二乙基亚硝胺诱导建立Apc基因突变大鼠与F344大鼠肝癌模型的比较

doi:10.3969/j.issn.1674-5817.2017.03.004

实验动物与比较医学 ›› 2017, Vol. 37 ›› Issue (3): 191-197.DOI: 10.3969/j.issn.1674-5817.2017.03.004

二乙基亚硝胺诱导建立Apc基因突变大鼠与F344大鼠肝癌模型的比较

谢蓓¹, 赵磊², 孙婧¹, 张丽娟¹, 库本高志³, 魏虎来¹

1.兰州大学基础医学院, 甘肃省新药临床前研究重点实验室, 兰州 730000;
2.中牧实业股份有限公司兰州生物药厂, 兰州 730046;
3.京都大学医学院实验动物研究所, 日本京都 6068501

收稿日期:2017-01-05 出版日期:2017-06-25 发布日期:2017-06-25
作者简介:谢蓓(1980-),女,讲师,博士,研究方向:肿瘤分子生物学。E-mail:xieb@lzu.edu.cn
基金资助:
甘肃省自然科学研究基金计划项目(1208RJZA190)

Comparison on Hepatocarcinoma Model Induced by Diethylnitrosamine in Apc-mutant Rat and F344 Rat

XIE Bei¹, ZHAO Lei², SUN Jing¹, ZHANG Li-juan¹, KURAMOTO Takashi³, WEI Hu-lai¹

1. Key Laboratory of Preclinical Study for New Drugs of Gansu Province,School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China;
2. CAHIC Lanzhou Biological Pharmaceutical Factory, Lanzhou 730046, China;
3. Institute of Laboratory Animals, Graduate School of Medicine,Kyoto University, Kyoto 6068501, Japan

Received:2017-01-05 Online:2017-06-25 Published:2017-06-25

摘要/Abstract

摘要： 目的采用二乙基亚硝胺(DEN)在F344大鼠、Kyoto Apc Delta(KAD)大鼠体内诱发制备肝癌模型,并比较其优劣。方法 KAD大鼠25只,随机法分组,阴性对照组(5只)给予正常饮水;DEN造模组(20只)前5周饮水中添加40 μg/mL DEN,6~20周给予正常饮水; 定期解剖大鼠,肉眼观察肝脏病变并取病变组织及癌旁组织制作病理切片。25只F344大鼠采用相同方法进行实验。结果 F344大鼠和KAD大鼠均可成功诱发肝癌,且肝癌发生病理过程与人类相似。造模16周时KAD大鼠就可见灰白色病灶点,3/4大鼠成瘤,平均病灶数为1.00±0.82 个; 造模20周时,KAD大鼠全部(4/4)成瘤, 病灶数为3.50±1.29 个; 而F344大鼠迟至20周时才可观察到类似病灶,3/4大鼠成瘤,病灶数为1.25±0.96 个。KAD大鼠的诱导成瘤性显著高于亲代F344大鼠(P<0.05)。结论与亲代F344大鼠相比,抑癌基因Apc突变的KAD大鼠经DEN诱导更易发生肝癌,且该模型具有肝癌诱发时间短、相同诱导时间肝癌发生率高、诱发病灶数多等优点,是化学诱发制备肝癌动物模型的良好模式动物。

关键词: KAD大鼠, F344大鼠, 肝癌诱导, 二乙基亚硝胺(DEN)

Abstract: Objective To establish hepatocarcinoma models induced by diethylnitrosamine (DEN) in F344 rats, KAD (Kyoto Apc Delta) rats and compare the advantages and disadvantages between them. Methods Twenty-five KAD rats were randomly divided into 2 groups. The 5 rats in control group were given the normal water. The 20 rats in experimental group were given the water containing 40 μg/mL DEN for 5 weeks, and the remaining 15 weeks they were given the normal water. Every 4 weeks, part of KAD rats was sacrificed to undergo pathological examination and make pathological sections of liver tissues and tumor tissues. Twenty-five F344 rats were treated the same as KAD rats. Results Hepatocarcinoma could be induced successfully in KAD rats and F344 rats. The same pathological developing process was found in them, which was similar with human. The average of 1.00±0.82 grey-white lesions could be found in 3 KAD rats (3/4) when they were induced in the 16th week, while no lesions could be found in F344 rats (0/4) at that time. Until the end of the experiments (20 weeks), 3.50 ±1.29 cancers and gray-white lesions had been developed in KAD rats, while only 1.25±0.96 could be found in F344 rats. The success rate of hepatocarcinoma induction in KAD rats was better than that in F344 rats significantly (P<0.05). Conclusion Comparing to F344 rats, KAD rats could be a better hepatocarcinoma induction model, with shorter induction time, higher sucess rate and numbers of hepatocarcinoma. KAD rat may be an ideal model for dynamically researching the hepatocarcinoma induction.

Key words: KAD rat, F344 rat, Hepatocarcinoma induction, Diethylnitrosamine (DEN)

中图分类号:

Q95-33

谢蓓, 赵磊, 孙婧, 张丽娟, 库本高志, 魏虎来. 二乙基亚硝胺诱导建立Apc基因突变大鼠与F344大鼠肝癌模型的比较[J]. 实验动物与比较医学, 2017, 37(3): 191-197.

XIE Bei, ZHAO Lei, SUN Jing, ZHANG Li-juan, KURAMOTO Takashi, WEI Hu-lai. Comparison on Hepatocarcinoma Model Induced by Diethylnitrosamine in Apc-mutant Rat and F344 Rat[J]. Laboratory Animal and Comparative Medicine, 2017, 37(3): 191-197.

