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

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  • Katie A. Lloyd, University of Liverpool
  • ,
  • Bryony N. Parsons, University of Liverpool
  • ,
  • Michael D. Burkitt, University of Liverpool
  • ,
  • Andrew R. Moore, University of Liverpool
  • ,
  • Stamatia Papoutsopoulou, University of Liverpool
  • ,
  • Malcolm Boyce, Trio Medicines Ltd.
  • ,
  • Carrie A. Duckworth, University of Liverpool
  • ,
  • Klaire Exarchou, University of Liverpool
  • ,
  • Nathan Howes, University of Liverpool
  • ,
  • Lucille Rainbow, University of Liverpool
  • ,
  • Yongxiang Fang, University of Liverpool
  • ,
  • Claus Oxvig
  • Steven Dodd, University of Liverpool
  • ,
  • Andrea Varro, University of Liverpool
  • ,
  • Neil Hall, University of Liverpool, University of East Anglia
  • ,
  • D. Mark Pritchard, University of Liverpool

Background & Aims: 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. Methods: 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 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) 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 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 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.

Original languageEnglish
JournalCellular and Molecular Gastroenterology and Hepatology
Pages (from-to)113-132
Number of pages20
Publication statusPublished - Jan 2020

    Research areas

  • Carcinogenesis, Hormone, Mouse Model, Signal Transduction, Tumorigenesis

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