The p51/p63 gene (TP63) codes for a p53-like protein (Nat. Med. 4:839, 1998) in various isoforms, and is required for development of the skin, oral tissues, limb and other ectodermal epithelia. High-level expression of p51/p63 frequently occurs in head-and-neck squamous cell carcinomas and cancers derived from the basal cells, implying participation of p51/p63 in carcinogenesis and/or manifestation of the cancer phenotype. p51/p63 not only trans-activates some of the p53-responsive genes, but also influences genes involved in cell differentiation and tissue development. We reported that p51/p63 activates ITGA3 and MFGE8 encoding integrin α3 and milk fat globule-EGF factor 8 (MFG-E8) respectively (J. Biol. Chem. 279:50069, 2004 and manuscript submitted by Okuyama et al.). To understand physiological functions of p51/p63, we performed p51/p63-silencing in a hypopharyngeal squamous cell carcinoma line, FaDu, with a recombinant retrovirus (Retro-p63i) and synthetic siRNAs (p63si). In addition to RT-PCR and Western blotting, gene expression profiling and immunocytostaining were also carried out to analyze cellular responses. Retro-p63i infected cells and p63si-transfected cells caused 50% and 80% decrease in the p51/p63 isoforms, respectively. In both experiments, we detected suppression of the proposed p51/p63-responsive genes. Moreover, these cells underwent significant growth suppression accompanied by morphological alterations including cell flattening. Cell-basement and cell-cell attachment was affected. These results suggest that p51/p63 facilitates proliferation of squamous cell carcinomas by inducing adhesion molecules.
(This study was supported by Grants-in Aid for Scientific Research on Priority Areas from MEXT, Japan.)
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA