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Netazepide inhibits expression of Pappalysin 2 in type-1 gastric neuroendocrine tumors
- Source :
- 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 & Pritchard, D M 2020, ' Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors ', Cellular and Molecular Gastroenterology and Hepatology, vol. 10, no. 1, pp. 113-132 . https://doi.org/10.1016/j.jcmgh.2020.01.010, Cellular and Molecular Gastroenterology and Hepatology, Cellular and Molecular Gastroenterology and Hepatology, Vol 10, Iss 1, Pp 113-132 (2020)
- Publication Year :
- 2020
-
Abstract
- 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.<br />Graphical abstract
- Subjects :
- HDC, histidine decarboxylase
0301 basic medicine
IGF, insulin-like growth factor
Atrophic gastritis
Carcinogenesis
IGFBP3
Achlorhydria
Benzodiazepines
Mice
0302 clinical medicine
Pregnancy-Associated Plasma Protein-A
Original Research
Gastrin
Benzodiazepinones
Gene knockdown
IGFBP, insulin-like growth factor binding protein
Stomach
Gastroenterology
mRNA, messenger RNA
Organoids
MMP, matrix metalloproteinase
Neuroendocrine Tumors
Treatment Outcome
medicine.anatomical_structure
Gene Knockdown Techniques
Cholecystokinin B receptor
qPCR, quantitative polymerase chain reaction
Immunohistochemistry
030211 gastroenterology & hepatology
Signal Transduction
Primary Cell Culture
PBS, phosphate-buffered saline
TIMP, tissue inhibitors of metalloproteinases
Mice, Transgenic
CHGA, chromogranin A
PAPPA2, pappalysin 2
03 medical and health sciences
Stomach Neoplasms
Cell Line, Tumor
Gastrins
CCK2R, cholecystokinin type-2 receptor
medicine
Animals
Humans
lcsh:RC799-869
Mouse Model
Hepatology
business.industry
Phenylurea Compounds
medicine.disease
Hormone
Receptor, Cholecystokinin B
Disease Models, Animal
030104 developmental biology
gNET, gastric neuroendocrine tumor
Gastric Mucosa
siRNA, small interfering RNA
ECL, enterochromaffin-like
Tumorigenesis
Cancer research
lcsh:Diseases of the digestive system. Gastroenterology
BSA, bovine serum albumin
business
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- 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 & Pritchard, D M 2020, ' Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors ', Cellular and Molecular Gastroenterology and Hepatology, vol. 10, no. 1, pp. 113-132 . https://doi.org/10.1016/j.jcmgh.2020.01.010, Cellular and Molecular Gastroenterology and Hepatology, Cellular and Molecular Gastroenterology and Hepatology, Vol 10, Iss 1, Pp 113-132 (2020)
- Accession number :
- edsair.doi.dedup.....7554914bc0596db17395b9f59dbcfa2f