The Role of Sphingosine Kinase 1 in Ras-initiated Lung Carcinogenesis

描述（由申请人提供）：在美国，吸烟是影响人类健康的最严重的可预防的危险因素，也是肺癌发展的最重要的危险因素。与K-Ras癌基因突变频率增加的非吸烟个体的肺癌相比，与吸烟相关的肺癌通常表现出明显的遗传变化。由于肺癌具有K-Ras癌基因突变的侵袭性特征，了解K-Ras癌基因如何驱动肿瘤进展以了解如何最好地治疗它是很重要的。使用我们病理肿瘤库的样本，我们已经确定鞘氨醇激酶1在人类肺癌中上调，并有初步证据表明K-Ras癌基因调节鞘氨醇激酶1 （SK1）的活性。SK1是负责产生脂质信号分子鞘氨醇-1-磷酸（S1P）的主要酶。S1P是一种脂质分子，在细胞增殖和细胞存活中起重要作用，在病理和发育性血管生成过程中是必需的。肿瘤高度依赖于调节其增殖、存活和血管募集的信号通路，这使得鞘氨醇-1-磷酸成为人类癌症研究和潜在治疗干预的有趣靶点。因此，我们希望研究SK1在肺癌进展中的作用，以及K-Ras是否导致S1P产生增强以促进肿瘤进展。使用来自野生型和SK1敲除小鼠的小鼠胚胎成纤维细胞（mef），我们将能够产生可诱导的致癌K-Ras细胞系，在四环素暴露时表达K-Ras癌基因。使用这种策略，我们将能够确定致癌K-Ras的表达是否会增加S1P的产生，从而增加增殖、存活或内皮细胞募集。其次，我们计划将SK1基因敲除小鼠与肺癌小鼠模型（KRasLA2小鼠）杂交，并确定与野生型相比，SK1基因敲除小鼠在生存和肿瘤进展方面是否存在差异。KRasLA2小鼠模型将帮助我们了解鞘脂代谢的改变如何影响肺癌的发展。公共卫生相关性：这项研究将通过为肺癌患者提供进一步的治疗选择，对公共卫生做出重大贡献。此外，这项研究将使我们更好地了解肺癌的发展过程，并对其他形式的癌症也有启示。

DESCRIPTION (provided by applicant): Cigarette smoking is the most serious preventable risk factor affecting human health in the United States and is the most significant risk factor for the development of lung cancer. Lung cancer associated with the use of tobacco often displays distinct genetic changes when compared to lung cancer from non-smoking individuals with an increased frequency of mutations in the K-Ras oncogene. Due to the aggressive characteristics of lung cancers with a mutation in the K-Ras oncogene, it is important to understand how the K-Ras oncogene drives tumor progression in order to understand how to best treat it. Using samples from our pathology tumor bank, we have determined that sphingosine kinase 1 is upregulated in human lung cancer and have preliminary evidence that the K-Ras oncogene regulates sphingosine kinase 1 (SK1) activity. SK1 is the primary enzyme responsible for producing the lipid signaling molecule, sphingosine-1-phosphate (S1P). S1P is a lipid molecule that plays a significant role in cellular proliferation, cellular survival, and is necessary during pathological and developmental angiogenesis. Tumors are highly dependent on signaling pathways that regulate their proliferation, survival, and recruitment of blood vessels for progression which makes sphingosine-1-phosphate an interesting target for study and potential therapeutic intervention in human cancer. Therefore, we wish to investigate the role of SK1 in lung cancer progression and if K-Ras leads to an enhancement of S1P production to promote tumor progression. Using mouse embryonic fibroblasts (MEFs) from both wildtype and SK1 knockout mice we will be able to generate inducible oncogenic K-Ras cell lines that express the K-Ras oncogene upon tetracycline exposure. Using this strategy we will be able to determine if the expression of oncogenic K-Ras increases S1P production to increase proliferation, survival or endothelial cell recruitment. Second, we plan to cross SK1 knockout mice with a mouse model of lung carcinogenesis (KRasLA2 mice) and determine if there are differences in survival and tumor progression compared to wildtype. The KRasLA2 mouse model will help us understand how alterations in sphingolipid metabolism can influence the development of lung cancer. PUBLIC HEALTH RELEVANCE: This research will contribute significantly to public health by providing further treatment options for patients affected by lung cancer. In addition, this research will better our understanding of how lung cancer progresses and have implications for other forms of cancer as well.