CSE/H2S促进鼻咽癌生长的作用及其分子机制

Nasopharyngeal carcinoma mainly occurs in southern China and southeast Asia and severely influences the quality of life of patients. H2S has been considered the third gaseous signaling molecule and plays important roles in physiological and pathophysiological conditions in mammals. Our previous results showed that the expression of CSE and the levels of H2S in human nasopharyngeal carcinoma were significantly higher than those in normal human nasopharyngeal epithelial cells. However, the effect of mechanism of CSE/H2S on the growth of human nasopharyngeal carcinoma is still unknown. In this project, we will mainly detect the effects of CSE/H2S on the proliferation, migration, and invasion of human nasopharyngeal carcinoma both in vitro and in vivo. The radioactive ligand-receptor binding assay, spectroscopy, and quantum chemical calculation will be adopted to determine whether H2S could increase the activities of Cu/Zn-SOD and Mn-SOD and reduce the ROS level by replacing the water which locates in the active center of Cu/Zn-SOD and Mn-SOD. Furthermore, Western blot analysis will be used to detect whether CSE/H2S could promote tumor growth and angiogenesis through MAPK and PI3K/AKT/mTOR signaling pathways. This project will provide insights into understanding the effect and molecular mechanism of CSE/H2S on promoting the growth of nasopharyngeal carcinoma, which will lay the foundation for the further development of CSE/H2S-related antitumor drugs.

鼻咽癌主要发生在我国南方和东南亚地区，严重影响患者的生存质量。H2S作为第三种气体信号分子，在哺乳动物体内发挥着重要的生理与病理生理学作用。我们前期研究发现与人正常鼻咽上皮细胞相比，人鼻咽癌细胞中CSE表达水平与H2S含量明显升高，但CSE/H2S在人鼻咽癌生长过程中的作用机制尚不明确。本项目主要通过体内外实验研究CSE/H2S对人鼻咽癌细胞增殖、迁移、侵袭的作用，采用放射性受体-配体结合实验、光谱学实验、量子化学计算等方法研究H2S能否通过取代Cu/Zn-SOD和Mn-SOD活性中心的H2O分子从而提高其活性并降低ROS水平，采用Western blot技术检测CSE/H2S是否通过MAPK和PI3K/AKT/mTOR信号通路发挥促进肿瘤生长和血管新生的作用，从而阐明CSE/H2S促进鼻咽癌生长的作用及其分子机制，为进一步开发CSE/H2S相关抗肿瘤药物奠定基础。

鼻咽癌(NPC)是一种上皮来源的恶性肿瘤，其具有独特的地理分布。胱硫醚-γ-裂解酶(CSE)参与癌症的发生和发展过程。然而，CSE在NPC生长过程中的作用尚不明确。在本研究中，我们发现人NPC细胞中CSE表达水平高于正常鼻咽细胞。CSE过表达促进NPC细胞增殖、迁移和侵袭能力，CSE下调具有相反作用。CSE过表达降低细胞色素C、裂解的caspase-3、裂解的caspase-9和裂解的聚-ADP-核糖聚合酶的表达，而CSE敲低表现出相反的效果。CSE过表达降低活性氧(ROS)水平和磷酸化(p)-细胞外信号调节蛋白激酶1/2、p-c-Jun N末端激酶和p-p38的表达，但促进p-磷脂酰肌醇3-激酶(PI3K)、p-AKT和p-哺乳动物雷帕霉素靶蛋白(mTOR)的表达，CSE敲除显示相反的效果。此外，CSE过表达通过介导增殖、血管生成、细胞周期和凋亡促进NPC移植瘤生长，CSE敲低则能够抑制移植瘤生长。总之，CSE通过ROS介导的MAPK和PI3K/AKT/mTOR信号通路促进NPC细胞生长。CSE可能是NPC诊断和预后的一种新的肿瘤标志物，可以开发抑制CSE表达/活性的新型供体/药物从而治疗NPC。