Title | PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Liu, S-H, Rao, DD, Nemunaitis, J, Senzer, N, Zhou, G, Dawson, D, Gingras, M-C, Wang, Z, Gibbs, RA, Norman, M, Templeton, NS, DeMayo, FJ, O'Malley, B, Sanchez, R, Fisher, WE, F Brunicardi, C |
Journal | PLoS One |
Volume | 7 |
Issue | 8 |
Pagination | e40452 |
Date Published | 2012 |
ISSN | 1932-6203 |
Keywords | Animals, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, Glucose Tolerance Test, Homeodomain Proteins, Humans, Immunohistochemistry, In Situ Nick-End Labeling, Insulin, Insulinoma, Islets of Langerhans, Male, Mice, Mice, SCID, Neoplasm Transplantation, Pancreas, Pancreatic Neoplasms, RNA Interference, Trans-Activators |
Abstract | Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that regulates insulin expression and islet maintenance in the adult pancreas. Our recent studies demonstrate that PDX-1 is an oncogene for pancreatic cancer and is overexpressed in pancreatic cancer. The purpose of this study was to demonstrate that PDX-1 is a therapeutic target for both hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Immunohistochemistry of human pancreatic and islet neoplasia specimens revealed marked PDX-1 overexpression, suggesting PDX-1 as a "drugable" target within these diseases. To do so, a novel RNA interference effector platform, bifunctional shRNA(PDX-1), was developed and studied in mouse and human cell lines as well as in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Systemic delivery of bi-shRNA(humanPDX-1) lipoplexes resulted in marked reduction of tumor volume and improved survival in a human pancreatic cancer xenograft mouse model. bi-shRNA(mousePDX-1) lipoplexes prevented death from hyperinsulinemia and hypoglycemia in an insulinoma mouse model. shRNA(mousePDX-1) lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of islet neoplasia. PDX-1 was overexpressed in pancreatic neuroendocrine tumors and nesidioblastosis. These data demonstrate that PDX-1 RNAi therapy controls hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia, therefore, PDX-1 is a potential therapeutic target for these pancreatic diseases. |
DOI | 10.1371/journal.pone.0040452 |
Alternate Journal | PLoS One |
PubMed ID | 22905092 |
PubMed Central ID | PMC3414490 |
Grant List | R01 CA095731 / CA / NCI NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States R01-DK46441 / DK / NIDDK NIH HHS / United States P01 CA094237 / CA / NCI NIH HHS / United States R01-CA095731 / CA / NCI NIH HHS / United States R01 DK046441 / DK / NIDDK NIH HHS / United States |
PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform.
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