Targets of Gene Overexpression at 17q in Gastric Tumorigenesis: Darpp32

描述（由申请人提供）：胃癌是全球第二大癌症相关死亡原因。越来越多的证据表明，癌症信号网络以一种复杂的方式连接在一起。这种复杂性转化为不良的临床结果，这是胃癌的一个共同特征。这种连接不仅对维持癌细胞存活很重要，而且对提供支持性特性（如血管生成）也很重要。控制驱动胃肿瘤发生的分子信号通路之间相互作用的分子靶点在很大程度上仍未被描述。因此，鉴定位于连接癌症信号通路的信号网络枢纽的关键分子靶点，是了解胃癌生物学和改进我们目前有限的诊断、预防和治疗方法的关键一步。在目前的提案中，我们计划继续我们的新发现，显示DARPP-32在两个关键信号通路的接口，NF-kB和STAT-3；因此在胃肿瘤发生级联的发生和发展中起着至关重要的作用。该提案研究了一个新的假设，即NF-kB对DARPP-32的转录上调连接了癌细胞信号通路，导致STAT3的激活，从而使DARPP-32成为两个重要信号通路之间的桥梁，放大了它们的致癌信号，促进了血管生成和肿瘤发生。我们提出三个具体目标来检验我们的假设。第一个目标是测试NF-kB对DARPP-32的转录调节，并研究DARPP-32调节STAT3信号传导的机制。这些研究将确定DARPP-32作为两个重要的致癌信号通路NF-kB和STAT3之间的桥梁的作用。在Aim 2中，我们将检查NF-kB - DARPP-32 - STAT3轴的生物学结果，探索其在调节血管生成中的作用，并确定靶向DARPP-32信号轴的治疗潜力。第三个目标，将利用DARPP-32过表达和敲低的遗传小鼠模型，确定DARPP-32在促进胃肿瘤发生中的作用。我们还将探讨NF-kB - DARPP-32 - STAT3在完全注释去鉴定的人胃癌组织样本中过表达的组织病理学和临床意义。考虑到胃癌的总体5年生存率仅为20%，我们的研究在概念上是创新的，具有重要意义。在我们的研究完成后，结果将对了解胃癌的生物学，影响我们对这种疾病的诊断、预后和可能的临床管理产生重大影响。

DESCRIPTION (provided by applicant): Gastric cancer is the second most common cause of cancer-related deaths worldwide. There is growing evidence suggesting that cancer signaling networks are wired in a complex manner. This complexity is translated into poor clinical outcome, a common feature of gastric cancer. This wiring is not only important for maintaining cancer cell survival but also for providing supportive properties such as angiogenesis. The molecular targets that govern this interaction between the molecular signaling pathways that drive gastric tumorigenesis remain largely uncharacterized. Therefore, the identification of critical molecular targets, located at the hub of the signaling networks that bridge cancer signaling pathways, is a key step in understanding the biology of gastric cancer and improving our currently limited diagnostic, preventive, and therapeutic approaches. In the present proposal, we plan to pursue our novel finding that shows DARPP-32 at the interface of two key signaling pathways, NF-kB and STAT-3; thus playing a crucial role in the development and progression of the gastric tumorigenesis cascade. The proposal examines a novel hypothesis that transcription up-regulation of DARPP-32 by NF-kB connects cancer cell signaling pathways leading to activation of STAT3, thereby placing DARPP-32 as a bridge between two important signaling pathways amplifying their oncogenic signals promoting angiogenesis and tumorigenesis. We propose three specific aims to test our hypothesis. The first aim will test the transcription regulation of DARPP-32 by NF-kB and examine the mechanisms by which DARPP-32 regulates STAT3 signaling. These studies will define the role of DARPP-32 as a bridge between two important oncogenic signaling pathways, NF-kB and STAT3. In Aim 2, we will examine the biological outcome of the NF-kB - DARPP-32 - STAT3 axis, explore its role in regulating angiogenesis, and determine the therapeutic potential of targeting the DARPP-32 signaling axis. The third aim, will determine the role of DARPP-32 in promoting gastric tumorigenesis using genetic mouse models of DARPP-32 overexpression and knockdown. We will also explore the histopathological and clinical significance of overexpression of NF-kB - DARPP-32 - STAT3 in fully annotated de-identified human gastric cancer tissue samples. Our studies are conceptually innovative and of critical significance given the fact that the overall 5-year survival for gastric cancer is only 20%. Upon completion of our studies, the results will have a significant impact on understanding the biology of gastric cancer affecting our diagnostic, prognostic, and possibly clinical management of this disease.