Netazepide Inhibits Expression of Pappalysin 2 in Type-1 Gastric Neuroendocrine Tumors

Lloyd, K. A., Parsons, B. N., Burkitt, M. D., Moore, A. R., Papoutsopoulou, S., Boyce, M., Duckworth, C. A., Exarchou, K., Howes, N., Rainbow, L., Fang, Y., Oxvig, C., Dodd, S., Varro, A., Hall, N. and Pritchard, D. M. (2020) Netazepide Inhibits Expression of Pappalysin 2 in Type-1 Gastric Neuroendocrine Tumors. Cellular and Molecular Gastroenterology and Hepatology. ISSN 2352-345X

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Background & Aims In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with development of type-1 gastric neuroendocrine tumors (gNETs). Twelve months’ treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type-1 gNETs in patients. We investigated the mechanisms by which netazepide induces gNET regression using gene expression profiling. Methods We obtained serum samples and gastric corpus biopsies from 8 patients with hypergastrinemia and type-1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type-1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGSGR gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples. Results Levels of pappalysin 2 (PAPPA2) mRNA were significantly reduced in gNET tissues from patients receiving netazepide therapy compared to tissues collected before therapy. PAPPA2 is a metalloproteinase that increases bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type-1 gNETs and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Upregulation of PAPPA2 was also found in stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner, in gastric AGSGR cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGSGR cells with small interfering RNAs significantly decreased their migratory response and tissue remodeling in response to gastrin. Gastrin altered the expression and cleavage of IGFBP3 and IGFBP5. Conclusions In an analysis of human gNETS and mice, we found that gastrin upregulates expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type-1 gNET development. These effects are inhibited by netazepide.

Item Type: Article
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 30 Jan 2020 04:15
Last Modified: 28 Mar 2020 01:28
DOI: 10.1016/j.jcmgh.2020.01.010

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