Abstract
The cytoprotective protein clusterin is often dysregulated during tumorigenesis, and in the stomach, upregulation of clusterin marks emergence of the oxyntic atrophy (loss of acid-producing parietal cells)-associated spasmolytic polypeptide-expressing metaplasia (SPEM). The hormone gastrin is important for normal function and maturation of the gastric oxyntic mucosa and hypergastrinemia might be involved in gastric carcinogenesis. Gastrin induces expression of clusterin in adenocarcinoma cells. In the present study, we examined the expression patterns and gastrin-mediated regulation of clusterin in gastric tissue from: humans; rats treated with proton pump (H+/K+-ATPase) inhibitors and/or a gastrin receptor (CCK2R) antagonist; H+/K+-ATPase β-subunit knockout (H/K-β KO) mice; and Mongolian gerbils infected with Helicobacter pylori and given a CCK2R antagonist. Biological function of secretory clusterin was studied in human gastric cancer cells. Clusterin was highly expressed in neuroendocrine cells in normal oxyntic mucosa of humans and rodents. In response to hypergastrinemia, expression of clusterin increased significantly and its localization shifted to basal groups of proliferative cells in the mucous neck cell-chief cell lineage in all animal models. That shift was partially inhibited by antagonizing the CCK2R in rats and gerbils. The oxyntic mucosa of H/K-β KO mice contained areas with clusterin-positive mucous cells resembling SPEM. In gastric adenocarcinomas, clusterin mRNA expression was higher in diffuse tumors containing signet ring cells compared with diffuse tumors without signet ring cells, and clusterin seemed to be secreted by tumor cells. In gastric cancer cell lines, gastrin increased secretion of clusterin, and both gastrin and secretory clusterin promoted survival after starvation- and chemotherapy-induced stress. Overall, our results indicate that clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and stimulates gastric cancer cell survival.
Highlights
In the gastric oxyntic mucosa, glands are divided into different zones containing characteristic cell lineages that normally differentiate from immature progenitor cells in isthmus [1,2,3]
In oxyntic mucosa of wildtype mice, CLU expression pattern was different from other rodents, with CLU expressed in ECL cells (HDC-positive) (Fig 1C) as well as in mucous neck cells (GSII-positive) (Fig 1D), as previously reported [17]
CLU expression in oxyntic mucosa of CCK2R-antagonized H. pylori-infected gerbils was restricted to non-proliferative single cells, including ECL cells (Fig 5A, 5B and 5D), and there were no visible signs of spasmolytic polypeptide-expressing metaplasia (SPEM) (Fig 5G), as the mucosa in general was unchanged from uninfected controls [27]. These results indicate that, in different animal models with hypergastrinemia due to diminished parietal cell proton pump function or H. pyloriinfection, CLU is overexpressed in basal groups of cells from the mucous neck cell-chief cell lineage, and that overexpression can be inhibited partially by antagonizing the CCK2R
Summary
In the gastric oxyntic mucosa, glands are divided into different zones containing characteristic cell lineages that normally differentiate from immature progenitor cells in isthmus [1,2,3]. The typical differentiation pattern is disrupted and the mucosa undergoes step-wise transformation, which for the intestinal type gastric adenocarcinoma is thought to progress through oxyntic atrophic (loss of acid-secreting parietal cells) gastritis, intestinal metaplasia and dysplasia before emergence of cancer [4, 5]. Gastrin is a key secretagogue for gastric acid, and regulates cell proliferation, apoptosis and migration, making it essential for normal growth and maturation of the oxyntic mucosa [9,10,11]. In oxyntic mucosa of rats, proton pump (H+/K+-ATPase) inhibitor (PPI)-induced hypergastrinemia led to increased CLU expression and a prominent shift in the CLU expression pattern [13]
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