Enhanced Cellular Proliferation and p53 Accumulation in Gastric Mucosa Chronically Infected With Helicobacter pylori

Abstract

This study evaluated whether the increased risk of development of gastric carcinoma due to chronic Helicobacter pylori infection could be linked with elevated cell proliferative activity and expression of p53 and bcl-2. Forty-eight patients undergoing therapy for H pylori-positive gastroduodenal ulcers were separated into not eradicated (NE; n = 23) and eradicated (E; n = 25) groups 6 months after the treatment. Serum pepsinogen (PG) 1:11 ratios and histologic changes in the gastric corpus and the antrum, assessed according to the modified Sydney System, as well as epithelial cell proliferation (mitosis, Ki67, and proliferating cell nuclear antigen [PCNA]), and expression of oncoproteins (p53 and bcl-2) were examined before and at 3 months and 6 months after treatment for H pylori. Manuscript received October 10, 1996; revision accepted January 3,1997.A d d r e s s r e p r i n t requests to Dr Mitomi: D e p a r t m e n t of Pathology, Kitasato University East Hospital, Asamizodai 2-1-1, Sagamihara, 228 Japan. infection was associated with a low PG 1:11 ratio, increased inflammation and activity score, and elevated cell proliferation, as evidenced by the Ki67 and PCNA labeling indexes and the mitotic index in the NE group. Scattered accumulation of p53 protein continued to be observed in the NE group after treatment but was significantly decreased in the E group. We conclude that persistent H pylori infection causes gastritis, with epithelial degeneration and regeneration that result in accentuation of epithelial cell proliferation and accumulation of p53 protein, presumably heightening the genetic instability consistent with the development of carcinoma. (Key words: Helicobacter pylori; Gastritis; Cell proliferation; Ki67; p53; Gastric carcinoma) Am J Clin Pathol 1997;108:26-34. degeneration and regeneration of the mucosal epithelium that could facilitate malignant transformation. To test that hypothesis, H pylori-positive patients received treatments aimed at eradication and were then divided into groups depending on whether eradication was successful. Determinations of the serum pepsinogen (PG) 1:11 ratio, as a parameter for inflammation, and anti-H pylori antibody titer were made, along with estimates of cellular proliferation and expression of p53 and bcl-2 proteins in the mucosa, for comparison between patients in whom H pylori was eradicated and those in whom it was not. PATIENTS AND METHODS PatientsForty-eight patients with H pylori infection were studied, including 31 with gastric ulcers, 13 with duodenal ulcers, and 4 with gastroduodenal ulcers. The regimens for eradication therapy were selected by a double-blind method. From the results of the rapid urease test and histologic detection of H pylori, 26

Molecular mechanisms ofH. pyloriassociated gastric carcinogenesis

“…Overexpression of bax and bak proteins encoded by the two pro-apoptotic members of the bcl-2 gene family has been associated with H. pylori infection and to induce apoptosis in the AGS gastric epithelial cell line and in gastric mucosal biopsi es from patients colonized by H. pylori [57] . In contrast, the expression of bcl-2 protein was not affected or even suppressed by this organism [37] . However, overexpression of bcl-2 with abnormal distribution of apop totic cells along the glands, which are usually found at the extremities of normal gastric glands, has been described in both intestinal metaplasia and gastric dysplasia, which occur as a result of longterm H. pylori infection [58,59] .…”

“…However, the enhanced p53 expression failed to have any effect on gastric epithelial cell proliferation or apoptosis, and there appeared to be a positive relationship between the accelerated cell turnover and p53 over-expression. The accumulation of p53 was also not associated with expression of the CDI p21, a down-stream effector of p53 [37,38] . We have recently in itiated a study investigating the role of p53 in H. pylori infected gastric cell lines and found that H. pylori associated apoptosis is independent to p53 status of gastric cells [39] .…”

Helicobacter pyloriCagA-Dependent Macrophage Migration Inhibitory Factor Produced by Gastric Epithelial Cells Binds to CD74 and Stimulates Procarcinogenic Events

“…As for the effect of H. pylori on p53, there is conflicting information available. Several studies suggest there are no changes in p53 levels of the gastric mucosa during infection (48,49), while others suggest that p53 levels are increased during infection (50,51). However, these studies only looked at total p53 present, but failed to investigate levels of phosphorylated p53.…”

Clinicopathologic Characteristics and Prognoses for Multicentric Occurrence and Intrahepatic Metastasis in Synchronous Multinodular Hepatocellular Carcinoma Patients

“…Chronic inflammation increases oxidative stress and the levels of reactive oxygen species (ROS), the latter of which is believed to be one of the most important factors leading to DNA damage (Lestienne, 1992;Hibi et al, 1997;Amuthan et al, 2001). Because mtDNA lacks histones, which protect against ROS-induced DNA injury, and there is no effective DNA repair system, damage to mtDNA is more frequent and serious than damage to nuclear DNA (Croteau et al, 1997).…”