CXCL12/CXCR4生物轴通过外泌体促进肾癌肺转移前微环境形成的作用及机制研究

在出现转移之前，肿瘤细胞分泌的外泌体能够诱导转移靶器官微环境的改变，使其更加适合肿瘤细胞定植，从而促进肿瘤转移。我们既往研究发现CXCL12/CXCR4生物轴尤其是CXCR4核定位在肾癌转移过程中起到重要作用（Oncogene，2019），在此基础上我们通过转录组测序筛选过表达野生型CXCR4、核定位序列突变型CXCR4和对照肾癌细胞外泌体转录组成分的差异，发现多种RNA成分存在明显差异，其中有多个RNA分子通过外泌体传输到达肺部后被成纤维细胞摄取，参与到肺转移前微环境的形成过程中。本项目拟从G蛋白偶联信号和细胞核信号两条作用通路进一步研究CXCL12/CXCR4生物轴调控外泌体中RNA成分的上游作用机制，以及相应的RNA促进肾癌肺转移前微环境形成的下游机制，为肾癌转移的预测、预防提供新的思路和依据。

Before metastasis, the exosomes secreted by tumor cells can induce pre-metastatic niche in the target organs, making them more suitable for tumor cell colonization, thereby promoting tumor metastasis. Our previous research found that CXCL12 / CXCR4 biological axis, especially the CXCR4 nuclear localization, plays an important role in the metastasis process of Renal Cell Carcinoma (Oncogene, 2019). On this basis, we used transcriptome sequencing in the exosomes of RCC cells overexpressing wild-type CXCR4, CXCR4 with nuclear localization sequence mutations or control lentivirus to explore differences in the transcriptional components of exosomes from different type of CXCR4. We found that there are significant differences in multiple RNA components. Among them, multiple RNA molecules are transported by exosomes to the lungs and taken up by fibroblasts to participate in lung pre-metastatic niche formation. This project intends to further explore the upstream mechanism of CXCL12/CXCR4 biological axis regulation of RNA components in exosomes from two pathways (G-protein signal and nuclear signal) and the downstream of the corresponding RNAs to promote the formation of the pre-metastatic niche. The mechanism provides new ideas for the prediction and prevention of RCC metastasis.