MicroRNAs in Pancreatic Cancer

描述(申请人提供)：胰腺癌是一种高度致命的恶性肿瘤，预后极差。已发现多种生化和遗传异常与胰腺癌有关。MUC4编码一种跨膜粘蛋白，是胰腺癌中差异表达最强的基因之一，在正常胰腺组织中未检测到表达。它在相当数量的胰腺癌中过表达，并且在胰腺肿瘤发展的早期，即癌前病变中观察到新的表达。研究表明，MUC4可以与HER2癌蛋白相互作用并稳定其表达，并且含有可能与细胞外基质、膜和细胞质蛋白相互作用的结构基序。MUC4促进胰腺癌细胞的生长和转移，最近的一项研究表明，它是一个独立的预后不良因素。所有这些研究都强调了确定MUC4异常表达的分子机制的重要性，以便将其用于临床治疗目的。一类新的基因调控RNAs，被称为microRNAs(MiRNAs)，因其能够影响各种生物过程而引起人们的极大兴趣。在人类中已经发现了大量的miRNAs。然而，靶向的mRNAs只被分配给了其中的几个。这一假设认为，胰腺癌中某类microRNAs的异常表达是MUC4基因异常表达的原因，并与胰腺癌细胞的恶性进展有关。这项建议将在三个具体目标上展开努力，研究候选MUC4靶向miRNAs在胰腺癌中的表达谱(Aim 1)，研究它们在MUC4调控中的作用(Aim 2)，以及表征它们对胰腺癌表型的影响(Aim 3)。综上所述，这些研究将揭示胰腺癌细胞中MUC4表达的一种新的调控机制，并归因于MUC4靶向的miRNAs在胰腺癌进展中的功能意义。从这些研究中获得的信息将对支持基于miRNA的胰腺癌治疗策略和临床分析的设计至关重要。公共卫生相关性：该提案将研究候选的MUC4靶向miRNAs在胰腺癌中的表达和功能意义，并可能为基于miRNA的胰腺癌治疗策略和临床检测的设计提供重要信息。

DESCRIPTION (provided by applicant): Pancreatic cancer is a highly lethal malignancy with an extremely poor prognosis. A wide variety of biochemical and genetic aberrations have been identified to be associated with the pancreatic cancer. MUC4, encoding for a transmembrane mucin protein, is among the most differentially-expressed genes in pancreatic adenocarcinoma with no detectable expression in the normal pancreas. It is overexpressed in a significant number of pancreatic carcinomas, and its neoexpression is observed early in pancreatic tumor development i.e., in precancerous lesions. MUC4 has been shown to interact with and stabilize the expression of HER2 oncoprotein and contains structural motifs that can putatively interact with extracellular matrix, membrane and cytoplasmic proteins. MUC4 potentiates tumor growth and metastasis of pancreatic cancer cells and a recent study have shown that it is an independent factor for poor prognosis. All these studies underscore the importance of identifying the molecular mechanisms involved in the aberrant expression of MUC4, so that, it can be exploited clinically for therapeutic purposes. A new class of gene regulatory RNAs, termed as microRNAs (miRNAs) has gained significant interest for their ability to influence various biological process. A large number of miRNAs has been identified in humans. Nevertheless, the target mRNAs have been assigned to only a few of them. The hypothesis of this proposal is that the aberrant expression of a certain class of microRNAs in pancreatic cancer is responsible for MUC4 dysregulation and is implicated in the malignant progression of pancreatic cancer cells. This proposal will initiate efforts in three specific aims on investigating the expression profile of candidate MUC4-targeted miRNAs in pancreatic cancer (Aim 1), studying their role in MUC4 regulation (Aim 2), and characterize their effect on pancreatic cancer phenotype (Aim 3). Taken together, the proposed studies will unfold a novel regulatory mechanism for MUC4 expression in pancreatic cancer cells and ascribe the functional significance to the MUC4-targeted miRNAs in pancreatic cancer progression. The information gained from these studies will be vital in supporting the design of miRNA-based therapeutic strategies and clinical assays in pancreatic cancer. PUBLIC HEALTH RELEVANCE: The proposal will investigate the expression and functional significance of the candidate MUC4-targeted miRNAs in pancreatic cancer and may provide important information to support the design of miRNA-based therapeutic strategies and clinical assays for pancreatic cancer.