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 shRNAPDX-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-shRNAhumanPDX-1 lipoplexes resulted in marked reduction of tumor volume and improved survival in a human pancreatic cancer xenograft mouse model. bi-shRNAmousePDX-1 lipoplexes prevented death from hyperinsulinemia and hypoglycemia in an insulinoma mouse model. shRNAmousePDX-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.
Highlights
Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that plays a critical role in regulating embryologic pancreas development as well as in insulin expression and islet maintenance in the adult pancreas [1,2,3,4]
PDX-1 is overexpressed in human specimens of pancreatic neuroendocrine tumors and nesidioblastosis, as well as mouse insulinoma cells and a transgenic islet hyperplasia mouse model
These data demonstrate that PDX-1 is significantly overexpressed in both human pancreatic neuroendocrine tumors, nesiodioblastosis and mouse islet neoplasia, suggesting it is a potential target for these diseases
Summary
Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that plays a critical role in regulating embryologic pancreas development as well as in insulin expression and islet maintenance in the adult pancreas [1,2,3,4]. Our recent studies demonstrate that PDX-1 is an oncogene [23,24]. It is markedly overexpressed in pancreatic cancer [23,25,26,27] and regulates proliferation and invasion of human pancreatic cancer cells in vitro and in vivo in mice [23]. Systemic delivery of shRNAhumanPDX-1 lipoplexes resulted in a marked reduction of tumor volume and prolonged survival in a human pancreatic cancer xenograft mouse model [23]
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