PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform.
PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform.
复制标题
DOI：
10.1371/journal.pone.0040452
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Brunicardi FC
中科院分区：
文献类型：
--
作者：
Liu SH;Rao DD;Nemunaitis J;Senzer N;Zhou G;Dawson D;Gingras MC;Wang Z;Gibbs R;Norman M;Templeton NS;Demayo FJ;O'Malley B;Sanchez R;Fisher WE;Brunicardi FC
胰腺和十二指肠同源框-1（PDX-1）是一种调节成人胰腺中胰岛素表达和胰岛维持的转录因子。我们最近的研究表明，PDX-1是胰腺癌的癌基因，并且在胰腺癌中过表达。本研究的目的是证明PDX-1是胰腺癌、胰岛素瘤和胰岛瘤形成小鼠模型中激素症状和肿瘤体积的治疗靶点。人类胰腺和胰岛肿瘤标本的免疫组织化学显示PDX-1过表达，表明PDX-1是这些疾病中的“可用药”靶点。为此，开发了一种新的RNA干扰效应器平台，双功能shRNAPDX-1，并在小鼠和人细胞系以及胰腺癌，胰岛素瘤和胰岛瘤形成的小鼠模型中进行了研究。在人胰腺癌异种移植小鼠模型中，全身递送bi-shRNAhumanPDX-1脂质复合物导致肿瘤体积显著减小并提高存活率。在胰岛素瘤小鼠模型中，bi-shRNAmousePDX-1脂质复合物防止了高胰岛素血症和低血糖症的死亡。shRNAmousePDX-1脂质复合物在胰岛瘤形成的免疫活性小鼠模型中逆转了高胰岛素血症和低血糖症。PDX-1在胰腺神经内分泌肿瘤和胰岛母细胞瘤中过表达。这些数据表明，PDX-1 RNAi疗法控制胰腺癌、胰岛素瘤和胰岛瘤形成的小鼠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。
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.
登录
查看更多内容
影响因子：
12.4
作者：
Ramesh, R;Saeki, T;Roth, JA
通讯作者：
Roth, JA
影响因子：
7.7
作者：
Bischof, LJ;Martin, CC;O'Brien, RM
通讯作者：
O'Brien, RM
影响因子：
2.7
作者：
Gannon, Maureen;Ables, Elizabeth Tweedie;Wright, Christopher V. E.
通讯作者：
Wright, Christopher V. E.
影响因子：
4.8
作者：
Jepeal, LI;Fujitani, Y;Wolfe, MM
通讯作者：
Wolfe, MM
影响因子：
2.2
作者：
Liu, Shihe;Wang, Xiao-Ping;Brunicardi, F. Charles
通讯作者：
Brunicardi, F. Charles