Modifier of Cancer Sensitivity to Statins

 描述(由申请人提供)：我们最近发现了一种名为甲状腺转录因子1(TTF-1，也称为NKX2-1)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下游的靶microRNA，我们发现TTF-1通过抑制ATP结合盒转运体1(ABCA1)及其相关的胆固醇外流功能上调了已知对胆固醇调节至关重要的miR-33a。因此，我们开始证明，较高的TTF-1表达可能会抑制胆固醇外流，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的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ABCA1。鉴于胆固醇对细胞活力至关重要的事实，我们推测，经TTF-1驱动的胆固醇降低的肺癌细胞将对胆固醇生物合成抑制剂敏感。事实上，TTF-1在人类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，他汀类药物是一种经常开出的降低全身胆固醇的药物。在目标1下，我们计划全面描述ABCA1对TTF-1过表达细胞对他汀类药物敏感性增强的功能要求。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。鉴于病理学家经常询问人类肺癌的TTF-1免疫阳性以指导诊断和他汀类药物的普遍使用，这项研究的结果将激励翻译和临床研究，以改善肺癌的治疗。

 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.