转移是肾癌患者死亡的主要原因，目前缺乏有效药物。最新研究发现肿瘤转移依赖于脂质供能，且肾透明细胞癌(ccRCC)的组织学特征为胞质内含有大量脂质。中药单体雷公藤红素(Celastrol, CeT)除显著降脂作用外对肿瘤的侵袭转移具有良好抑制作用。我们前期研究发现：CeT明显抑制肾癌细胞侵袭迁移，并减少胞内胆固醇酯蓄积，故提出科学假说：CeT通过介导Wnt5a/PKC/SREBP-1c信号通路调节脂质代谢抑制肿瘤细胞上皮间充质转化(EMT)，进而抗肾癌转移。本研究拟收集肾癌患者临床样本，阐明脂质紊乱与肾癌转移的临床相关性；采用荷脂肾癌细胞模型，高脂肾癌肺、肝转移模型等，分别从细胞、整体水平探讨CeT对脂质代谢、EMT和肾癌转移的影响。采用慢病毒转染系统和CRISPR/Cas9技术构建稳定细胞株并结合功能阻断实验，阐明其分子机制。本研究将揭示CeT抗肾癌转移的新机制，为肿瘤转移防治提供新思路。

The invasion and metastasis of clear cell renal cell carcinoma (ccRCC) is the main cause of death in the patient with kidney cancer. However, there is no effective drug for prevention and treatment of ccRCC metastasis. Previous study has found that cancer metastasis depends on lipid metabolism. The histological characteristics of ccRCC are numerous lipids and glycogen in the cytoplasm of cancer cells. The traditional Chinese medicine celastrol exhibits significant lipid-lowering effect and obvious inhibitory effect on invasion and metastasis of cancer cells. Our previous studies demonstrated that celastrol dramatically inhibited the invasion and metastasis of ccRCC cells, as well as reduce the accumulation of intracellular cholesterol esters. We therefore propose a hypothesis that celastrol can inhibit epithelial-mesenchymal transition (EMT) of cancer cells by regulating lipid metabolism via Wnt5a/PKC/SREBP-1c signaling, and thereby suppresses metastasis of ccRCC. The present study intends to collect clinical samples to clarify the clinical relevance of lipid disorder and metastasis. Lipid-loading renal cancer cell models, orthotopic xenograft model, lung and liver metastasis model of renal cancer with a high-fat diet will be used to explore the effects of celastrol on lipid metabolism, EMT and ccRCC metastasis, as well as the key molecules of lipid metabolism regulation in RCC metastasis. Furthermore, the stable cell line with overexpression of Wnt5a will be constructed by lentivirus infection system, and the stable knockout Wnt5a cell line will be constructed by CRISPR/Cas9 method. The treatments of inhibitor or agonist in ccRCC cell lines will be used to clarify its molecular mechanisms. Our study will help to identify potential mechanisms for celastrol, and provide novel targets for anti-metastasis therapy.