肾透明细胞癌细胞内胆固醇堆积的发生机制及其生物学功能研究

肾细胞癌是人类常见的恶性肿瘤，其中约80%以上是肾透明细胞癌（ccRCC）。ccRCC具有以胆固醇代谢异常为显著特征的脂质代谢异常。目前国际上对ccRCC胆固醇代谢异常的机制及其在ccRCC发生发展过程中的生物学意义缺乏系统研究。我们前期的研究提示：ccRCC中上调的miR-144-3p 降低ABCA1的表达，并与胆固醇胞内堆积有关；ccRCC的胆固醇胞内堆积可以介导分子靶向治疗药物TKI和mTOR抑制剂的耐药。本研究将系统探索ccRCC胆固醇代谢异常的关键分子机制及其生物学功能，包括上调的miR-144-3p通过ABCA1导致胆固醇堆积的机制，明确ccRCC胆固醇代谢异常与靶向药物TKI和mTOR抑制剂耐药的关系。研究结果将有助于我们了解异常胆固醇代谢与ccRCC发生发展和分子靶向药物耐药的关系，并可能为ccRCC的治疗提供新思路和新靶点。

Renal cell carcinoma (RCC) is one of the most common types of human malignancies. The pathological type of more than 80% of RCC is clear cell renal cell carcinoma (ccRCC). ccRCC has dysregulated lipid metabolism, characterized by the increase of cholesterol and accumulation of lipid drops. However, many questions have not been addressed on the mechanism and function of abnormal cholesterol metabolism in ccRCC. Our preliminary data showed that elevated miR-144-3p in ccRCC down-regulated ABCA1 expression and was related with cholesterol accumulation, and cholesterol accumulation might mediate drug resistance of Tyosine kinase inhibitor (TKI) and mTOR inhibitor (mTORI). The present study will explore the key molecules and their biological function of abnormal cholesterol metabolism in ccRCC, including the mechanism of how miR-144-3p causes cholesterol accumulation and how cholesterol accumulation mediates TKI and mTORI resistance in ccRCC. The project will help understand the relationship between abnormal cholesterol metabolism and RCC carcinogenesis and may provide new strategies and novel targets for RCC therapy.