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

Lloyd, Katie A, Parsons, Bryony N ORCID: 0000-0003-3599-1089, Burkitt, Michael D, Moore, Andrew R, Papoutsopoulou, Stamatia ORCID: 0000-0001-6665-8508, Boyce, Malcolm, Duckworth, Carrie A ORCID: 0000-0001-9992-7540, Exarchou, Klaire, Howes, Nathan, Rainbow, Lucille ORCID: 0000-0003-0447-6885
et al (show 6 more authors) (2020) Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors. CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, 10 (1). pp. 113-132.

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<h4>Background & aims</h4>In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of 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 induced gNET regression using gene expression profiling.<h4>Methods</h4>We obtained serum samples and gastric corpus biopsy specimens 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 (Thermofisher Scientific, UK) 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 AGS<sub>GR</sub> gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples.<h4>Results</h4>Levels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the 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. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGS<sub>GR</sub> cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGS<sub>GR</sub> 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.<h4>Conclusions</h4>In an analysis of human gNETS and mice, we found that gastrin up-regulates the 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
Uncontrolled Keywords: Tumorigenesis, Carcinogenesis, Mouse Model, Hormone, Signal Transduction
Depositing User: Symplectic Admin
Date Deposited: 18 Feb 2020 15:27
Last Modified: 19 Jan 2023 00:02
DOI: 10.1016/j.jcmgh.2020.01.010
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