基于解痉多肽表达化生探讨ciRS-7/miR-7在胃癌前病变证候演变中的作用机制

The prevention of precancerous lesions of gastric cancer (PLGC) is the main content of secondary prevention of gastric cancer. And dampness, toxin, deficiency and blood stasis are considered to be the major pathogenesis of PLGC, whose key pathology is spasmolytic polypeptide-expressing metaplasia (SPEM) . The relationship of SPEM and helicobacter pylori (Hp) gives a clue of characteristics of syndrome evolution by the major pathogenesis of PLGC. The prior clinical research results show that the syndrome of spleen stomach dampness heat and spleen Qi deficiency are related to the homeostasis of Th1 and Th2 cells, and microRNA-7(miR-7) is a tumor suppressor for PLGC by indirectly regulating the expression of Th1 cells. Furthermore, the advance experiment results of this research prove that the potential regulation property of miR-7 in the different syndrome of deficiency and solid spleen and stomach, with the literature results of inhibition of ciRS-7 for miR-7, however, the mechanism of ciRS-7/miR-7 in syndrome evolution of PLGC is unclear. In this research, the international generally accepted model of SPEM will combine with pre-existing syndrome model, with combination of disease and syndrome mouse model for dampness, toxin, deficiency and blood stasis independently. The relationship of syndrome and PLGC, cytokines and the influence for gastric mucosa lesions will be observed, in order to explain the target and molecule mechanism of ciRS-7/miR-7 mediated the syndrome evolution of PLGC. This research extends the thought and method of Chinese medicine for PLGC, and lays a theory and experiment foundation for the prevention of PLGC.

胃癌前病变（PLGC）是胃癌二级预防的重要内容，其关键病理环节解痉多肽表达化生（SPEM）与幽门螺杆菌（Hp）的关系体现了PLGC主要病机“湿、毒、虚、瘀”所致的证候演变特征。前期研究发现Hp感染下脾胃虚实证候演变与Th1/Th2细胞平衡相关，miR-7间接调节Th1细胞在PLGC发展过程中为抑癌基因，预实验提示miR-7调节脾胃虚实证候演变中SPEM的进展，及文献提示ciRS-7抑制miR-7活性，但ciRS-7/miR-7在PLGC证候演变中的作用机制尚不明确。本课题通过国际公认的SPEM模型与现有的证候模型有机结合，分别复制“湿、毒、虚、瘀”病证结合的动物模型，观察不同证候与PLGC相互作用、与炎症因子的关系及对胃黏膜病变的影响，阐明ciRS-7/miR-7介导PLGC证候演变的作用靶点及分子机制。本课题拓宽了中医药研究PLGC的思路及方法，为中医药防治该病变奠定了理论和实验基础。

胃癌前病变(PLGC)是胃癌二级预防的重要内容，其关键病理环节解痉多肽表达化生(SPEM)与幽门螺杆菌(Hp)的关系体现了PLGC主要病机“湿、毒、虚、瘀”所致的证候演变特征。前期研究发现Hp感染下脾胃虚实证候演变与Th1/Th2细胞平衡相关，miR-7间接调节Th1细胞在PLGC发展过程中为抑癌基因，并参与调节脾胃虚实证候演变中SPEM的进展，而ciRS-7抑制miR-7活性，为了证实ciRS-7/miR-7在PLGC证候演变中的作用机制，本课题通过免疫荧光、原位杂交等技术检测慢性萎缩性胃炎（CAG）患者胃黏膜SPEM组织中TFF2与miR-7的表达，构建国际公认的SPEM小鼠模型与现有的证候模型有机结合，观察不同证候与PLGC相互作用、与炎症因子的关系及对胃黏膜病变的影响，阐明ciRS-7/miR-7介导PLGC证候演变的作用靶点及分子机制。结果发现：①CAG患者胃黏膜SPEM组织中miR-7下调为早期事件，miR-7介导调节TFF2参与化生进展至胃癌的发生发展过程，使用健脾益胃中药复方（益胃消瘀颗粒）可促进SPEM病灶自恢复进程；②动物实验证实了在癌前病灶已形成的前提下，虽无Hp感染，在外感湿热之邪、进食肥甘厚腻、饥饱失常、过劳伤脾等诱因下，机体可突破自身代偿修复能力，延缓SPEM恢复甚至使PLGC进一步进展，这可能跟miR-7a-5p介导炎症因子IL-1β使得Th1/Th2细胞失衡相关；③作为正气的miR-7在ciRS-7作用下，可能通过介导炎症因子靶向于EGFR形成反馈调节环，调节PLGC发生发展及证候演变，这是PLGC发生前期（即SPEM时期）由湿毒实证转换为脾虚为本、瘀毒夹杂的证候演变的可能机制。本课题拓宽了中医药研究PLGC的思路及方法，为中医药防治该病变奠定了理论和实验基础，研究成果将具有重要理论意义和潜在的应用前景，不仅有利于药物的研制和开发，并可为中医药证候理论现代化研究提供可借鉴的新模式。