肝癌细胞exosomal miRNAs是重要的信号分子，其表达谱的变化将导致细胞命运的改变。我们在前期研究中发现，肝癌细胞exosomal miRNAs分泌具有选择性，共培养实验发现其摄取也具有选择性； exosomes调控分子Vps4A参与调控其分泌与摄取以发挥抑癌作用，并可导致下游PI3K-Akt通路失活；过表达Vps4A可引起RNA结合蛋白GW182在肝癌细胞内积聚。提示肝癌细胞可能通过选择性分泌和摄取exosomal miRNAs以维持其“癌”性。为深入阐明此作用机制，本项目拟开展如下研究：①通过临床样本和体内外实验模型，筛选显著影响exosomal miRNAs选择性分泌/摄取的分子；②进一步通过IP和RIP实验，探讨exosomes调控分子和RNA结合蛋白共同调控其选择性分泌/摄取的机制。为探讨通过调控exosomal miRNAs来“干扰”肝癌的发生发展奠定理论基础。

Exosomal miRNAs are important signaling molecules in human hepatoma cells. Changes in the expression profile of exosomal miRNAs will lead to alternations in cell fate. We found in previous studies that the secretion of exosomal miRNAs was a selective process. In co-culture experiments, the uptake of exosomal miRNAs was also a selective course. Vps4A, a regulator of exosomes, participated in regulating the secretion and uptake of exosomal miRNAs to exert a tumor-suppressive effect and caused the inactivation of the PI3K/Akt signaling pathway. Over-expression of Vps4A facilitated the accumulation of RNA binding protein GW182 in hepatoma cells. These results suggest that the hepatocellular carcinoma cells may selectively secrete and uptake exosomal miRNAs to maintain their tumor characteristics. To elucidate the mechanism, we plan to carry out following researches. First, through clinical samples and in vivo and in vitro experimental models, we aim to sort a batch of molecules which can significantly affect the secretion and uptake of exosomal miRNAs. Next, by immunoprecipitation and RNA immunoprecipitation experiments, we will further investigate the comodulation mechanism of exosome regulators and RNA binding proteins in the selective secretion and uptake of exosomal miRNAs. We are looking forward to providing fundamental basis for targeting exosomal miRNAs to interfere the occurrence and development of hepatocellular carcinoma.