抗纤抑癌方对肝癌前病变大鼠整合素α5β1/FAK信号通路的影响
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摘要
目的:基于整合素α5β1/FAK信号通路探讨抗纤抑癌方干预肝癌前病变的作用机制。方法:雄性Wistar大鼠85只,随机分为正常组、模型组、抗纤抑癌低、中、高剂量组及鳖甲软肝组。采用二乙基亚硝胺腹腔注射制备肝癌前病变模型,用抗纤抑癌方进行干预,以复方鳖甲软肝片作为对照;采用HE、Masson染色观察大鼠肝脏组织病理情况,实时荧光定量PCR及Western blot法检测肝组织中ITG-α5、ITG-β1、FN及FAK mRNA及蛋白的表达水平。结果:抗纤抑癌方可明显改善大鼠肝脏组织纤维化程度,降低肝细胞的变性、坏死;与模型组相比,抗纤抑癌中、高剂量组能显著降低ITG-α5、ITG-β1、FN、FAK mRNA的表达及ITG-α5、ITG-β1蛋白的表达(P<0.01,P<0.05);与鳖甲软肝组相比,抗纤抑癌中、高剂量组能显著降低ITG-α5、ITG-β1、FN mRNA的表达及ITG-β1蛋白的表达(P<0.05)。结论:抗纤抑癌方可通过调控整合素α5β1/FAK信号抑制肝癌前病变。
Objective: To explore the mechanism of Kangxian Yi'ai Formula in the intervention of precancerous lesions of the liver based on integrin α5β1/FAK signaling pathway. Methods: Eighty-five male Wistar rats were randomly divided into the normal group, model group, Kangxian Yi'ai Formula low dose, medium dose and high dose group, and Biejia Ruangan group. The animal model of hepatic precancerous lesions was induced by diethylnitrosamine. Kangxian Yi'ai Formula was used to intervene. Biejia Ruangan Tablets were taken as a control drug. The pathological changes of liver tissues were observed by HE and Masson staining. The expression of ITG-α5, ITG-β1, FN, FAK mRNA and protein in liver tissues was detected by real-time fluorescence quantitative PCR and Western blot method. Results: Kangxian Yi'ai Formula could significantly ameliorate hepatic fibrosis and reduce hepatocyte degeneration and necrosis. Compared with the model group, the expression of ITG-α5, ITG-β1, FN, FAK mRNA and the expression of ITG-α5, ITG-β1 protein in the Kangxian Yi'ai middle dose and high dose groups were significantly decreased(P<0.01, P<0.05). The expression of ITG-α5, ITG-β1, FN mRNA, and ITG-β1 protein in the Kangxian Yi'ai middle dose and high dose groups were significantly lower than that in the Biejia Ruangan Group(P<0.05). Conclusion: Kangxian Yi'ai Formula could delay the occurrence of hepatic precancerous lesions by regulating the integrin α5β1/FAK signaling pathway.
Objective: To explore the mechanism of Kangxian Yi'ai Formula in the intervention of precancerous lesions of the liver based on integrin α5β1/FAK signaling pathway. Methods: Eighty-five male Wistar rats were randomly divided into the normal group, model group, Kangxian Yi'ai Formula low dose, medium dose and high dose group, and Biejia Ruangan group. The animal model of hepatic precancerous lesions was induced by diethylnitrosamine. Kangxian Yi'ai Formula was used to intervene. Biejia Ruangan Tablets were taken as a control drug. The pathological changes of liver tissues were observed by HE and Masson staining. The expression of ITG-α5, ITG-β1, FN, FAK mRNA and protein in liver tissues was detected by real-time fluorescence quantitative PCR and Western blot method. Results: Kangxian Yi'ai Formula could significantly ameliorate hepatic fibrosis and reduce hepatocyte degeneration and necrosis. Compared with the model group, the expression of ITG-α5, ITG-β1, FN, FAK mRNA and the expression of ITG-α5, ITG-β1 protein in the Kangxian Yi'ai middle dose and high dose groups were significantly decreased(P<0.01, P<0.05). The expression of ITG-α5, ITG-β1, FN mRNA, and ITG-β1 protein in the Kangxian Yi'ai middle dose and high dose groups were significantly lower than that in the Biejia Ruangan Group(P<0.05). Conclusion: Kangxian Yi'ai Formula could delay the occurrence of hepatic precancerous lesions by regulating the integrin α5β1/FAK signaling pathway.
引文
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[2]Galle P R,Forner A,Llovet J M,et al.EASL Clinical Practice Guidelines:Management of hepatocellular carcinoma.Journal of Hepatology,2018,69(1):182-236
[3]吴孟超,汤钊猷,刘彤华,等.原发性肝癌规范化病理诊断指南年版.临床肝胆病杂志,2015,31(6):833-839
[4]Di T L,Sangiovanni A,Borzio M,et al.Advanced precancerous lesions in the liver.Best Practice&Research Clinical Gastroenterology,2013,27(2):269-284
[5]Moreno-Layseca P,Streuli C H.Signalling pathways linking integrins with cell cycle progression.Matrix Biology Journal of the International Society for Matrix Biology,2014,34(4):144-153
[6]Zhang K,Jiang M N,Zhang C H,et al.Effects of Ganfukang,on of connective tissue growth factor and focal adhesion kinaseprotein kinase B signal pathway in hepatic fibrosis rats.Chinese Journal of Integrative Medicine,2013,20(6):438-444
[7]焦云涛,杨先照,刘蕊洁,等.抗纤抑癌方干预肝纤维化大鼠肝星状细胞活化的实验研究.时珍国医国药,2017,28(5):1099-1101
[8]杨先照,江锋,叶永安.抗纤抑癌方调控HGF/c-Met mRNA干预肝癌前病变的实验研究.世界中医药,2015,28(9):1316-1319
[9]Kew M C.The role of cirrhosis in the etiology of hepatocellular carcinoma.Journal of Gastrointestinal Cancer,2014,45(1):12-21
[10]孙超,吴铭杰,江泽群,等.白花蛇舌草有效成分2-羟基-3-甲基蒽醌通过IL-6/STAT3信号通路诱导肝癌细胞凋亡作用机制.中华中医药杂志,2018,33(12):5346-5350
[11]贾文燕,贺松其,文彬,等.鳖甲煎丸对肝癌细胞周期及Wnt/β-catenin信号通路中β-catenin、COX-2蛋白表达水平的影响.中华中医药杂志,2015,30(8):2964-2967
[12]杨青,洪莉.整合素的研究进展.实用医学杂志,2015,31(6):1023-1025
[13]Nieberler M,Reuning U,Reichart F,et al.Exploring the role of RGDrecognizing ITG-s in cancer.Cancers,2017,9(9):116
[14]胡梦龙.整合素β1在肿瘤研究中的进展.临床合理用药杂志,2018,11(11):180-181
[15]孙达欣,宋景双.黏附斑激酶对恶性肿瘤的抗失巢凋亡作用及其机制研究进展.现代肿瘤医学,2018,26(2):306-310
[16]白瑞丹,张洪,黄萃园,等.FAK抑制剂对人肝星状细胞Akt/GSK-3β/β-catenin信号通路的影响.中国医院药学杂志,2018,28(1):59-63
[17]Shang N,Arteaga M,Zaidi A,et al.FAK kinase activity is required for the progression of c-Met/β-catenin-driven HCC.Gene Expression,2016,17(1):79-88