Induction of MDM2-P2 transcripts correlates with stabilized wild-type p53 in betel- and tobacco-related human oral cancer

MDM2, a critical element of cellular homeostasis mechanisms, is involved in complex interactions with important cell-cycle and stress-response regulat ors including p53, The mdm2-P2 promoter is a transcriptional target of p53, The aim of this study was to determine the association between mdm2-P2 tra nscripts and the status of the p53 gene in betel- and tobacco-related oral squamous cell carcinomas (SCCs) to understand the mechanism of deregulation of MDM2 and p53 expression and their prognostic implications in oral tumor igenesis. Elevated levels of MDM2 proteins were observed in 11 of 25 (44%) oral hyperplastic lesions, nine of 15 (60%) dysplastic lesions, and 71 of 1 00 (71%) SCCs. The intriguing feature of the study was the identification a nd different subcellular localization of three isoforms of MDM2 (ie, 90 kd, 76 kd, and 57 kd) in oral SCCs and their correlation with p53 overexpressi on in each tumor. The hallmark of the study was the detection of mdm2-P2 tr anscripts in 12 of 20 oral SCCs over-expressing both MDM2 and p53 proteins while harboring wild-type p53 alleles. Furthermore, mdm2 amplification was an infrequent event in betel- and tobacco-associated oral tumorigenesis, Th e differential compartmentalization of the three isoforms of MDM2 suggests that each has a distinct function, potentially in the regulation of p53 and other gene products implicated in oral tumorigenesis. In conclusion, we re port herein the first evidence suggesting that enhanced translation of mdm2 -P2 transcripts (S-mdm2) may represent an important mechanism of overexpres sion and consequent stabilization and functional inactivation of wild-type p53 serving as an adverse prognosticator in betel- and tobacco-related oral cancer. The clinical significance of the functional inactivation of wild-t ype p53 by MDM2 is underscored by the significantly shorter median disease- free survival time (16 months) observed in p53/MDM2-positive cases as compa red to those which did not show co-expression of these proteins (median tim e, 26 months; P = 0.02).