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

描述（由申请人提供）：胃癌是全球癌症相关死亡的第二大常见原因。越来越多的证据表明，癌症信号网络以复杂的方式连接。这种复杂性转化为较差的临床结果，这是胃癌的常见特征。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然没有表征。因此，识别位于连接癌症信号通路的信号网络中心的关键分子靶标是理解胃癌生物学和改善我们目前有限的诊断，预防和治疗方法的关键步骤。在本提案中，我们计划继续我们的新发现，即DARPP-32位于两个关键信号通路NF-kB和STAT-3的界面;因此在胃肿瘤发生级联的发展和进展中发挥关键作用。该提案研究了一种新的假设，即NF-kB对DARPP-32的转录上调连接了导致STAT 3激活的癌细胞信号传导途径，从而将DARPP-32作为两个重要信号传导途径之间的桥梁，放大其致癌信号，促进血管生成和肿瘤发生。我们提出了三个具体目标来检验我们的假设。第一个目标将测试NF-kB对DARPP-32的转录调节，并检查DARPP-32调节STAT 3信号传导的机制。这些研究将定义DARPP-32作为两个重要致癌信号通路NF-kB和STAT 3之间的桥梁的作用。在目标2中，我们将检查NF-kB - DARPP-32 -STAT 3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信号传导轴的治疗潜力。第三个目标，将使用DARPP-32过表达和敲低的遗传小鼠模型确定DARPP-32在促进胃癌发生中的作用。我们还将探索NF-kB - DARPP-32 -STAT 3在完全注释的去识别的人胃癌组织样品中过表达的组织病理学和临床意义。我们的研究在概念上是创新的，并且鉴于胃癌的总体5年生存率仅为20%的事实，具有重要意义。在完成我们的研究后，结果将对理解胃癌的生物学产生重大影响，影响我们对这种疾病的诊断，预后和可能的临床管理。

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.