Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
PLoS One. 2012;7(8):e40452. doi: 10.1371/journal.pone.0040452. Epub 2012 Aug 8.
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.
胰腺十二指肠同源盒-1（PDX-1）是一种转录因子，可调节成人体内胰岛素的表达和胰岛的维持。我们最近的研究表明，PDX-1 是胰腺癌的癌基因，在胰腺癌中过度表达。本研究的目的是证明 PDX-1 是治疗胰腺癌、胰岛素瘤和胰岛肿瘤模型中激素症状和肿瘤体积的靶点。对人类胰腺和胰岛肿瘤标本的免疫组织化学分析显示，PDX-1 过表达明显，提示 PDX-1 是这些疾病中“可药物化”的靶点。为此，我们开发了一种新型 RNA 干扰效应器平台，双功能 shRNA（PDX-1），并在小鼠和人细胞系以及胰腺癌、胰岛素瘤和胰岛肿瘤模型中进行了研究。双 shRNA（人 PDX-1）脂质体的全身给药导致肿瘤体积明显缩小，荷人胰腺癌细胞异种移植小鼠的存活率提高。双 shRNA（鼠 PDX-1）脂质体可预防胰岛素瘤小鼠模型因高胰岛素血症和低血糖而死亡。shRNA（鼠 PDX-1）脂质体可逆转胰岛肿瘤免疫功能正常小鼠模型的高胰岛素血症和低血糖。PDX-1 在胰腺神经内分泌肿瘤和胰岛细胞增生症中过表达。这些数据表明，PDX-1 RNAi 疗法可控制胰腺癌、胰岛素瘤和胰岛肿瘤模型中的激素症状和肿瘤体积，因此，PDX-1 是这些胰腺疾病的潜在治疗靶点。
