基于“瘤毒”理论探讨南蛇藤提取物调控PDCD4抑制EMT逆转胃癌前病变的作用及机制

Reversing precancerous lesions of gastric cancer (PLGC) is an effective measure reduce the mortality and morbidity of gastric cancer. Based on tumor poison theory, we believe that inhibition of tumor poison might prove to be a promising strategy for restraining tumor progression in gastric cancer. It is very important to develop new drugs that can reverse PLGC from Chinese traditional medicine which has the function of inhibiting tumor poison. Previous studies was performed to investigate the inhibitory effects of Celastrus orbiculatus (COE) on inhibition of tumor poison and EMT in gastric cancer. Epithelial-to-mesenchymal transition (EMT), the bridge of gastritis and gastric cancer, has been accepted to play an important role in the development of PLGC. It was reported that PDCD4 considered to be a tumor suppressor gene which closely related with PLGC and EMT. Therefore, in our study, we explored the role of PDCD4 in COE-mediated inhibition of EMT and reversing PLGC in vivo. We also investigated the interaction between Snail and Twist in controlling EMT of gastric epithelium cells and explored the underlying molecular mechanism by which COE modulates the EMT-mediated alteration involving Snail and Twist. These findings reveal that application of COE in treating PLGC boasts promising prospect and will become potential therapy all over the world.

逆转胃癌前病变（PLGC）是预防胃癌发生，降低其病死率的有效措施。基于瘤毒理论，我科在PLGC的治疗中，以抑制瘤毒为先导，辨证论治，取得了较好的效果。因此从能够抑制瘤毒的中药中开发具有逆转PLGC作用的新药具有重要意义。前期研究发现，中药南蛇藤具有抑制瘤毒的作用，其提取物（COE）可明显抑制胃癌上皮间质转化（EMT）的发生；而EMT被认为是胃炎与胃癌之间的桥梁，与PLGC过程密切相关。基与此，本项目拟结合体内外实验，从EMT角度探讨COE逆转PLGC的作用及机制。选择在PLGC及EMT中具有调控作用的分子PDCD4为切入点，在细胞动物水平进行关联研究；探讨COE对模型大鼠PLGC的影响；揭示PDCD4在COE抑制EMT逆转PLGC中的作用；阐明COE通过PDCD4调控下游转录因子Snail和Twist的效应与机制。本研究可揭示COE逆转PLGC的分子机制，为开发生物利用度高的新药奠定基础。

胃癌前病变（PLGC）是胃癌发生和发展过程中的一个重要阶段，具有双向转化的特点。逆转PLGC是预防胃癌发生，降低其病死率的有效措施。中医药对PLGC的总体症状改善及病理学逆转情况均有显著疗效。因此，以中医药理论为指导，以临床疗效为基础，宏观与微观相结合，深入探讨中医药逆转PLGC的作用及机制，可为胃癌的预防提供新的思路，具有十分重要的意义。上皮间质转化（EMT）被认为是胃炎与胃癌之间的桥梁，与PLGC的形成过程密切相关。因此，EMT被认为是逆转胃癌前病变的关键靶点。既往研究表明，中药南蛇藤提取物（COE）具有较强的抑制H.pylori生长的作用，且能明显抑制胃癌EMT的发生。因此本项目在前期研究工作的基础上，从分子水平上深入探讨COE逆转PLGC的作用及机制。我们发现COE能够逆转H.pylori感染的胃癌前病变的发生，其机制抑制EMT的发生有关。最新研究表明，PDCD4是一种新的抑癌基因。在H.pylori诱导胃癌EMT的分子机制中，PDCD4参与其中并发挥一定的作用。基于此，我们探讨PDCD4及其下游转录因子Snail和Twist在COE抑制EMT逆转PLGC中的作用。我们发现，COE能够通过调控PDCD4及其下游转录因子Snail和Twist来抑制EMT的发生。本研究不仅为COE作为胃癌预防的重要手段进行理论上的新探索，更重要的是为开发生物利用度高的胃癌防治新药奠定基础。

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