地龙提取液对结肠炎相关性结肠癌Wnt/β-catenin信号通路的影响
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摘要
[目的]探讨地龙提取液对结肠炎相关性结肠癌疗效及其作用机制。[方法]小鼠随机分为空白组、模型组、地龙提取液(低、中、高剂量组)和美沙拉嗪组,并采用AOM/DSS法复制结肠炎相关性结肠癌癌前病变动物模型。治疗结束后分别测量各组小鼠胸腺、脾脏及结肠的质量,并光镜下观察结肠组织病理学改变,免疫印迹法检测结肠组织中Wnt/β-catenin信号通路中相关蛋白的表达。[结果]地龙提取液能够显著增加小鼠胸腺的质量和结肠长度(P<0.05),减少脾脏和结肠质量(P<0.05),降低AOM/DSS诱导小鼠的成瘤率(P<0.05),改善CAC小鼠结肠组织的病理学形态;此外,地龙提取液能够显著减少CAC小鼠结肠组织中Wnt3a、phospho-GSK-3β、β-catenin、c-Myc、cyclin-D1蛋白表达(P<0.05),增加APC、Axin1、GSK-3β、phospho-β-catenin、Bcl-2蛋白的表达(P<0.05)。[结论]地龙提取液能够预防结肠炎后结肠癌的发生与发展,其作用机制是通过抑制Wnt/β-catenin信号通路的活化实现的。
[Objective]To observe the effect of Earthworm extract on colitis associated colon cancer mice and its mechanism.[Methods]72mice were randomly divided into the control group,model group,Earthworm extract low,medium,high dose group and Mesalazine group,colitis associated colon cancer precancerous lesions model was duplicated by AOM/DSS method.After treatment,the weight of thymus,spleen and colon in each group were measured.The pathological changes of colon tissue were observed under light microscope,and the expression of related proteins in Wnt/β-catenin signaling pathway were detected by Western blot.[Results]The weight of thymus and colon length were increased significantly after treated with the Earthworm extract(P<0.05),while the weight of the spleen and colon were decreased significantly after treatment(P<0.05),and tumor formation rate was also reduced after treatment(P<0.05).Pathological morphology of colon tissue in CAC mice was improved in Earthworm extract low,medium,high dose group and Mesalazine group.In addition,Earthworm extract could significantly reduce the expression of Wnt3 a,phospho-GSK-3β,β-catenin,c-Myc,cyclin-D1proteins(P<0.05),and increase the expression of APC,Axin1,GSK-3β,phospho-β-catenin,Bcl-2proteins in colon tissue of mice in CAC(P<0.05).[Conclusion]Earthworm extract can prevent the occurrence and development of colitis associated colon cancer,and its mechanism is achieved by inhibiting the activation of Wnt/β-catenin signaling pathway.
[Objective]To observe the effect of Earthworm extract on colitis associated colon cancer mice and its mechanism.[Methods]72mice were randomly divided into the control group,model group,Earthworm extract low,medium,high dose group and Mesalazine group,colitis associated colon cancer precancerous lesions model was duplicated by AOM/DSS method.After treatment,the weight of thymus,spleen and colon in each group were measured.The pathological changes of colon tissue were observed under light microscope,and the expression of related proteins in Wnt/β-catenin signaling pathway were detected by Western blot.[Results]The weight of thymus and colon length were increased significantly after treated with the Earthworm extract(P<0.05),while the weight of the spleen and colon were decreased significantly after treatment(P<0.05),and tumor formation rate was also reduced after treatment(P<0.05).Pathological morphology of colon tissue in CAC mice was improved in Earthworm extract low,medium,high dose group and Mesalazine group.In addition,Earthworm extract could significantly reduce the expression of Wnt3 a,phospho-GSK-3β,β-catenin,c-Myc,cyclin-D1proteins(P<0.05),and increase the expression of APC,Axin1,GSK-3β,phospho-β-catenin,Bcl-2proteins in colon tissue of mice in CAC(P<0.05).[Conclusion]Earthworm extract can prevent the occurrence and development of colitis associated colon cancer,and its mechanism is achieved by inhibiting the activation of Wnt/β-catenin signaling pathway.
引文
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[16]李素艳,黄杰安,谭林,等.NIK和IKKβ连接蛋白、Cmyc和细胞周期蛋白D1在结肠癌组织中的表达及意义[J].中国全科医学,2015,18(24):2922-2928.
[17]Miyawaki Y,Kawachi H,Ooi A,et al.Genomic copynumber alterations of MYC and FHIT genes are associated with survival in esophageal squamous-cell carcinoma[J].Cancer Sci,2012,103(8):1558-1566.
