肾癌转移是该疾病导致死亡的主要原因。外泌体通过携带miRNA在原发灶和转移前微环境之间进行信息交流而维持生态上的互动, 催化肿瘤转移的发生和发展。我们前期研究发现肾癌患者血清中游离CD9阳性外泌体含量丰富, 富集CD9阳性外泌体作用于裸鼠肾癌原位模型能提高肺转移的发生率,并上调成纤维化相关指标。据此, 我们推测肾癌释放CD9阳性外泌体能通过携带特异的miRNA激活肺转移前微环境的成纤维细胞而促进肺转移灶形成。围绕此科学假说, 我们将利用分子细胞技术、动物模型及临床样本:1)明确CD9阳性外泌体通过作用于转移前微环境,介导肿瘤转移;2)揭示CD9阳性外泌体通过携带miRNA介导转移前微环境构建的相关分子机制;3)证实宿主体内肾癌转移能力与干扰CD9阳性外泌体的关系。本研究将完整揭示CD9阳性外泌体通过携带miRNA在介导肿瘤转移前微环境构建中的机制,为控制肾癌的转移提供新的思路。

Metastasis is the leading cause of death in renal cell carcinoma (RCC) patients. The miRNAs packed into exosome play a role in information exchange between primary tumor and pre-metastatic niche, which promotes the cancer progression and metastasis. Our previous study has found that the level of CD9 postive exosome was significantly higher in the serum of RCC patients. Mice injected with CD9 positive exosome had increased expression of fibroblast associated proteins and more lung metastatic lesions . This observation has led us to hypothesize that RCC-secreted CD9 positive exosomal miRNA could initiate fibroblasts in pre-metastatic niche to promote lung metastasis. We plan to divide this investigation into three steps to validate the hypothesis. 1)To confirm the effect of CD9 positive exosome in pre-metastatic niche to promote lung metastasis; 2)To elucidate the molecular mechanism of CD9 positive exosomal miRNA initiating the fibroblasts in pre-metastatic niche; 3)To study the function of CD9 positive exosomal miRNA in vivo. This project aims to provide new strategy and theoretical foundation to improve the treatment for this disease.