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

描述（由申请人提供）：吸烟是美国影响人类健康的最严重的可预防风险因素，也是肺癌发展的最重要风险因素。 与烟草使用相关的肺癌通常显示出明显的遗传变化，与非吸烟个体的肺癌相比，K-Ras癌基因突变频率增加。 由于K-Ras癌基因突变的肺癌具有侵袭性特征，因此了解K-Ras癌基因如何驱动肿瘤进展以了解如何最好地治疗它非常重要。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（SK 1）活动 SK 1是负责产生脂质信号分子鞘氨醇-1-磷酸（S1 P）的主要酶。 S1 P是一种脂质分子，在细胞增殖、细胞存活中起重要作用，并且在病理性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、存活和血管募集以进行进展的信号传导途径，这使得1-磷酸鞘氨醇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SK 1在肺癌进展中的作用，以及K-Ras是否导致S1 P产生的增强以促进肿瘤进展。 使用来自野生型和SK 1敲除小鼠的小鼠胚胎成纤维细胞（MEF），我们将能够产生在四环素暴露后表达K-Ras癌基因的可诱导致癌K-Ras细胞系。 使用这种策略，我们将能够确定致癌K-Ras的表达是否增加S1 P的产生，以增加增殖，存活或内皮细胞募集。 其次，我们计划将SK 1基因敲除小鼠与肺癌发生小鼠模型（KRasLA 2小鼠）杂交，并确定与野生型相比，生存率和肿瘤进展是否存在差异。KRasLA 2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，为公共卫生做出重大贡献。 此外，这项研究将更好地了解肺癌的进展，并对其他形式的癌症也有影响。

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.