[18]陈楚杰,黄杰安,徐春燕.人结肠癌组织中NIBP、CyclinE和CyclinD1蛋白表达变化及意义[J].山东医药,2016,56(25):13-16.
[19]竺平,杨柏霖,陈红锦,等.藤黄诱导人结肠癌细胞HCT116和SW480凋亡及调节BAX、Bcl-2和p53表达的研究[J].中药药理与临床,2014(6):101-105.
[20]喻春梅,王承党.溃疡性结肠炎相关性结肠癌化学预防的研究进展[J].国际消化病杂志,2011,31(2):71-74.
[2]曾理,谭永港,张永锋,等.溃疡性结肠炎相关性结肠癌差异蛋白筛选的初步研究[J].深圳中西医结合杂志,2015,25(14):8-10,199.
[3]杜航,孙佳明,郭晓庆,等.地龙的化学成分及药理作用[J].吉林中医药,2014,34(7):707-709.
[4]王春毅,王佳林,刘洪,等.DLC-1过表达抑制结肠癌细胞生长及与Wnt/β-catenin信号通路的关系[J].重庆医科大学学报,2014(12):1736-1739.
[5]何运元,王营,王黎,等.人参皂苷Rg3调控WNT/β-catenin信号通路抑制结肠癌细胞生长的实验研究[J].肿瘤基础与临床,2012,25(3):189-194.
[6]张瑞,朱娜,马静,等.一种溃疡性结肠炎相关性结肠癌小鼠模型的建立[J].山西医科大学学报,2016,47(8):720-723.
[7]Mattar M C,Lough D,Pishvaian M J,et al.Current management of inflammatory bowel disease and colorectal cancer[J].Gastrointest Cancer Res,2011,4(2):53-61.
[8] Rutter M D,Saunders B P,Wikinson K H,et al.Thirty-year analysis of a colonoscopic surveillance program for neoplasis on ulcerative colits[J].Gastroenterology,2006,130(4):1030-1038.
[9] Canavan C,Abrams K R,Mayberry J.Meta-analysis:colorectal and small bowel cancer risk in patients with Crohn's disease[J].Aliment Pharmacol Ther,2006,23(8):1097-1104.
[10]Xie J,Itzkowitz S H,Cancer in inflammatory bowel disease[J].World J Gastroenterol,2008,14(3):378-389.
[11]Matkowskyj K A,Chen Z E,Rao S R,et al.Dysplastic lesions in inflammatory bowel disease molecular pathogenesis to morphology[J].Arch Pathol Lab Med,2013,137(3):338-350.
[12]Vu M,Chang JY,Chen J,et al.Inflammatory bowel disease associated colorectal neoplasia[J].J Gastrointest Dig Syst,2012,23(8):2.
[13]Alghamdi S,Khan I,Beeravolu N,et al.BET protein inhibitor JQ1inhibits growth and modulates WNT signaling in mesenchymal stem cells[J].Stem Cell Res Ther,2016,7(1):22.
[14]马松林,张姮,廖宇圣,等.Wnt3a对结肠癌SW480细胞增殖的影响及作用机制[J].山东医药,2016,56(37):18-20.
[15]Jackson BC,Holmes RS,Backos DS,et al.Comparative genomics,molecular evolution and computational modeling of ALDH1B1and ALDH2[J].Chem Biol Interact,2013,202(1):11-21.
[16]李素艳,黄杰安,谭林,等.NIK和IKKβ连接蛋白、Cmyc和细胞周期蛋白D1在结肠癌组织中的表达及意义[J].中国全科医学,2015,18(24):2922-2928.
[17]Miyawaki Y,Kawachi H,Ooi A,et al.Genomic copynumber alterations of MYC and FHIT genes are associated with survival in esophageal squamous-cell carcinoma[J].Cancer Sci,2012,103(8):1558-1566.
[18]陈楚杰,黄杰安,徐春燕.人结肠癌组织中NIBP、CyclinE和CyclinD1蛋白表达变化及意义[J].山东医药,2016,56(25):13-16.
[19]竺平,杨柏霖,陈红锦,等.藤黄诱导人结肠癌细胞HCT116和SW480凋亡及调节BAX、Bcl-2和p53表达的研究[J].中药药理与临床,2014(6):101-105.
[20]喻春梅,王承党.溃疡性结肠炎相关性结肠癌化学预防的研究进展[J].国际消化病杂志,2011,31(2):71-74.