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Tissue-specific induced DNA methyltransferase 1 (Dnmt1) in endocrine pancreas by RCAS-TVA-based somatic gene transfer system promotes β-cell proliferation

Cancer Gene Therapy volume 26, pages 94–102 (2019)Cite this article

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Abstract

We reported that inactivation of menin (the protein product of MEN1) increases activity of Dnmt1 and mediates DNA hypermethylation in the development of multiple endocrine neoplasia type 1 (MEN1) syndrome. We have developed a RCAS-TVA-based somatic gene transfer system that enables tissue-specific delivery of Dnmt1 to individual β-cells of the pancreas in a RIP-TVA mouse model. In the present study, we mediated Dnmt1 expression in islet β-cells in RIP-TVA mice by utilizing the RCAS-TVA system to test if the upregulation of Dnmt1 can promote β-cell proliferation. In vitro, we demonstrated that upregulation of Dnmt1 increased β-cell proliferation. In vivo, our results showed that the levels of serum insulin were increased in the RIP-TVA mice with RCASBP-Dnmt1 infection compared with wild-type control mice with RCASBP-Dnmt1 infection. Furthermore, we confirmed that mRNA and protein expression of Dnmt1 as well as Dnmt1 enzyme activity were upregulated in the RIP-TVA mice with RCASBP-Dnmt1 infection compared with wild-type control mice with RCASBP-Dnmt1 infection. Finally, we demonstrated that upregulation of Dnmt1 resulted in hyperplasia through β-cell proliferation. We conclude that the upregulation of Dnmt1 promotes islet β-cell proliferation and targeting Dnmt1 may be a promising therapy for patients suffering from pancreatic neuroendocrine tumors.

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Authors and Affiliations

  1. Department of Medical Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Ziqiang Yuan

  2. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Ziqiang Yuan, Juliet C. Gardiner, Elaine C. Maggi, Asha Adem, Sylvia Lee, Peter Romanienko & Steven K. Libutti

  3. Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA

    Elaine C. Maggi

  4. Department of Pathology and Lab Medicine, Weill Cornell Medicine, New York, NY, USA

    George Zhang & Yi-Chieh Nancy Du

  5. Department of Surgery, Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Steven K. Libutti

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  1. Ziqiang Yuan
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Correspondence to Steven K. Libutti.

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Yuan, Z., Gardiner, J., Maggi, E.C. et al. Tissue-specific induced DNA methyltransferase 1 (Dnmt1) in endocrine pancreas by RCAS-TVA-based somatic gene transfer system promotes β-cell proliferation. Cancer Gene Ther 26, 94–102 (2019). https://doi.org/10.1038/s41417-018-0046-x

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