The role of the obestatin/GPR39 system in human gastric adenocarcinomas

Abstract

Obestatin, a 23-amino acid peptide encoded by the ghrelin gene, and the GPR39 receptor were reported to be involved in the control of mitogenesis of gastric cancer cell lines; however, the relationship between the obestatin/GPR39 system and gastric cancer progression remains unknown. In the present study, we determined the expression levels of the obestatin/GPR39 system in human gastric adenocarcinomas and explored their potential functional roles. Twenty-eight patients with gastric adenocarcinomas were retrospectively studied, and clinical data were obtained. The role of obestatin/GPR39 in gastric cancer progression was studied in vitro using the human gastric adenocarcinoma AGS cell line. Obestatin exogenous administration in these GPR39-bearing cells deregulated the expression of several hallmarks of the epithelial-mesenchymal transition (EMT) and angiogenesis. Moreover, obestatin signaling promoted phenotypic changes via GPR39, increasingly impacting on the cell morphology, proliferation, migration and invasion of these cells. In healthy human stomachs, obestatin expression was observed in the neuroendocrine cells and GPR39 expression was localized mainly in the chief cells of the oxyntic glands. In human gastric adenocarcinomas, no obestatin expression was found; however, an aberrant pattern of GPR39 expression was discovered, correlating to the dedifferentiation of the tumor. Altogether, our data strongly suggest the involvement of the obestatin/GPR39 system in the pathogenesis and/or clinical outcome of human gastric adenocarcinomas and highlight the potential usefulness of GPR39 as a prognostic marker in gastric cancer.

Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth

“…Similar increase in GPR39 expression was found in human esophageal squamous cell carcinoma and was linked to enhanced cell growth in the KYSE30 esophageal carcinoma cell line 58 . While a direct role for Zn 2+ was not determined, upregulation of GPR39 was also demonstrated in aggressive cancer cell lines of breast, ovarian and prostate, and melanoma 59 and was linked to EGFR transactivation 60 . Moreover, GPR39 overexpression in porcine intramuscular preadipocytes enhanced their differentiation and proliferation via the PI3K pathway.…”

microRNA‐1914, which is regulated by lncRNA DUXAP10, inhibits cell proliferation by targeting the GPR39‐mediated PI3K/AKT/mTOR pathway in HCC

“…GPR39, a G protein-coupled receptor activated by zinc, controls proliferation and differentiation in different cells [27][28][29]. GPR39 is also dysregulated in cancers [30][31][32]. Here, we showed that miR-1914 inhibited PI3K/AKT/ mTOR signalling.…”

The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease

“…As such, GPR39 was overexpressed in primary human esophageal squamous cell carcinomas and its silencing reduced the tumorigenicity of these cells [ 178 ]. A recent study suggested that GPR39 expression is modulated in gastric adenocarcinoma [ 179 ], yet this study applied a previously incorrectly suggested ligand of GPR39 and not Zn 2+ [ 180 ]. Interestingly, a link between the ZnR/GPR39 and mRNA levels of the Zn 2+ transporter ZIP13 was recently shown in bone [ 61 ], but whether ZnR/GPR39 regulates other members of the ZIP family of Zn 2+ transporters is unknown.…”