Novel treatment strategy of targeting epigenetic dysregulation in pancreatic neuroendocrine tumors.
Publication/Presentation Date
4-1-2023
Abstract
BACKGROUND: Epigenetic dysregulation is an integral step in the progression of pancreatic neuroendocrine tumors. We hypothesized that tumor suppressor repression by DNA methyltransferase 1 in pancreatic neuroendocrine tumors could be targeted with epigenetic treatment.
METHODS: Resected pancreatic neuroendocrine tumors from 32 patients were stained for DNA methyltransferase 1 and scored. Human (BON1) and murine (STC) pancreatic neuroendocrine tumor cells were treated with DNA methyltransferase 1 inhibitor 5-azacytidine and chemotherapeutic agents 5-fluorouracil and temozolomide. Cell proliferation assay and tumor suppressor gene analysis were performed with qRT-PCR and Clarion S microarray. Tumor measurements were compared in a murine treatment model.
RESULTS: High DNA methyltransferase scores were associated with high Ki-67 (6.7% vs 70.6% P < .01), mitotic rate (0.0% vs 31.3%), and grade (20.0% vs 80.4%, P < .01). Treatment with 5-azacytidine and chemotherapy resulted in a reduction of cell proliferation compared to chemotherapy alone in BON1 (77.3% vs 53.1%, P < .001) and STC (73.4% vs 34.2%, P < .001). Treatment with 5-azacytidine and chemotherapy resulted in upregulation of tumor suppressors CDKN1A (7.6 rel. fold, P < .001), BRCA2 (4.3 rel. fold, P < .001), and CDH1 (6.0 rel. fold, P = .026) in BON1 and CDKN1a (14.5 rel. fold, P < .001) and CDH (17.5 rel. fold, P < .001) in STC. In microarray, 5-azacytidine drove global genetic changes in combination treatment. In vivo tumors treated with chemotherapy measured 88.6 ± 19.54 mm
CONCLUSION: Epigenetic dysregulation with DNA methyltransferase 1 is associated with pancreatic neuroendocrine tumors and is a potential targetable strategy. 5-azacytidine and chemotherapy in combination can reduce cell proliferation, upregulate silenced tumor suppressor genes, and decrease in vivo tumors in pancreatic neuroendocrine tumors.
Volume
173
Issue
4
First Page
1045
Last Page
1051
ISSN
1532-7361
Published In/Presented At
Zhu, C., Sandilos, G., Williamson, J., Emery, R., Platoff, R., Joneja, U., Acharya, N. K., Lin, A., Badach, J., Zilberman, B., Madzo, J., Jelinek, J., Zhang, P., & Hong, Y. K. (2023). Novel treatment strategy of targeting epigenetic dysregulation in pancreatic neuroendocrine tumors. Surgery, 173(4), 1045–1051. https://doi.org/10.1016/j.surg.2022.12.008
Disciplines
Medicine and Health Sciences
PubMedID
36642656
Department(s)
Department of Pathology and Laboratory Medicine
Document Type
Article