信号分子硫化氢通过自噬调控肝癌微环境的机制研究

肝星状细胞 （HSC）在肝癌微环境中发挥重要作用，其分泌PDGFR -α与肝癌侵袭、转移密切相关，但机制仍不清楚。我们前期研究:HSC可分泌硫化氢（H2S），且PDGFR-α可通过自噬途径被降解，H2S亦通过PI3K-Akt-mTOR 及 AMPK-TSC2 信号通路调控肝癌细胞自噬。.本课题拟应用肝癌细胞与HSC共培养，研究H2S对肝癌细胞自噬、PDGFR-α降解的影响，观察自噬体的形成，检测自噬相关基因（Beclin1、Atg5和Atg7等）的表达。其次通过信号通路激动及抑制实验，探讨PI3K-Akt-mTOR 及 AMPK-TSC2 信号通路在H2S调控自噬中的作用。最后利用不同临床分期肝癌患者组织进一步证实H2S在肝癌微环境中调控自噬作用。旨在阐明H2S对肝癌细胞自噬、PDGFR-α降解、肝癌微环境影响及作用机制，为以 H2S-PDGFR-α途径为靶点的HCC治疗提供理论依据。

Hepatic stellate cell (HSC) plays an important role in carcinogenesis and progress of hepatocellular carcinoma (HCC),the presence of PDGFR-α in activated HSC is related with invasion and transfusion of HCC. However, the specific mechanism needs further study. Our previous study found that hydrogen sulfide (H2S) synthesize and secreted by HSC could influence HCC cell autophagy by PI3K-Akt-mTOR and AMPK-TSC2 pathway, PDGFR α may be degraded by autophagy.. In this study we will focus on H2S and PDGFR α, then clarify the role and mechanism of H2S in how to influence HCC cell autophagy and PDGFR-α degradation in liver micro enviroment. Firstly, we will research the effect of H2S on liver microenviroment , such as hepatoma autophagy ,the autophagosome formation and the autophagy-related genes (Atgs) expression via co-culture of HCC and HSC. Secondly, explore the role of secreted H2S in the above autophagy process and its regulation on the activation of PI3K-Akt-mTOR and AMPK-TSC2 signaling pathways. Finally, to investigate the effects of H2S on the tumor growth, invasion, autophagy and the underling mechanisms using the tissue of different stage hepatocellular carcinoma patients. This study will provide an experimental basis for H2S-PDGFR α pathway application in the treatment of HCC.