p21(Waf1/Cip1) expression and the p53/MDM2 feedback loop in gastric carcinogenesis

Data are non-existent regarding coincidental alterations in the expression: of p53 and its downstream target genes MDM2 and p21(Waf1/Cip1) in gastric c arcinogenesis, An immunohistochemical study was therefore performed to exam ine the interrelationships of p53, MDM2, and p21(Waf1/Cip1) expression in a series of Caucasian early gastric carcinomas and precursor lesions, In nor mal gastric mucosa, chronic gastritis, and intestinal metaplasia, the surfa ce cells expressed p21(Waf1/Cip1) in the absence of detectable nuclear p53 and MDM2 protein, Nuclear p53 protein accumulation was found in 60 per cent of the! carcinomas, with significant differences in staining characteristi cs between the Lauren types in the absence of detectable MDM2 protein (p<0. 005). Nearly 80 per cent of the carcinomas expressed p21(Waf1/Cip1), irresp ective of Lauren type, Stratification of the carcinomas according to histol ogical grade and growth pattern did not result in significant differences i n p53 and p21(Waf1/Cip1) expression. Finally, no Significant correlation wa s found between overall p53 and p21(Waf1/Cip1) expression in early gastric carcinomas. It is concluded that p21(Waf1/Cip1) expression in the non-neopl astic mucosa most likely relates to cell senescence and/or terminal differe ntiation, perhaps-even in a p53-independent manner, In view of p53/MDM2 hom eostasis, the differences in p53 staining characteristics between intestina l and diffuse-type carcinomas probably result, at least in part, from a dif ference in the prevalence of p53 gene mutations. Moreover, p53-independent induction of p21(Waf1/Cip1) expression apparently occurs in a considerable proportion of early carcinomas. Finally, in contrast to other carcinomas, p 21(Waf1/Cip1) expression is not significantly correlated with histological grade in gastric carcinomas, suggesting possible defects downstream of p21( Waf1/Cip1) as an underlying cause for this apparent discrepancy. Copyright (C) 1999 John Wiley & Sons, Ltd.