Enhanced epithelial cell turnover associated with p53 accumulation and high p21(WAF1/CIP1) expression in ulcerative colitis

To cast light on accelerated epithelial cell turnover as an important risk factor of dysplasia and carcinoma development in patients with long-standin g ulcerative colitis (UC), we examined cell proliferation and cell death, a s well as expression of apoptosis-related markers, including p53 and p21(WA F1/CIP1), in a series of cases. Biopsy specimens (n = 176; 84, active phase ; 92, remission) were endoscopically obtained from 25 Japanese patients wit h UC. As controls, 68 biopsy specimens of normal mucosa were also examined from 27 Japanese patients with colon polyps. We counted the numbers of mito ses, apoptotic bodies, Ki-67-immunoreactive cells, and p21(WAF1/CIP1)-immun oreactive cells per 1000 crypt cells and the numbers of p53-positive cells per crypt. All of the indices in active UC were significantly higher than i n either remitting UC cases or normal cases (mean mitotic index = 0.52, 0.2 8, and 0.15%, respectively; apoptotic index = 5.40, 2.91, and 1.30%, respec tively; Ki-67 labeling index = 39.5, 28.3, and 26.8%, respectively; p21(WAF 1/CIP1) labeling index = 33.6, 20.0, and 19.0%, respectively; p53 labeling index = 0.66, 0.13, 0.13 per crypt, respectively). In addition, the mitotic , apoptotic, and Ki-67 labeling indices were increased in remitting UC of m ore than 10 years' duration, in comparison with those of less than 10 years ' duration or the normal group. Immunostaining of serial sections revealed a small number of crypt cells coexpressing p53 and p21(WAF1/CIP1). Increase s in both epithelial cell proliferation and cell death, partially associate d with p53 accumulation and high p21(WAF1/CIP1) expression, are thus charac teristic of active phase UC, as well as in remission of longstanding UC. Ac celerated epithelial cell turnover caused by chronic inflammation and epith elial damage might predispose the mucosa to DNA damage, resulting in an ele vated risk of mutation in line with dysplasia and carcinoma development in patients with UC.