外泌体介导的超保守非编码RNA uc.188促肝癌肺转移的作用机制研究

远处转移靶器官微环境的形成在肿瘤转移过程中起到至关重要的作用。 前期通过RNA 表达谱芯片分析,本项目发现超保守非编码RNA uc.188在发生肺转移的肝癌患者血液/肿瘤组织中表达升高且与肿瘤转移密切相关。进一步体内外实验证明外泌体介导的uc.188可诱导肝癌细胞肺转移灶形成，且裸鼠肺部微环境在肝癌细胞转移前已经发生改变：外泌体uc.188诱导肺血管内皮细胞间质化，促血管增生能力及与肿瘤细胞的黏附能力，最终导致肝癌细胞向肺器官转移。初步机制研究提示：外泌体uc.188可以激活肺血管内皮细胞NF-κB信号的转录活性，但具体机制尚不清楚。因此，本项目拟通过对外泌体uc.188调控肺血管内皮细胞间质化、血管生成能力及黏附能力等机制探究，揭示超保守非编码RNA uc.188通过外泌体介导的形式作用于肺部微环境促癌细胞向肺器官转移的具体机制，将为肝癌细胞肺转移的预防和早期诊治提供新的思路。

The premetastatic niche, which was organized by the primary tumor cells before metastasis, plays important roles in the tumor formation of metastatic cell in distant organs. Our preliminary research results have identified an ultraconserved noncoding RNA, uc.188, was significantly increased in the plasma/tumor tisuess of liver cancer patients with lung metastasis and positively associated with distant metastasis. Furthermore, integrating the results obtained from biological experiments showed that exosomal uc.188 promotes lung metastasis in liver cancer and the microenvironment of lung in nude mice have changed before uc.188-trandeuced cancer cells metastasis to lung: exosomal uc.188 induce endothelial-mesenchymal transition (EndoMT) in lung metastasis focuses; enhance the adhesion between endothelial cells and tumor cells; enhance the tube-forming ability of vascular endothelial cells in the lung, thus promoting the metastasis of tumor cells and the growth of colonization to form metastatic foci. By using the immunoprecipitation and mass spectrometry methods, we identified that exosomal uc.188 activated the NF-κB signaling in endothelial cells, but the mechanism is not yet clear. In the current project, we will explore the biological function and underlying mechanism in which uc.188-induced exosome promotes liver cancer metastasis via pre-metastatic niche formation, which might provide a new molecular target for the diagnosis and treatment of lung metastasis of liver cancer.