CYLD调节脂自噬对肾癌转移及索拉菲尼耐药的影响及机制

Once metastasis happens, RCC (Renal cell carcinoma) patients will suffer a dramatically worse prognosis. Represented by sorafenib, target therapy is the last chance for them to get effective therapy. Unfortunately,the efficiency drops due to acquired drug-resistance. RCC metastasis and acquired sorafenib resistance have become worldwide problems in RCC treatment. The recent focus on this issue are autophagy and lipid metabolism. RCC tissues are rich in lipid droplets(LDs), high level of lipid metabolism plays an important role in occurrence and developmant of RCC. Recently,lipophagy，an unique type of autophagy has been defind,plays a role in LDs degradation to supply free fatty acid for lipid metabolism, promoting RCC cell survival and supposed to be an important reason of RCC metastasis and acquired sorafenib resistance. CYLD is a tumor suppressor gene. Our preliminary research demonstrates its lower expression level in matastasis RCC tissue，and has relationship with higher LDs degradation and lipophagy level，plays an important role in RCC metastasis. Further study shows the sensitivity of sorafined will get recovered by upregulating CYLD expression in RCC cells ,interestingly,lipophagy is downregulated in this process. The underlying mechanisms are still unclear. Therefore, the present study is designed to explore the role of of CYLD regulated lipophagy on renal cell carcinoma metastasis and resistance of sorafenib by carrying out in vitro and in vivo animal studies , then evaluated the possibility of revering RCC acquired sorafenib resistance.

肾癌一旦转移，预后急转直下，以索拉菲尼为代表的靶向治疗是此类患者最后的“救命稻草”，但易发生获得性耐药。转移及索拉菲尼耐药已成为世界性难题，近期研究多聚焦于脂代谢与自噬。肾癌细胞中富含脂滴，高脂代谢在肾癌发生发展中起重要作用。一种独特的自噬形式-脂自噬（lipophagy），降解脂滴，提供游离脂肪酸行脂代谢供能，促进肿瘤存活，被推测是转移及索拉菲尼耐药的原因。圆柱瘤基因（CYLD）是种抑癌基因，我前期研究提示：较非转移性肾癌，转移性肾癌中CYLD表达更低，脂滴降解、脂自噬水平更高，提示脂自噬与CYLD相关，在肾癌转移中起重要作用。进一步研究显示上调CYLD可恢复索拉菲尼耐药细胞敏感性，伴有脂自噬下调。而其具体机制仍不清。本课题以脂自噬为中心，以CYLD为切入点，结合临床，运用细胞生物学及荷瘤鼠模型等方法，探讨CYLD调节脂自噬对肾癌转移的影响及机制，探索调节脂自噬逆转索拉菲尼耐药的新思路。

肾癌一旦发生转移，预后急转直下，以索拉菲尼为代表的靶向治疗是此类患者最后的“救命稻草”，但易发生获得性耐药。肾癌转移及索拉菲尼耐药已成为该领域世界性难题，近期对其研究多聚焦于脂代谢与细胞自噬。肾癌细胞中富含脂滴，高脂代谢在肾癌发生发展中起重要作用。一种独特的自噬形式-脂自噬（lipophagy），可降解脂滴，提供游离脂肪酸进行脂代谢供能，促进肿瘤存活，被推测是肿瘤转移及索拉菲尼耐药的原因之一。圆柱瘤基因（CYLD）是种抑癌基因，我们前期研究提示上调CYLD可以使索拉菲尼耐药细胞治疗敏感性恢复，此过程伴有脂自噬上调，而其具体机制仍然不清。本课题以脂自噬为中心，以CYLD为切入点，结合临床数据，运用细胞生物学实验及建立荷瘤鼠模型等方法，探讨肾癌中CYLD调节脂自噬对肾癌转移的影响及机制，并探讨调节脂自噬逆转肾癌索拉菲尼获得性耐药的新思路。在该课题基金资助下，我主要结果有以下：1.首次证实肾癌索拉菲尼耐药与脂自噬上调有关，通过使用乌苯美司调节脂自噬可以抑制获得性索拉菲尼耐药；2.虽然证实CYLD与肾癌转移没有直接相关性，但是证实其调节脂自噬及脂代谢需要Hippo-YAP通路参与，为进一步探索泛素化体系与YAP依赖的脂代谢在肿瘤中的作用做了铺垫；3.证实脂代谢关键限速酶HADHA，ACAT1/2等在肾癌转移及预后中的关键作用及机制；4.证实CYLD调节Livin在膀胱癌化疗耐药中的作用。基于以上结果，以第一或者通讯作者发表SCI论文12篇，进一步理解脂自噬这种独特自噬形式及其调节方式在恶性肿瘤中的作用，为探索肾癌靶向治疗耐药产生的机制及逆转其获得性耐药提供理论支撑和临床指导。