upregulated N-cadherin, which recruited more Src homology and collagen to N-cadherin and activated extracellular signal-regulated kinase (ERK) signaling, and consequently potentiated cell motility, excretion of matrix metalloproteinase-9, and invasion. In T24 cells originally lacking endogenous Delta Np63 alpha expression, exogenous expression of Delta Np63 alpha attenuated invasion by downregulating N-cadherin expression and ERK activity, confirming an invasin-suppressive role of Delta Np63 alpha in urothelial carcinoma cells. We further documented loss of Delta Np63 expression accompanied by N-cadherin upregulation during muscle-invasive recurrence in patients whose bladder cancer had progressed from LPN tumors to muscle-invasive disease. These results suggest that loss of Delta Np63 alpha. and subsequent upregulation of N-cadherin is one of the mechanisms underlying progression of bladder cancer. [Cancer Res 2009;69(24):9263-70]