参考文献

[1] Heindryckx F, Colle I, Van Vlierberghe H.Experimental mouse models for hepatocellular carcinoma research[J]. Int J Exp Pathol, 2009, 90(4):367-386.
[2] Wu L, Tang ZY, Li Y.Experimental models of hepatocellular carcinoma: developments and evolution[J]. J Cancer Res Clin Oncol, 2009, 135(8):969-981.
[3] Cortinovis C, Klimek F, Nogueira E.Rat hepatocarcinogenesis induced by N-nitrosodiethylamine and N-nitrosomorpholine continuously administered at low doses[J]. Am J Pathol, 1991, 139(5):1157-1171.
[4] Tanaka T, Kojima T, Kawamori T, et al.Chemoprevention of diethylnitrosamine-induced hepatocarcinogenesis by a simple phenolic acid protocatechuic acid in rats[J]. Cancer Res, 1993, 53(12):2775-2779.
[5] Okubo H, Moriyama M, Tanaka N, et al.Detection of serum and intrahepatic hepatocyte growth factor during DEN-induced carcinogenesis in the rat[J] . Hepatol Res, 2002, 24(4):385-394.
[6] Jayaprakash R, Ramesh V, Sridhar MP, et al.Antioxidant activity of ethanolic extract of Tinospora cordifolia on N-nitrosodiethylamine (diethylnitrosamine) induced liver cancer in male Wistar albino rats[J] . J Pharm Bioallied Sci, 2015, 7(Suppl 1):S40-S45.
[7] Ma G, Bai R, Jiang H, et al.Assessment of hemodynamics in a rat model of liver cirrhosis with precancerous lesions using multislice spiral CT perfusion imaging[J]. Biomed Res Int, 2013, 813174.
[8] Yoshimi K, Tanaka T, Takizawa A, et al.Enhanced colitis-associated colon carcinogenesis in a novel Apc mutant rat[J]. Cancer Sci, 2009, 100(11):2022-2027.
[9] Tanaka T, Shimizu M, Kochi T, et al.Apc-mutant Kyoto Apc Delta (KAD) rats are susceptible to 4-NQO-induced tongue carcinogenesis[J]. Cancers (Based), 2014, 6(3):1522-1539.
[10] Yoshimi K, Tanaka T, Serikawa T, et al.Tumor suppressor APC protein is essential in mucosal repair from colonic inflammation through angiogenesis[J]. Am J Pathol, 2013, 182(4):1263-1274.
[11] Irving AA, Yoshimi K, Hart ML, et al.The utility of Apc-mutant rats in modeling human colon cancer[J] . Dis Model Mech, 2014, 7(11):1215-1225.
[12] Yoshimi K, Hashimoto T, Niwa Y, et al.Use of a chemically induced-colon carcinogenesis-prone Apc-mutant rat in a chemotherapeutic bioassay[J] . BMC Cancer, 2012, 12:448.
[13] Newell P, Villanueva A, Friedman SL, et al.Experimental models of hepatocellular carcinoma[J]. J Hepatol, 2008, 48(5):858-879.
[14] Hoshida Y, Fuchs BC, Tanabe KK.Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges[J] . Curr Cancer Drug Targets, 2012, 12(9):1129-1159.
[15] Park ST, Jang JW, Kim GD, et al.Beneficial effect of metronomic chemotherapy on tumor suppression and survival in a rat model of hepatocellular carcinoma with liver cirrhosis[J]. Cancer Chemother Pharmacol, 2010, 65(6):1029-1037.
[16] De Minicis S, Kisseleva T, Francis H, et al.Liver carcinogenesis: rodent models of hepatocarcinoma and cholangiocarcinoma[J]. Dig Liver Dis, 2013, 45(6):450-459.
[17] Colnot S, Decaens T, Niwa-Kawakita M, et al.Liver-targeted disruption of Apc in mice activates β-catenin signaling and leads to hepatocellular carcinoma[J]. Proc Natl Acad Sci U S A, 2004, 101(49):17216-17221.
[18] Thompson MD, Monga SP.WNT/β-catenin signaling in liver health and disease[J] . Hepatology, 2007, 45(5):1298-1305.
[19] Shang N, Arteaga M, Zaidi A, et al.FAK is required for c-Met/β-catenin-driven hepatocarcinogenesis[J]. Hepatology, 2015, 61(1):214-226.
[20] Hoshida Y, Nijman SM, Kobayashi M, et al.Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma[J]. Cancer Res, 2009, 69(16):7385-7392.
[21] Liu LJ, Xie SX, Chen YT, et al.Aberrant regulation of Wnt signaling in hepatocellular carcinoma[J]. World J Gastroenterol, 2016, 22(33):7486-7499.

二乙基亚硝胺诱导建立Apc基因突变大鼠与F344大鼠肝癌模型的比较

Comparison on Hepatocarcinoma Model Induced by Diethylnitrosamine in Apc-mutant Rat and F344 Rat

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 2

编辑推荐

Metrics

本文评价

[1]	李迎, 杜小燕, 崔晓霞, 马兰芝, 尚世臣, 赵志兵, 赵权, 李桂军, 王冬平, 陈振文. CMU/1和CMU/2长爪沙鼠与F344大鼠及BALB/c小鼠4项凝血指标分析[J]. 实验动物与比较医学, 2018, 38(1): 57-59.
[2]	王奕森1，朱萍妹1，徐平2，施恩2，潘华1，周光兴1. 雄性F344大鼠自发性不育症与精子参数及精子核成熟度关系研究[J]. , 2007, 27(2): 94-98.