Role and mechanism of action of p62/Sqstm1 in Ras-induced tumorigenesis in lung

描述(申请人提供)：肺癌是美国与癌症相关的主要死亡原因。目前的治疗方法并不能治愈大多数这种类型的肿瘤。靶向抗肿瘤疗法可能会被证明更有效，但它们的发展将需要更好地了解所涉及的信号级联反应。RAS癌基因在人类癌症中经常发生突变，在疾病的发生和发展中发挥着毋庸置疑的重要作用。在肺腺癌中，至少有25%的病例存在RAS基因突变，这表明RAS相关信号通路的组成部分有望成为肺癌治疗的候选靶点。RAS癌基因转化激活了核因子-？B，它是细胞存活的关键调节因子，也是肿瘤进展的重要介质。非典型PKCs(APKCs)及其接头p62参与了核因子-βB的激活调控。最近的研究结果表明，核因子？B途径的基因失活可以预防或促进肿瘤的发展，这取决于靶器官和炎症反应是否参与。然而，核因子-βB失活在肺肿瘤中的作用还没有文献报道。初步研究表明，在可诱导的小鼠肺癌模型中，RAS可重复地产生肺腺瘤和腺癌，而这些RAS诱导的肺癌需要p62。证据表明，这是一种细胞自主效应，因为p62的缺失严重削弱了RAS转化不朽胚胎成纤维细胞的能力。此外，RAS转化通过一种尚未明确的机制诱导p62蛋白的积累。这些重要的观察结果有力地表明，p62在RAS诱导的肺肿瘤发生和细胞转化中是必需的。该项目的长期目标是定义可能成为肺癌治疗靶点的新信号分子。这项建议的总体目标是严格检验p62/aPKC/NF-？B通路在RAS诱导的肿瘤转化中起关键作用的假设，特别是在肺癌中。这将通过评估这些重要的信号媒介在调节RAS诱导的转化中的作用和作用机制来实现。为了达到这一目的，我们设计的具体目标是：1)验证p62通过aPKCs在体内调控RAS诱导的肺癌的假说；2)检验IKK2或IKK1是RAS诱导的肺癌形成的关键介质的假说；3)阐明p62/aPKC/NF-1B通路在RAS诱导的肺癌转化中的细胞和分子机制及其在人类肺癌中的相关性。这项工作将增加我们对肺癌调控机制的理解，并从长远来看，将为开发新的、更特异的、因此毒性较低的治疗这种肿瘤的方法提供必要的知识。公共卫生相关性：肺癌是美国与癌症相关的主要死亡原因，2007年估计有213,380例新病例和160,390例死亡。目前的治疗方法并不能治愈大多数这种类型的肿瘤。这项研究将阐明与肺部肿瘤发生有关的分子信号。预计通过这项工作获得的知识将有助于开发新的、更具体的、从而更有效的治疗这种类型的癌症的药物疗法。

DESCRIPTION (provided by applicant): Lung cancer is the leading cancer-related cause of death in the United States. Current treatments do not lead to a cure for most patients with this type of neoplasia. Targeted anti-tumor therapies are likely to prove more effective, but their development will require a better understanding of the signaling cascades involved. Ras oncogenes are frequently mutated in human cancers where they play an unquestionably important role in the genesis and progression of the disease. In lung adenocarcinomas, mutations in Ras are present in at least 25% of cases, suggesting that the components of Ras-related signaling pathways are promising candidates for therapeutic targets in lung cancer treatment. Ras oncogenic transformation activates NF-?B, a critical regulator of cell survival and an essential mediator of tumor progression. The atypical PKCs (aPKCs) and their adapter p62 are implicated in the control of NF-?B activation. Recent results demonstrate that genetic inactivation of the NF-?B pathway may either prevent or promote tumor development, depending on the target organ and whether or not the inflammatory response is involved. However, the effect of NF-?B inactivation in lung neoplasia has not yet been documented. Preliminary studies demonstrate that Ras reproducibly produces lung adenomas and adenocarcinomas in an inducible model of lung cancer in mice, and that p62 is required for these Ras-induced lung tumors. The evidence suggests that this is a cell-autonomous effect in that the absence of p62 severely impairs the ability of Ras to transform immortal embryo fibroblasts. In addition, Ras transformation induces p62 protein accumulation through a yet-to-be-defined mechanism. These important observations strongly indicate that p62 is necessary for Ras-induced lung tumorigenesis and cell transformation. The long-term goal of this project is to define novel signaling molecules that could be therapeutic targets in lung cancer. The overall objective of this proposal is to rigorously test the hypothesis that the p62/aPKC/NF-?B pathway is critical in Ras-induced tumor transformation, specifically in lung cancer. This will be achieved by assessing the roles and mechanism of action of these important signaling mediators in the regulation of Ras-induced transformation. The specific aims designed to achieve this are to 1) Test the hypothesis that p62 regulates Ras-induced lung cancer in vivo through the aPKCs; 2) Test the hypothesis that IKK2 or IKK1 are critical mediators of Ras-induced formation of lung tumors; 3) Elucidate the cellular and molecular mechanisms of the p62/aPKC/NF-?B pathway in Ras-induced transformation and its relevance in human lung cancer. This work will increase our understanding of the mechanisms involved in the regulation of lung cancer, and in the long term will provide the knowledge necessary for the development of novel, more specific, and thus less toxic, therapies for this type of neoplasia. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cancer-related cause of death in the United States, with an estimated 213,380 new cases and 160,390 deaths in 2007. Current treatments do not lead to a cure for most patients with this type of neoplasia. This research will elucidate the molecular signals implicated in the initiation of lung neoplasias. It is expected that the knowledge gained through this work will contribute to the development of new, more specific and, thus, more effective drug therapies for this type of cancer.