High level expression of Delta N-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)?

Undifferentiated nasopharyngeal carcinoma (NPC) is an epithelial malignancy that is consistently associated with Epstein-Barr virus (EBV) but which ve ry rarely has p53 gene mutations in primary tumours, Since the tumour suppr essor p53 is mutated in most human canters or the wild type protein is inac tivated in a significant number of the remainder, here we have investigated cellular factors that could compromise p53 function in primary NPC, Twenty -five primary tumours were judged to carry only wild type p53 by SSCP analy sis of all exons and sequence determination of exons 4-9, Only one tumour w as found to express significant levels of hMdm2 and in 24/25 there were no detectable mutations or deletions in exons 1 beta and 2 of the p14(ARF) gen e. However, immunohistochemistry consistently revealed that all the tumour cells express substantial amounts of the p53-related protein p63, Semi-quan titative RT- PCR analysis of mRNA from tumour biopsies showed that the domi nant species expressed was invariably the truncated Delta N-isotype. Since this can block p53-mediated transactivation, it is potentially a dominant-n egative isoform, In normal nasopharyngeal epithelium the distribution of p6 3 was restricted to the proliferating basal and suprabasal layers. We sugge st that Delta N-p63 is a good candidate as a suppressor of wild type p53 fu nction in these tumours and also that it may prove to be a valuable diagnos tic marker for undifferentiated NPC.