Expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and p53 tumor suppressor in dysplastic progression and adenocarcinoma in Barrett esophagus.

Abstract

Barrett esophagus predisposes individuals to esophageal carcinoma, which develops from intermediate stages of tissue dysplasia primarily in the vicinity of the gastroesophageal junction. Understanding the cellular and molecular events in the progression of Barrett esophagus to adenocarcinoma may contribute to its early diagnosis and treatment. Mutation and overexpression of the tumor suppressor p53 have previously been observed in Barrett high grade dysplasia and adenocarcinoma. The expression of the cyclin-dependent kinase (CdK) inhibitor p21 can be up-regulated by p53, resulting in the down-regulation of cell division at the G(1)/S-phase transition. The current study examined the correlation between the expression of p21 and p53 by quantifying their levels during the progression of dysplasia and adenocarcinoma in Barrett esophageal tissues. Barrett esophageal tissue samples that were negative or indefinite for dysplasia, contained dysplasia, and contained adenocarcinoma were examined by immunohistochemistry. Paraffin embedded sections of lining and glandular epithelia were adsorbed with primary murine antibodies against human p21 or p53 followed by horseradish peroxidase secondary antibody. An immunoreactivity score for each primary antibody and section was obtained by multiplying a staining intensity factor by the percent of positively stained cells. Nuclear p21 expression was detectable immunohistochemically in Barrett esophagus that was negative for dysplasia, but it was significantly elevated (P </= 0.05) in tissues scored as indefinite for dysplasia, positive for low grade or high grade dysplasia, and positive for adenocarcinoma. Importantly, p53 expression did not parallel p21 expression. p53 levels were low in the early stages of Barrett dysplasia and were increased in high grade dysplasia and adenocarcinoma. There were no differences in p21 or p53 levels between glandular and lining epithelia in Barrett tissue throughout the histologic stages of neoplastic progression evaluated in this study. p21 expression in Barrett tissue scored as indefinite for dysplasia or low grade dysplasia was significantly elevated relative to p53 expression. Elevated levels of p21 were also observed in high grade dysplasia and adenocarcinoma, in which they do not appear to be effective in down-regulating cell division. Analysis of p21 and p53 expression may aid in the evaluation of tissue abnormalities in Barrett esophagus.