芹黄素Apigenin抑制肝癌细胞胞外囊泡分泌及肝癌进展的分子机理

细胞外囊泡（Extracellular vesicles,EV）是细胞间通讯的核心载体。在多种生理病理过程中，特别是癌症进展的不同阶段均起着重要作用。我们前期的研究发现，黄酮类的天然化合物芹黄素（Apigenin，AP）显著抑制肿瘤细胞中胞外囊泡的产生和分泌，并且进而抑制相关的生物学功能，例如肿瘤血管生成。因此在本项目中，我们计划进一步研究芹黄素抑制肝癌细胞EV产生和分泌的分子机理。具体包括：确定芹黄素抑制肝癌细胞EV产生和分泌并进而抑制肝癌进展；确定芹黄素抑制肝癌细胞EV产生和分泌的主要信号通路和关键信号分子，我们重点关注小G蛋白如Cdc42，RhoA在该信号通路中的作用；最后我们将在小鼠中验证本研究中发现的EV产生和分泌的分子机理，并且依据该分子机制初步筛选和优化潜在的抑制EV分泌的小分子抑制剂。以上研究对细胞外囊泡产生和分泌的分子机理的深入了解，以及其在癌症治疗中的应用都很有意义。

Extracellular vesicles (EV) serve as critical mediators of cell-to-cell communication. They play a vital role in a variety of physiological or pathophysiological processes. The most widely described is their role in cancer: By regulating intercellular communication, EVs affect the tumor microenvironment, stimulate angiogenesis, and promote tumor growth, thereby contributing to different stages of cancer progression. Our current study found that apigenin significantly decreases tumor-derived EV (both exosomes and microvesicles) biogenesis and inhibits the EV-related biological functions such as tumor angiogenesis in tumor progression. This research proposal stems from my current work on apigenin. We will further explore the molecular mechanism of apigenin inhibiting EV biogenesis in hepatocellular carcinoma (HCC) : We will first determine the inhibition of apigenin on hepatoma cell-derived EV biogenesis and the progression of hepatocellular carcinoma. Then, we will identify the main signaling pathways and key signaling molecules that regulates EV biogenesis in hepatocellular carcinoma. We are particularly interested in the role of small G proteins such as Cdc42, Rac1, RhoA, and Arf6 in these signaling pathways. Finally, the molecular mechanism of EV biogenesis found in this study will be further verified in mice. We will further optimize the potential small molecule inhibitors of EV biogenesis. The studies proposed here will contribute to our understanding about EV biogenesis and benefit the application of EVs in cancer therapy.