PBLD参与肝癌细胞与血管内皮细胞的“微环境对话”调控肝癌血管生成的机制研究

肝癌的生长、侵袭和转移均依赖于新生血管的形成，VEGF/VEGFR信号通路在肿瘤血管生成过程中具有中枢性的调控作用。我们前期研究发现，抑癌基因PBLD在肝癌中的表达水平与VEGF、HIF1-α等多个血管形成相关基因呈负相关，预实验结果提示PBLD可以通过抑制HIF-1α/VEGF影响肝癌血管生成，同时可以影响肝癌细胞来源外泌体中miR-940的表达，而miR-940可负向调控内皮细胞中VEGFR-2上游转录因子ETS1的表达。基于文献资料分析和前期研究基础，本研究拟通过临床标本分析、细胞转染、外泌体/HUVEC和肝癌细胞/HUVEC共培养体系、荧光素酶报告基因系统等细胞学实验及动物实验，深入阐明PBLD抑制肝癌血管生成的分子调控网络，尤其是通过外泌体途径传递的miR-940调控ETS1/VEGFR2信号轴抑制肝癌血管新生的具体机制，为探索新的抗肿瘤血管生成治疗策略提供科学依据和理论基础。

The growth, invasion and metastasis of hepatocellular carcinoma (HCC) depend on angiogenesis, and the VEGF / VEGFR signaling pathway plays a central regulatory role in the process of tumor angiogenesis. Our previous research found that the expression level of the tumor suppressor gene PBLD in HCC was negatively correlated with multiple angiogenesis-related genes, such as VEGF, HIF1-α and so on. Our preliminary experiment results suggested that PBLD affected HCC angiogenesis by inhibiting HIF-1α / VEGF pathway. In addition, PBLD also affected miR-940 expression in HCC-derived exosomes which negatively regulated the expression of ETS1, a transcription factor upstream of VEGFR-2 in endothelial cells. Based on literature analysis and previous research, clinical specimen analysis, cell transfection, exosomes / HUVEC and HCC / HUVEC co-culture systems as well as luciferase reporter gene system will be performed to elucidate the molecular regulatory network of PBLD in the regulation of angiogenesis in HCC. And the mechanism that PBLD transmitted miR-940 through exosome pathway and targeted ETS1 / VEGFR2 signal axis of HUVEC to inhibit angiogenesis in HCC will be specially clarified in detail. This project will provide a scientific and theoretical basis for exploring new anti-tumor angiogenesis treatment strategies.