CBS-H2S体系调控SIRT1/Notch1/Hes1通路促进食管鳞癌淋巴结转移的研究

淋巴结转移是食管鳞癌患者死亡及预后的重要因素，目前其发生机制未完全明了，也尚无理想的治疗药物，故进一步探索其发生机制，寻找有效的治疗新靶点具有重要意义。H2S是继NO和CO后的第三种气体信号分子，系列研究发现其可能参与肿瘤的转移过程，但迄今尚无直接证据。我们前期研究发现，内源性H2S合成酶-胱硫醚-β-合酶（CBS）高表达与食管鳞癌的淋巴结转移密切相关。因此，本研究将在前期工作的基础上，首先采用组织芯片法验证人食管鳞癌组织中CBS表达与淋巴结转移的关系；然后构建不同CBS表达水平以及CBS基因敲除的细胞模型和裸鼠移植瘤模型，研究CBS-H2S体系对淋巴结转移的促进作用；最后利用上述细胞和动物模型研究CBS-H2S体系对SIRT1/Notch1/Hes1通路的调控作用。本项目旨在探索CBS-H2S体系在食管鳞癌淋巴结转移过程中的作用及机制，从而为后续针对该途径的药物研发提供理论依据。

Lymph node metastasis is an important factor in death and prognosis of patients with esophageal squamous cell carcinoma. At present, its pathogenesis is not fully understood and there is no ideal therapeutic drug, so it is of great significance to further explore its pathogenesis and find an effective new therapeutic target. H2S is the third gas signaling molecule after NO and CO, and a series of studies have found that H2S may be involved in the process of tumor metastasis, but there is no direct evidence yet. Our previous study found that the high expression of CBS-H2S system is closely related to the lymph node metastasis of esophageal squamous cell carcinoma. Therefore, on the basis of previous work, this project will firstly verify the relationship between CBS expression and lymph node metastasis in human esophageal squamous cell carcinoma using tissue chip method. Then, cell models and xenograft models in nude mice with different CBS expression levels and CBS gene knockout were constructed to study the promoting effect of CBS-H2S system on lymph node metastasis. Finally, the regulation effect of CBS-H2S system on SIRT1/Notch1/Hes1 pathway was investigated by using the above cell and animal models. The purpose of this project is to explore the important role of CBS-H2S generation pathway in the process of lymph node metastasis of esophageal squamous cell carcinoma, and to provide theoretical basis for the subsequent research and development of lymph node metastasis treatment drugs targeting this pathway.