基于EGFR信号通路探讨疏肝健脾化痰法逆转慢性萎缩性胃炎癌前病变的机制

Chronic atrophic gastritis with intestinal metaplasia or dysplasia as precancerous lesions of gastric cancer is a necessary first step, the evolution has certain reversibility. No ideal drug has been found to reverse the atrophy and metaplasia or dysplasia lesions. Therefore, actively seeking effective prevention and treatment of chronic atrophic gastritis precancerous lesions, blocking the development of gastric cancer, has become an important way to prevent gastric cancer and reduce the incidence. According to the previous clinical practice, the research group considered that liver depression and spleen deficiency are important pathological features of chronic atrophic gastritis. Phlegm is a pathological product of liver depression and spleen deficiency, which can aggravate the disease. Whether the stagnation of liver Qi and spleen deficiency is the aggravating damage of mucous membrane and the factors that promote the evolution of precancerous lesions to gastric cancer have not been scientifically revealed. It is found that the Ras-Raf-MEK-ERK pathway mediated by EGFR signal is closely related to the protection and repair of gastric mucosal barrier. This study by observing the mucosal protective effect of Chaishao Decoction on Jun six rats with chronic atrophic gastritis precancerous lesions, from the overall perspective, organs and molecular level, in-depth study on the protection of chronic atrophic gastritis and precancerous lesions of the signal transduction mechanism and comparative study, to provide experimental basis for the intervention to the progression of gastric cancer precancerous lesions,which has important significance to reveal the effective way to prevent and cure the precancerous lesions of chronic atrophic gastritis.

慢性萎缩性胃炎伴肠化生或异型增生作为癌前病变是胃癌的必经始动环节，演变有一定的可逆性。目前无理想药物逆转癌前病变。因此寻找有效防治胃癌前病变、阻断其发展的方法，已成为预防胃癌重要途径。课题组根据前期临床，认为肝郁脾虚是慢性萎缩性胃炎的重要病理特点，痰是肝郁脾虚的病理产物，能加剧病情。然而肝郁脾虚痰阻是否是加重黏膜损伤，促使癌前病变演变为胃癌的因素尚未得到科学揭示。文献表明，EGFR信号介导的Ras-Raf-MEK-ERK通路与胃粘膜屏障保护和修复功能关系密切。本研究通过观察柴芍六君汤对大鼠慢性萎缩性胃炎癌前病变的粘膜保护作用，从整体角度、组织器官和分子水平，对疏肝健脾化痰法保护胃癌前病变的信号转导机制作深入探讨，揭示疏肝健脾化痰作用于胃癌前病变的分子生物学机制，为其干预癌前病变向胃癌发展提供实验依据，进而阐释癌前病变肝郁脾虚痰阻的分子生物学基础，对揭示胃癌前病变的有效防治途径有重要意义。

慢性萎缩性胃炎伴肠化生或异型增生作为癌前病变已经被广泛接受，其胃黏膜病理改变有一定的可逆性，而中医药在整体观念指导下进行辨证论治，日益显示出防癌抗变的优势，已成为胃癌防治研究的热点。EGFR信号通路是关键的细胞增殖和凋亡相关信号通路之一，研究发现其下游信号转导通路Ras/Raf/MEK/ERK途径和JAK/STAT途径是调控胃黏膜细胞增殖和凋亡的关键通路。前期临床研究发现肝郁脾虚是慢性萎缩性胃炎的重要病理特点，痰是肝郁脾虚的病理产物，也是慢性胃炎“炎癌转化”过程的重要影响因素。然而慢性萎缩性胃炎癌前病变肝郁脾虚痰阻交互作用的分子生物学内涵尚未得到科学揭示。本项目采用维酶素、柴芍六君汤、柴胡疏肝散和六君子汤干预慢性萎缩性胃炎癌前病变大鼠，通过对行为学表现、胃黏膜组织病理学、胃黏膜损伤修复指标、细胞增殖和凋亡相关指标的观察检测，结果表明柴芍六君汤、柴胡疏肝散、六君子汤均能不同程度地改善慢性萎缩性胃炎癌前病变大鼠的一般行为学表现和胃黏膜组织病理学形态，疏肝健脾化痰法能够下调其EGF、TGF-α含量，调控胃黏膜增殖凋亡相关基因PCNA、Ag-NOR、VEGF和p53、Bcl-2表达，从而降低炎症水平。进一步研究胃黏膜组织EGFR信号转导通路相关指标发现疏肝健脾化痰法防治慢性萎缩性胃炎癌前病变的作用机制与抑制EGFR/JAK/STAT信号转导通路异常激活有关。本研究从“方证对应”角度初步揭示慢性萎缩性胃炎癌前病变肝郁脾虚痰阻的分子生物学基础，为中医药防治胃癌前病变提供科学的实验依据。