RP11-59E19.1通过锚定肾透明细胞癌干细胞Notch1蛋白抑制肿瘤血管生成

Clear cell renal cell carcinoma stem cells (CSCs) is essential for angiogenesis and drug resistance in clear cell renal cell carcinoma (ccRCC). Our previous studies found that dysregulated long noncoding RNA RP11-59E19.1 is closely related with microvessel density and prognosis in ccRCC. Furthermore, RP11-59E19.1 plays an important role in regulating endothelial differentiation, and inhibits ccRCC angiogenesis by reducing vascular endothelial cells differentiated from CSCs. Based on the previous results, this subject specifically aims to: reveal the mechanism that RP11-59E19.1 anchors in Notch1 protein, inhibits the cleavage of Notch1 induced by γ-secretase, reduces NICD release and blocks the activation of Notch1 /γ-secretase/NICD pathway finally; confirms the effect that RP11-59E19.1 suppresses tumor angiogenesis by regulating vascular endothelial cells differentiated from CSCs; detects whether RP11-59E19.1 could serve as a potential clinical prognostic marker and novel therapeutic target in ccRCC. This subject will explore the potential mechanisms underlying the effect of long noncoding RNA in tumor angiogenesis from the aspect of cancer stem cells, discuss the potential function of RP11-59E19.1 on ccRCC prognosis, and provide a new strategy to improve ccRCC treatment.

肾透明细胞癌干细胞(CSCs)是肾透明细胞癌（ccRCC）血管生成和药物抵抗的关键。我们前期研究筛选发现异常表达的长链非编码RNA RP11-59E19.1与ccRCC血管密度和预后密切相关，并可抑制CSCs分化为血管内皮细胞。本课题拟在此基础上，通过揭示RP11-59E19.1靶向锚定Notch1蛋白，抑制γ-secretase剪切Notch1蛋白释放胞内活性蛋白NICD的机制；明确RP11-59E19.1阻断CSCs向血管内皮分化，发挥抗肿瘤血管生成的作用；判断RP11-59E19.1作为ccRCC临床预后指示标记物和新治疗靶点的可能性。该课题从肿瘤干细胞的层面探讨lncRNA在肿瘤血管生成过程中的机制，为抗ccRCC血管治疗提供新的理论基础。

1.项目背景：肾透明细胞癌干细胞(CSCs)是肾透明细胞癌（ccRCC）血管生成和药物抵抗的关键。我们前期研究发现肾透明细胞癌（CCRCC）具有高度转移的特性。干细胞和癌细胞之间的基质交流对于癌细胞转移扩散具有重要的影响作用。.2.主要研究内容：本项目通过研究从ccRCC患者的肾癌干细胞（CSC）分离的外泌体对ccRCC细胞的上皮-间质转化（EMT）和肺转移进展的影响，揭示了一种可以作为临床潜在的转移性诊断生物标志物。.3.重要结果：CSCs外泌体促进ccRCC细胞增殖并加速EMT的进程。CSC外泌体传递到癌细胞的具有生物活性的miR-19b-3p是通过抑制PTEN的表达诱导EMT。ccRCC肺转移患者的CSC外泌体对EMT的促进作用最强。CD103+CSC外泌体在肿瘤细胞和肺中富集，突显CD103赋予的趋向性。患有肺转移的ccRCC患者的血液样本中CD103+外泌体增加。.4.关键数据：ccRCC患者来源的CSCs外来体的分离与鉴定；CSC外泌体加速ccRCC细胞的EMT；CSC外泌体的作用由miR-19b-3p转运所介导的；miR-19b-3p通过调节PTEN来促进EMT；CSC外泌体在体内促进ccRCC细胞的肿瘤发生和转移；CD103具有指导外泌体转移部位的作用。.5.科学意义：本项目证明CSC外泌体将miR-19b-3p转运到ccRCC细胞并启动EMT促进转移。同时，CD103+可引导CSC外泌体靶向癌细胞和器官，赋予ccRCC更高的肺转移能力，提示CD103+外泌体是潜在的转移性诊断生物标志物。为探索和理解ccRCC肺转移发生的机制提供新的理论视点，进而寻找治疗肾透明细胞癌提供新的突破口。