Rab42调控肝癌外泌体HB-EGF分泌靶向作用于血管内皮细胞促进血管生成的机制研究

血管生成是肿瘤生长转移过程中重要的环节之一，但是调控肿瘤血管生成的机制仍未完全揭示。Rab蛋白作为细胞内囊泡运输的分子开关，发挥着调控外泌体分泌的重要作用。Rab42是功能未知的Rab家族新成员，我们前期研究发现Rab42不仅能促肝癌血管生成，还促进肝癌分泌携带肝素结合性表皮生长因子(HB-EGF)的外泌体，但其机制尚不明确。我们通过基因芯片对比发现Rab42可以激活与内皮细胞运动相关的信号通路和基因。我们推测Rab42有可能是通过激活PI3K信号通路调控肝癌外泌体HB-EGF分泌，作用于血管内皮细胞，调控相关信号传导及生长因子分泌，促进血管内皮细胞增殖迁移，进而促进新生血管形成和肝癌转移。本项目欲在前期研究基础上证实上述假说，明确Rab42调控肝癌外泌体HB-EGF分泌诱导血管生成的具体机制，并探讨外泌体HB-EGF作为肝癌血管生成预测指标及干预靶点的可行性，为肝癌靶向治疗提供新的思路。

Angiogenesis is one of the most important events in tumor growth and metastasis, but the mechanism regulating tumor angiogenesis is not fully clarified. As a molecular switch for intracellular vesicle transport, Rab proteins play an important role in regulating exosome secretion. Rab42 is a new member of the Rab family, and its function remains unclear. Our previous research has found that Rab42 can not only promote the angiogenesis of hepatocellular carcinoma (HCC), but also promote HCC to secrete exosomes¬-delivered heparin-binding epidermal growth factor (HB-EGF). However, the mechanism underlying these observations is still not clarified. Genechip comparison revealed that Rab42 could activate signaling pathways and genes related to endothelial cell movement. Therefore, we speculate that Rab42 may regulate the secretion of HCC exosomes¬-delivered HB-EGF(exo-HB-EGF) via the PI3K signaling pathway. After released into the tumor microenvironment, exo-HB-EGF may act on vascular endothelial cells to regulate signaling signal transduction and growth factor secretion, promote the proliferation and migration of vascular endothelial cells, thereby promote neovascularization and HCC metastasis. In this study, we intend to confirm the above hypothesis on the basis of previous research, clarify the mechanism of Rab42 in regulating the secretion of exo-HB-EGF and inducing angiogenesis. In addition, we want to explore the feasibility of exo-HB-EGF as a predictor and intervention target for angiogenesis of HCC, and hope to provide new ideas for targeted treatment of HCC.