冬凌草甲素和乙素抑制食管上皮细胞转化的分子机制研究

Esophageal squamous cell carcinoma incidence rates are still high in China. The esophageal epithelial cell transformation is one of the key step in esophageal cancer development. The precancerous lesion of esophageal cancer are bidirectional instability and preventable. How to block and reverse the precancerous lesion of esophageal cancer is an important strategy for esophageal cancer chemoprevention. Our preliminary study shows that the components from Rabdosia rubescens, such as oridonin and Rubescensine B can effectively inhibit epithelial growth factor (EGF) induced transformation of esophageal epithelial cells. Rabdosia rubescens can inhibit esophageal epithelial cell transformation induced by by N－nitrosomethylbenzylamine in rats. Rabdosia rubescens have also been used for preventing of respiratory disease and cancer of the esophagus in traditional chinese medicine. However, the related mechanism and the molecular targets of Rabdosia rubescens and its ingredients are still need to be investigated. The study will use virtual screening technology, protein kinase chip, molecular interaction platform and animal model to elucidate the mechanism and it targets of oridonin and Rubescensine B for inhibiting esophageal epithelial cells transformation. The study will explore the transformation inhibition mechanism of oridonin and Rubescensine B. It is also very important for preventing esophageal cancer with ingredients of traditional Chinese medicine.

我国食管癌的发病率依然居高不下。食管上皮细胞转化是食管癌发生的关键环节之一。食管癌早期呈双向不稳定性。如何阻断食管上皮细胞的转化是食管癌化学预防的重要策略。我们前期研究显示冬凌草的有效成分冬凌草甲素、冬凌草乙素能够有效抑制表皮生长因子诱导的食管上皮细胞转化。初步研究结果显示冬凌草汤剂对甲基苄基亚硝胺诱导的大鼠食管癌模型有食管癌化学预防的作用。且民间有使用冬凌草预防呼吸道疾病和食管癌的传统。但冬凌草及其有效成分预防食管上皮细胞转化的作用机制、作用的分子靶点还不清楚。本研究拟利用计算机虚拟筛选技术、蛋白激酶芯片、分子相互作用平台、动物模型等阐明冬凌草甲素、乙素食管癌化学预防的作用、分子靶点和抑制食管上皮转化的机制。该研究对于探索食管上皮细胞转化过程，开发以冬凌草成分为主的化学预防药物具有重要的意义。

我国食管癌的发病率依然居高不下。食管上皮细胞转化是食管癌发生的关键环节之一。我们研究显示冬凌草的有效成分冬凌草甲素、冬凌草乙素能够有效抑制表皮生长因子诱导的食管上皮细胞转化。冬凌草汤剂对甲基苄基亚硝胺诱导的大鼠食管癌模型有食管癌化学预防的作用。冬凌草甲素通过抑制PI3K/AKT信号通路，冬凌草乙素通过抑制ERK/RSK2信号通路来抑制食管上皮细胞转化。冬凌草甲素以ATP竞争性模式与AKT蛋白激酶结合并抑制其活性。冬凌草甲素通过靶向AKT蛋白抑制食管鳞癌细胞的体外增殖、周期进展并促进凋亡的发生，冬凌草甲素还显著下调AKT激酶下游蛋白GSK-3β、mTOR和NF-κB的活化。