秋水仙碱经由Hippo信号通路对小鼠肝癌的影响及其机制研究OACSTPCD
Effects of colchicine via Hippo signaling pathway on mouse liver cancer and its mechanism research
目的 探明秋水仙碱经由Hippo信号通路对小鼠肝癌的影响及其机制研究.方法 6周龄的雄性C57BL/6J小鼠随机分为3组:对照组、模型组、秋水仙碱组,建立二乙基亚硝胺(DEN)/四氯化碳(CCl4)/乙醇(C2H5OH)诱导小鼠肝癌模型及秋水仙碱(0.1 mg/kg)干预.第1至2周,模型组和秋水仙碱组腹腔注射1.0％DEN,每周1次;第3周至第7周,灌胃4溶于橄榄油溶液(5 ml/kg)每周2次;第8周至第18周,灌胃20％CCl4溶于橄榄油溶液(6 ml/kg)每周2次.秋水仙碱组连续灌胃给药20周.对照组给予相应的溶媒.进行肝指数、谷丙转氨酶(ALT)、谷草转氨酶(AST)血清生化指标的检测,蛋白印迹(Western blot)和免疫荧光检测各组小鼠肝组织中MST1、pYAP、YAP、pTAZ、TAZ蛋白的表达水平.结果 对照组小鼠肝脏表面光滑,质地柔软,模型组肝脏粗糙,质地较硬,有颗粒状结节,秋水仙碱组以上病变得到明显改善.HE染色显示,对照组小鼠肝小叶结构正常,模型组肝小叶结构紊乱,可见少量脂滴,组织广泛坏死,炎性细胞浸润,存在脂肪空泡,而秋水仙碱干预后小鼠肝脏病变程度减轻.免疫荧光和Western blot结果显示,模型组小鼠较对照组小鼠肝组织中pYAP、pTAZ的蛋白表达水平降低,MST1、YAP、TAZ的蛋白表达水平增加;秋水仙碱干预后,上调MST1、pYAP、pTAZ蛋白表达水平,下调YAP、TAZ的蛋白表达水平.结论 秋水仙碱对小鼠肝癌的治疗作用可能与其激活的Hippo信号通路有关.
Objective To investigate the effect and mechanism of colchicine on mouse liver cancer via Hippo sig-naling pathway.Methods The 6-week-old male C57BL/6J mice were randomly divided into 3 groups:diethylni-trosamine(DEN)/carbon tetrachloride(CCl4)/ethanol(C2H5OH)induced mouse liver cancer model and col-chicine(0.1 mg/kg)intervention were established in control group,model group and colchicine group.From week 1st to week 2nd,the model group and the colchicine group were intraperitoneally injected with 1.0％DEN once a week.From week 3rd to week 7th,20％CCl4 dissolved in olive oil solution(5 ml/kg)was intragastric ad-ministration twice a week.From week 8th to week 18th,20％CC14 dissolved in olive oil solution(6 ml/kg)was intragastric twice a week.The colchicine group was given continuous intragastric administration for 20 weeks.The control group was given the corresponding solvent.Liver index,alanine aminotransferase(ALT)and aspartate ami-notransferase(AST)serum biochemical indexes were detected.Western blot and immunofluorescence were used to detect the expression levels of MST1,pYAP,YAP,pTAZ and TAZ proteins in liver tissues of mice in each group.Results The liver surface of mice in the control group was smooth and soft,while the liver of mice in the model group was rough and hard with granular nodules.The above lesions were significantly improved in the colchicine group.HE staining showed that the liver lobular structure of mice in the control group was normal,while the liver lobular structure of mice in the model group was disordered,with a small amount of fat droplets,extensive tissue necrosis,inflammatory cell infiltration,and fat vacuoles.The degree of liver lesions of mice after colchicine inter-vention was significantly reduced.The results of immunofluorescence and Western blot showed that compared with the control group,the protein expression levels of pYAP and pTAZ in liver tissue of model group mice were signifi-cantly decreased,while the protein expression levels of MST1,YAP and TAZ increased.After colchicine interven-tion,the protein expression levels of MST1,pYAP and pTAZ were significantly up-regulated,while the protein ex-pression levels of YAP and TAZ were down-regulated.Conclusion The therapeutic effect of colchicine on mouse liver cancer may be related to its activated Hippo signaling pathway.
徐燕燕;朱乐乐;李苗苗;杨雁
安徽医科大学药理学教研室,合肥 230032
药学
秋水仙碱Hippo信号通路肝癌二乙基亚硝胺四氯化碳乙醇
colchicinehippo signaling pathwayliver cancerdiethylnitrosaminecarbon tetrachlorideethanol
《安徽医科大学学报》 2024 (002)
肝纤维化—肝癌发生发展进程中YAP/TAZ和pSmad3C/3L-ERK/JNK/p38交互作用及丹酚酸B干预的机制
185-192 / 8
国家自然科学基金(编号:82074073)
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