The cytoprotective protein clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and promotes gastric cancer cell survival

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.

Subtle Protective Roles of Clusterin in Gastric Metaplasia After Acute Oxyntic Atrophy

“…Gastric cancer is preceded by mucosal remodeling like spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia. The cytoprotective protein clusterin (CLU) is highly expressed in oxyntic mucosa during the emergence of metaplasia, but it is unknown whether CLU promotes or counteracts the process 1, 2, 3, 4. Here, we use clusterin knockout (CLU-KO) mice to examine the role of CLU in the emergence, recovery, and repair of gastric metaplasia after tamoxifen-induced acute oxyntic atrophy 5 .…”

Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H+/K+ATPase Beta Subunit Knockout Mice

“…This showed that numerous genes previously reported to be associated with SPEM were overexpressed in KO/PEG versus WT/PEG mice, including tff2, clu, muc6, cd44 and wfdc2, with no significant change in KO mice receiving NTZ (Table 2). It was confirmed by both IHC and ISH that KO/PEG mice had pronounced expression of the SPEM markers TFF2 and clusterin in the gastric corpus [23] (Figures 3 and 4), and that the SPEM did not seem to be affected by NTZ. There was also overexpression of markers of intestinalizing transcripts such as cftr and muc4.…”

“…We have previously found that the SPEM marker clusterin is highly expressed in ECL cells of normogastrinemic rats, but in rats with hypergastrinemia due to PPI administration, clusterin expression was considerably increased, through a dominant shift in the expression towards cells of the mucous neck-chief cell lineages. [23]. Moreover, clusterin was found to be highly upregulated in mucus neck and SPEM cells of the H + /K + ATPase beta subunit KO mice of different ages [23].…”

“…[23]. Moreover, clusterin was found to be highly upregulated in mucus neck and SPEM cells of the H + /K + ATPase beta subunit KO mice of different ages [23]. However, the finding of accelerated SPEM development in gastrin KO mice given DMP-777 [17] demonstrates of 18 that SPEM development in mice cannot depend entirely on gastrin.…”

“…We have previously described SPEM in oxyntic mucosa of 3-month-old H + /K + ATPase beta subunit KO mice [23]. Others have reported mice of age 35 days to be depleted of mature chief cells based on morphological criteria in HE stained sections [50].…”