Title | Tissue-specific induced DNA methyltransferase 1 (Dnmt1) in endocrine pancreas by RCAS-TVA-based somatic gene transfer system promotes β-cell proliferation. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Yuan Z, Gardiner JC, Maggi EC, Adem A, Zhang G, Lee S, Romanienko P, Du Y-CNancy, Libutti SK |
Journal | Cancer Gene Ther |
Volume | 26 |
Issue | 3-4 |
Pagination | 94-102 |
Date Published | 2019 03 |
ISSN | 1476-5500 |
Keywords | Alpharetrovirus, Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Chickens, Disease Models, Animal, DNA (Cytosine-5-)-Methyltransferase 1, Fibroblasts, Gene Transfer Techniques, Genetic Vectors, Humans, Islets of Langerhans, Mice, Mice, Transgenic, Molecular Targeted Therapy, Multiple Endocrine Neoplasia Type 1, Pancreatic Neoplasms, Proto-Oncogene Proteins, Up-Regulation |
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. |
DOI | 10.1038/s41417-018-0046-x |
Alternate Journal | Cancer Gene Ther |
PubMed ID | 30190513 |
PubMed Central ID | PMC7540611 |
Grant List | P50 CA174521 / CA / NCI NIH HHS / United States R01 CA170911 / CA / NCI NIH HHS / United States |
Related Faculty:
Yi-Chieh (Nancy) Du, Ph.D.