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Thymidylate synthase accelerates Men1-mediated pancreatic tumor progression and reduces survival

  1. Author:
    Vijayakurup, Vinod
    Maeng, Kyungah
    Lee, Hye Seung
    Meyer, Benjamin S
    Burkett,Sandra
    Nawab, Akbar
    Dougherty, Michael W
    Jobin, Christian
    Mahmud, Iqbal
    Garrett, Timothy J
    Feely, Michael
    Lee, Kyoung Bun
    Kaye, Frederic J
    Guijarro, Maria V
    Zajac-Kaye, Maria

  2. Author Address

    Department of Anatomy and Cell Biology, University of Florida, Gainesville, United States of America., Department of Pathology, College of Medicine, Seoul National University, Seoul, Korea, Republic of., Molecular Cytogenetics Core Facility, National Cancer Insititute, Frederick, United States of America., Department of Medicine, College of Medicine University of Florida, Gainesville, United States of America., Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, United States of America., Department of Medicine, University of Florida, Gainesville, United States of America.,
    1. Year: 2022
    2. Date: Sep 01
    3. Epub Date: 2022 09 01
  2. Journal: JCI Insight
    1. 7
    2. 19
  4. Type of Article: Article
  5. Article Number: e147417
  1. Abstract:

    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 Men1 gene in pancreatic islet cells (hTS/Men1-/-). We demonstrated that increased hTS expression was associated with earlier tumor onset and accelerated PanNET development as compared to control Men1-/- and Men1+/?N3-8 mice. We also observed decrease in overall survival of hTS/Men1+/- and hTS/Men1-/- mice as compared to 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 survival of 88 PanNET patients and observed that high TS protein expression independently predicted worse clinical outcome. In summary, elevated hTS directly participates in promoting PanNET tumorigenesis with reduced survival in Men1 mutant background. This work will re-focus attention on new strategies to inhibit TS activity for PanNET treatment.

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External Sources

  1. View Full Text
  2. DOI: 10.1172/jci.insight.147417
  3. PMID: 36048542
  4. View record in Web of Science®
  5. WOS: 000868146200001
  6. PII : 147417

Library Notes

  1. Fiscal Year: FY2022-2023
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