Modifier of Cancer Sensitivity to Statins

癌症对他汀类药物敏感性的调节剂

• 批准号: 9251790
• 负责人: David Mu
• 金额: $ 19.12万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251790
• 关键词: 14q13; ATP binding cassette transporter 1; Alpha Cell; Arachidonic Acids; Biological Models; Breast Cancer Cell; Cancer Biology; Cell Survival; Cells; Cholesterol; Cholesterol Homeostasis; Clinical Research; Data; Diagnosis; Drops; Gene Expression; Gene Expression Profiling; Genes; Growth; Human; Introns; Link; Liver; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Metabolism; MicroRNAs; Modeling; Oncogenes; Outcome; Outcome Study; Pathologist; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Plant Roots; Polyunsaturated Fatty Acids; Proteins; Publishing; Recurrence; Regulation; Research; Role; SRE-2 binding protein; Signal Transduction; Site; Somatic Cell; TP53 gene; Time; Translational Research; Up-Regulation; Xenograft procedure; base; cancer cell; cancer type; cholesterol biosynthesis; cytotoxicity; efficacy testing; improved; inhibitor/antagonist; knock-down; lung xenograft; malignant phenotype; mevalonate; mutant; novel; overexpression; prostate cancer cell; public health relevance; therapeutic evaluation; thyroid transcription factor 1; transcription factor; tumor; uptake

 DESCRIPTION (provided by applicant): We have recently discovered an unexpected connection between a critical lung cancer gene termed thyroid transcription factor 1 (TTF-1 also known as NKX2-1) and cholesterol metabolism. By searching for downstream target microRNAs of TTF-1, we found that TTF-1 upregulates miR-33a which is known to be critical for cholesterol regulation by suppressing ATP-binding cassette transporter 1 (ABCA1) and its associated cholesterol efflux function. Thus, we set out to demonstrate that a higher TTF-1 expression would presumably inhibit cholesterol efflux and raise intracellular cholesterol level. Surprisingly in our preliminary studies we found that raising TTF-1 expression actually lowers intracellular cholesterol level, which we believe is attributed to our discovery that TTF-1 directly transactivates ABCA1. In view of the fact that cholesterol is essential for cell viability, we surmised that lung cancer cells primed with a TTF-1-driven decrease of cholesterol would be sensitized to cholesterol biosynthesis inhibitors. Indeed, enforced expression of TTF-1 in human lung cancer cells enhanced cellular sensitivity to statins, a frequently prescribed medication to lower systemic cholesterol. Under Aim 1, we plan to comprehensively characterize the functional requirement of ABCA1 for the enhanced statin sensitivity of cells with TTF-1 overexpression. Subsequently, under Aim 2 we wish to use both orthotopic and anonymized patient-derived lung cancer model systems to test the efficacy of statins against TTF-1+ lung adenocarcinomas. Given the fact that pathologists routinely interrogate human lung cancers for TTF-1 immunopositivity to guide diagnosis and the prevalent use of statins, the outcome of this study will inspire translational and clinical research to improve lung cancer management.

 描述（由申请人提供）：我们最近发现了一种称为甲状腺转录因子1（TTF-1，也称为NKX 2 -1）的关键肺癌基因与胆固醇代谢之间的意外联系。通过寻找TTF-1的下游靶microRNA，我们发现TTF-1通过抑制ATP结合盒转运蛋白1（ABCA 1）及其相关的胆固醇流出功能上调miR-33 a，而miR-33 a已知对胆固醇调节至关重要。因此，我们着手证明较高的TTF-1表达可能会抑制胆固醇流出并提高细胞内胆固醇水平。令人惊讶的是，在我们的初步研究中，我们发现提高TTF-1表达实际上降低了细胞内胆固醇水平，我们认为这归因于我们发现TTF-1直接反式激活ABCA 1。鉴于胆固醇对细胞活力至关重要的事实，我们推测，用TTF-1驱动的胆固醇降低引发的肺癌细胞将对胆固醇生物合成抑制剂敏感。事实上，TTF-1在人肺癌细胞中的强制表达增强了细胞对他汀类药物的敏感性，他汀类药物是一种常用的降低全身胆固醇的药物。在目标1下，我们计划全面表征ABCA 1对于TTF-1过表达的细胞的增强的他汀类药物敏感性的功能需求。随后，在目标2下，我们希望使用原位和匿名患者来源的肺癌模型系统来测试他汀类药物对TTF-1+肺腺癌的疗效。鉴于病理学家常规询问人类肺癌的TTF-1免疫阳性以指导诊断和他汀类药物的普遍使用，本研究的结果将激发转化和临床研究以改善肺癌管理。