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Lookup NU author(s): Marina Saisana, Professor Michael Griffin, Dr Felicity May
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2021, The Author(s). Background: Gastric adenocarcinoma is common and consequent mortality high. Presentation and mortality are increased in obese individuals, many of whom have elevated circulating insulin concentrations. High plasma insulin concentrations may promote, and increase mortality from, gastric adenocarcinoma. Tumour promotion activities of insulin and its receptor are untested in gastric cancer cells. Methods: Tumour gene amplification and expression were computed from sequencing and microarray data. Associations with patient survival were assessed. Insulin-dependent signal transduction, growth, apoptosis and anoikis were analysed in metastatic cells from gastric adenocarcinoma patients and in cell lines. Receptor involvement was tested by pharmacological inhibition and genetic knockdown. RNA was analysed by RT-PCR and proteins by western transfer and immunofluorescence. Results: INSR expression was higher in tumour than in normal gastric tissue. High tumour expression was associated with worse patient survival. Insulin receptor was detected readily in metastatic gastric adenocarcinoma cells and cell lines. Isoforms B and A were expressed. Pharmacological inhibition prevented cell growth and division, and induced caspase-dependent cell death. Rare tumour INS expression indicated tumours would be responsive to pancreatic or therapeutic insulins. Insulin stimulated gastric adenocarcinoma cell PI3-kinase/Akt signal transduction, proliferation, and survival. Insulin receptor knockdown inhibited proliferation and induced programmed cell death. Type I IGF receptor knockdown did not induce cell death. Conclusions: The insulin and IGF signal transduction pathway is dominant in gastric adenocarcinoma. Gastric adenocarcinoma cell survival depends upon insulin receptor. That insulin has direct cancer-promoting effects on tumour cells has implications for clinical management of obese and diabetic cancer patients.
Author(s): Saisana M, Griffin SM, May FEB
Publication type: Article
Publication status: Published
Journal: Gastric Cancer
Year: 2022
Volume: 25
Pages: 107-123
Print publication date: 01/01/2022
Online publication date: 23/09/2021
Acceptance date: 12/08/2021
Date deposited: 07/10/2021
ISSN (print): 1436-3291
ISSN (electronic): 1436-3305
Publisher: Springer Nature
URL: https://doi.org/10.1007/s10120-021-01236-y
DOI: 10.1007/s10120-021-01236-y
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