Transcriptional control in the genesis of pancreatic intraepithelial neoplasia

描述（由申请人提供）：胰腺癌是一种毁灭性的疾病，5年生存率低于5%。了解触发胰腺癌发生和发展的分子事件将为开发新的诊断和预后标志物提供途径，并为治疗这种疾病提供新的治疗靶点。胰腺上皮内瘤变（PanINs）是胰腺癌中已知最早的病变。这些病变是浸润前的，但随着时间的推移会发展为浸润性胰腺腺癌。K-ras癌基因的激活突变在胰腺癌中非常常见。此外，小鼠模型显示，致癌性K-ras足以诱导PanIN- 1a的形成，这是PanIN最早的病变。因此，K-ras激活似乎是胰腺癌的关键起始事件；然而，很少知道哪些K-ras效应物是这种起始活性所必需的。在细胞培养转化模型中，我们发现转录因子MondoA受活化的H-ras调控，并且在体内响应K-ras激活，在PanIN- 1A病变中也表达。这些数据表明，MondoA的上调可能有助于正常导管上皮细胞转录程序的改变，从而驱动它们向PanINs的转化。MondoA是一种基本的螺旋-环-螺旋亮氨酸拉链转录因子，与Myc原癌蛋白有关。与Myc不同，MondoA及其伙伴Mlx定位于线粒体外膜。MondoA:Mlx复合物在线粒体和细胞核之间穿梭，表明它们在这两个细胞器之间传递细胞内生物能量状态的信息。为了支持这一模型，MondoA: Mlx复合物是糖酵解和其他代谢途径的直接转录调节因子。在这里，我们将使用我们开发的小鼠MondoA的条件空等位基因来确定MondoA是否是产生PanINs所必需的K-ras效应子（目的1）。为了了解胰腺癌中mondoa调控的转录网络，我们将进行微阵列分析以发现mondoa调控的靶点，并确定其全基因组定位以确定哪些靶点是直接的（目的2）。最后，我们将检查这些直接的MondoA靶点在正常上皮管和PanINs中的表达（目的3）。转录调节因子MondoA可能是致癌性K-Ras在胰腺导管腺癌发展中的关键效应因子。我们将测试MondoA对于胰腺浸润前病变的发展及其调节的基因是否必要。MondoA调节基因是胰腺癌新的诊断/预后标志物和治疗干预的新靶点。

DESCRIPTION (provided by applicant): Pancreatic cancer is a devastating disease with a 5 year survival rate of under 5%. Understanding the molecular events that trigger initiation and progression of pancreatic cancer will provide avenues for the development of new diagnostic and prognostic markers and provide new therapeutic targets for the treatment of this disease. Pancreatic intraepithelial neoplasias (PanINs) are the earliest known lesions in pancreatic cancer. These lesions are pre-invasive but progress to invasive pancreatic adenocarcinoma over time. Activating mutations in the K-ras oncogene are very common in pancreatic cancer. Furthermore, mouse models reveal that oncogenic K-ras is sufficient to induce the formation of PanIN-1As, which are the earliest stage PanIN lesion. As such, K-ras activation appears to be a key initiating event for pancreatic cancer; however, little is known about which K-ras effectors are required for this initiation activity. We have discovered that the transcription factor MondoA is regulated by activated H-ras in a cell culture model of transformation and is also expressed in PanIN- 1A lesions in response to K-ras activation in vivo. These data suggest that upregulation of MondoA may contribute to changes in the transcriptional program of normal ductal epithelia cells to drive their conversion to PanINs. MondoA is a basic helix-loop-helix leucine zipper transcription factor and is related to the Myc proto-oncoprotein. Unlike Myc, MondoA and its partner, Mlx, localize to the outer mitochondrial membrane. MondoA:Mlx complexes shuttle between the mitochondria and the nucleus, suggesting that they communicate information about intracellular bioenergetic state between these two organelles. In support of this model, MondoA: Mlx complexes are direct transcriptional regulators of glycolysis and likely other metabolic pathways. Here we will determine whether MondoA is a necessary K-ras effector for the generation of PanINs using a conditional null allele of murine MondoA that we have developed (Aim 1). To understand the MondoA-regulated transcriptional network in pancreatic cancer, we will perform microarray analysis to discover MondoA-regulated targets and we will determine its genome-wide localization to identify which targets are direct (Aim 2). Finally, we will examine the expression of these direct MondoA targets in normal epithelial ducts and in PanINs (Aim 3). The transcriptional regulator MondoA may be a critical effector of oncogenic K-Ras in the development of pancreatic ductal adenocarcinoma. We will test whether MondoA is necessary for the development of preinvasive lesions the pancreas and the genes it regulates. MondoA regulated genes represent new diagnostic/prognostic markers and new targets for therapeutic intervention for pancreas cancer.