Thymidylate synthase accelerates Men1-mediated pancreatic tumor progression and reduces survival.
Mouse models
Oncogenes
Oncology
Tumor suppressors
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
10 10 2022
10 10 2022
Historique:
received:
25
01
2021
accepted:
31
08
2022
pubmed:
2
9
2022
medline:
12
10
2022
entrez:
1
9
2022
Statut:
epublish
Résumé
Clinical studies of cancer patients have shown that overexpression or amplification of thymidylate synthase (TS) correlates with a worse clinical outcome. We previously showed that elevated TS exhibits properties of an oncogene and promotes pancreatic neuroendocrine tumors (PanNETs) with a long latency. To study the causal impact of elevated TS levels in PanNETs, we generated a mouse model with elevated human TS (hTS) and conditional inactivation of the Men1 gene in pancreatic islet cells (hTS/Men1-/-). We demonstrated that increased hTS expression was associated with earlier tumor onset and accelerated PanNET development in comparison with control Men1-/- and Men1+/ΔN3-8 mice. We also observed a decrease in overall survival of hTS/Men1+/- and hTS/Men1-/- mice as compared with control mice. We showed that elevated hTS in Men1-deleted tumor cells enhanced cell proliferation, deregulated cell cycle kinetics, and was associated with a higher frequency of somatic mutations, DNA damage, and genomic instability. In addition, we analyzed the survival of 88 patients with PanNETs and observed that high TS protein expression independently predicted worse clinical outcomes. In summary, elevated hTS directly participates in promoting PanNET tumorigenesis with reduced survival in Men1-mutant background. This work will refocus attention on new strategies to inhibit TS activity for PanNET treatment.
Identifiants
pubmed: 36048542
pii: 147417
doi: 10.1172/jci.insight.147417
pmc: PMC9675466
doi:
pii:
Substances chimiques
Men1 protein, mouse
0
Proto-Oncogene Proteins
0
Thymidylate Synthase
EC 2.1.1.45
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
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