The Role of RAC1 in Cancer

项目摘要 肺癌是全球癌症死亡的主要原因。据估计 2006年，仅在美国就有超过163，500人死于这种疾病。的 死亡率高的原因是在晚期发现和诊断， 对晚期肺癌缺乏有效的治疗。为了确定治疗方法， 晚期癌症，我们必须首先了解分子机制， 如果我们要确定适当的目标， 治疗学肺腺癌中最常见的突变之一是 K-ras基因的激活突变，在所有肺腺癌的20-30%中发现。 我们利用这些知识建立了一种小鼠肺腺癌模型， 很接近人类的疾病 考虑到新出现的数据暗示Rac家族的小G蛋白在 Ras诱导的肿瘤发生，我们检测了Rac 1作为癌基因的潜在功能， 以及肺腺癌对K-ras下游Rac 1的需求。的Rac 小G蛋白是多种信号通路的调节剂，包括介导 细胞骨架重组、基因表达、内吞作用和细胞增殖， 生存这些通路的失调是肿瘤发生中反复出现的主题。 我们的研究结果表明，Rac 1的天然剪接形式在一个细胞中被上调， 人肺腺癌的显著百分比，Rac 1是K- ras诱导的肺肿瘤。此外，虽然Rac 1单独缺失与 细胞活力和增殖，当结合K-ras激活在原代上皮细胞 细胞中，Rac 1的缺失导致增殖的显著降低。因此，有一种合成的 在表达致癌K-ras的细胞中Rac 1功能的需要。 这些研究将有助于阐明肿瘤发生和发展的过程 并增强我们对肺癌分子通路的理解。的 发现Rac 1的缺失在激活的K-ras的情况下是“致命的”，这就提出了一种可能性， 在Ras突变的肿瘤中靶向Rac 1将是治疗上有益的， 可能对正常细胞的毒性有限。

Project Summary Lung cancer is the leading cause of cancer deaths worldwide. It is estimated that in 2006, more than 163,500 people, in the US alone, will die from this disease. The reasons for the high death rate are detection and diagnosis at advanced stages and a lack of efficient treatments for advanced lung cancer. To identify treatments for advanced stage cancers, we must first understand the molecular mechanisms underlying the disease if we are to identify appropriate targets for the development of therapeutics. One the most common mutations found in lung adenocarcinoma are activating mutations of the K-ras gene, found in 20-30% of all lung adenocarcinomas. We have used this knowledge to develop a mouse model of lung adenocarcinoma that closely recapitulates the human form of the disease. Given the emerging data implicating the small G-proteins of the Rac family in Ras-induced tumorigenesis we examined the potential function of Rac1 as an oncogene and the requirement for Rac1 downstream of K-ras in lung adenocarcinoma. The Rac small G-proteins are regulators of diverse signaling pathways including those mediating cytoskeleton reorganization, gene expression, endocytosis and cell proliferation and survival. The deregulation of these pathways is a reoccurring theme in tumorigenesis. Our findings indicate that a naturally occurring splice form of Rac1 is upregulated in a significant percentage of human lung adenocarcinomas and that Rac1 is required for K- ras induced lung tumors. Furthermore, while Rac1 deletion alone was compatible with cell viability and proliferation, when combined with K-ras activation in primary epithelial cells, loss of Rac1 caused a profound reduction in proliferation. Thus, there is a synthetic requirement for Rac1 function in cells expressing oncogenic K-ras. These studies will shed light on the process of tumor initiation and progression and enhance our understanding of the molecular pathways involved in lung cancer. The finding that loss of Rac1 is "lethal" in the context of activated K-ras raises the possibility that targeting Rac1 in Ras-mutated tumors would be therapeutically beneficial with, perhaps, limited toxicity towards normal cells.