原发性肝癌常见动物模型的研究进展

夏猛; 孙玉浩; 王萌; 冷静

doi:10.3969/j.issn.1001-5256.2021.08.042

原发性肝癌常见动物模型的研究进展

DOI: 10.3969/j.issn.1001-5256.2021.08.042

夏猛¹,
孙玉浩¹,
王萌²,
冷静^1, ,

1.
广西中医药大学基础医学院，南宁 530200
2.
广西中医药大学第一附属医院脾胃二科室，南宁 530023

基金项目:

国家自然科学基金地区基金 (81860805);

国家自然科学基金地区基金 (81660753);

广西中医药大学歧黄高层次人才团队培育项目 (2018001)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：夏猛、孙玉浩负责论文设计，撰写论文；王萌参与搜集数据，修改论文；冷静负责指导撰写文章并最后定稿。

详细信息

通信作者:
冷静，ljgxy@yahoo.com.cn

夏猛和孙玉浩对本文贡献相同，同为第一作者

中图分类号: R735.7
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- 被引次数: 0
出版历程
- 收稿日期: 2020-12-31
- 录用日期: 2021-02-18
- 出版日期: 2021-08-20

Research advances in commonly used animal models of primary hepatocellular carcinoma

1.
School of Basic Medicine, Guangxi University of Chinese Medicine, Nanning 530200, China
2.
Second Department of Spleen and Stomach, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China

Research funding:

Regional Foundation of National Natural Science Foundation of China (81860805);

Regional Foundation of National Natural Science Foundation of China (81660753);

Qihuang High-level Talent Team Cultivation Project of Guangxi University of Chinese Medicine (2018001)

摘要

摘要: 原发性肝癌是常见的恶性肿瘤之一，由于其治疗上的困难性和复杂性，采用动物模型来研究其发病机制和筛选药物是当前研究的热点，为研究者更清楚了解不同动物模型的特点及适用性。综述了小鼠、大鼠、兔、树鼩等常用的实验动物及建模方法，包括自发型、诱发型、移植型和基因修饰型等，综合文献研究可见，肝癌模型各有特点，当依据实际需要选用合适的模型，其中在中医药研究中，诱发型动物模型较为常用。在模拟人体遗传等因素发病方面，转基因模型无疑是一个很好的模式生物研究平台。为开展肝癌模型研究或者药物筛选研究提供文献参考依据。
- 肝肿瘤 /
- 疾病模型, 动物 /
- 动物, 实验
Abstract: Primary hepatocellular carcinoma is one of the most common malignant tumors, and due to the difficulty and complexity of its treatment, application of animal models to investigate its pathogenesis and screen drugs has become a research hotspot in recent years. In order to help researchers better understand the characteristics and applicability of different animal models, this article reviews the commonly used experimental animals such as mice, rats, rabbits, and tree shrews and corresponding modeling methods, including spontaneous type, induced type, transplantation type, and gene-modified type. Literature review shows that each liver cancer model has its own characteristics, and an appropriate model should be selected based on actual needs. Among these models, induced animal models are more commonly used in the study of traditional Chinese medicine. Transgenic model is a good research platform for model biology in simulating human genetic factor and other factors. This article provides a reference for the research on liver cancer model and drug screening.
- Liver Neoplasms /
- Disease Models, Animal /
- Animols, Laboratory

HTML全文

表 1 不同动物的常用造模方法

动物	诱发型	移植型	转基因型
小鼠	DEN和/或CCl₄/乙醇的联合诱导^[17-18]	腋下注射H22(小鼠肝癌细胞)或将HepG2用微量注射器注入小鼠肝脏^[19]	癌基因过表达的c-Myc模型；慢性炎症的TAK1^LPC-KO及AlbLTαβ模型^[20]；HBV转基因模型^[21]
大鼠	DEN和/或CCl₄/乙醇的联合诱导；DEN+2-乙酰氨基芴联合诱导^[22]	将Walker-256瘤株注入大鼠肝叶实质^[23]
兔		X2瘤株移植接种于兔的肝脏^[7]
树鼩	HBV +黄曲霉毒素B1(AFB1)诱导^[24]
土拨鼠	HV诱导^[15]
斑马鱼		显微注射Hep3B(人肝癌细胞)到斑马鱼卵黄囊中，构建异种移植斑马鱼^[25]	Xmrk/kras转基因模型、myc转基因模型^[26-27]; [HBx，src]与[HBx，src，p53^-/+]转基因模型^[28]

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参考文献(54)

[1]	MALEČKOVÁ A, TONAR Z, MIK P, et al. Animal models of liver diseases and their application in experimental surgery[J]. Rozhl Chir, 2019, 98(3): 100-109. http://www.ncbi.nlm.nih.gov/pubmed/31018641
[2]	CHO K, RO SW, SEO SH, et al. Genetically engineered mouse models for liver cancer[J]. Cancers (Basel), 2019, 12(1): 14. DOI: 10.3390/cancers12010014.
[3]	REFINETTI R, KENAGY GJ. Diurnally active rodents for laboratory research[J]. Lab Anim, 2018, 52(6): 577-587. DOI: 10.1177/0023677218771720.
[4]	ZHANG DX, ZHANG LJ, LI GM. Experimental study on the causes of affecting liver failure and liver regeneration after hepatectomy in rats[J]. Chin J Curr Adv Gen Surg, 2020, 23(6): 421-426. DOI: 10.3969/j.issn.1009-9905.2020.06.001. 张东欣, 张立军, 栗光明. 影响大鼠肝切除术后肝功能衰竭和肝再生原因的实验研究[J]. 中国现代普通外科进展, 2020, 23(6): 421-426. DOI: 10.3969/j.issn.1009-9905.2020.06.001.
[5]	WEBER K. Differences in types and incidence of neoplasms in wistar han and sprague-dawley rats[J]. Toxicol Pathol, 2017, 45(1): 64-75. DOI: 10.1177/0192623316672075.
[6]	PAUL D, CHANDRAKALA P, SURENDRAN S, et al. Pharmacokinetic interaction study of novel combination of palbociclib and sorafenib for hepatocellular carcinoma in SD rats[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2019, 1108: 25-31. DOI: 10.1016/j.jchromb.2019.01.003.
[7]	KELLER S, CHAPIRO J, BRANGSCH J, et al. Quantitative MRI for assessment of treatment outcomes in a rabbit VX2 hepatic tumor model[J]. J Magn Reson Imaging, 2020, 52(3): 668-685. DOI: 10.1002/jmri.26968.
[8]	YI HM, CAI BH, AI X, et al. Establishment of rabbit liver VX2 tumor model using percutaneous puncture inoculation of tumor fragment guided and evaluated by ultrasonography[J]. Curr Med Sci, 2019, 39(5): 820-824. DOI: 10.1007/s11596-019-2111-6.
[9]	XIA W, LAI YJ, DU L, et al. Application of tree shrew in animal models of human tumor diseases[J]. Progress Veterinary Med, 2019, 40(3): 109-113. DOI: 10.3969/j.issn.1007-5038.2019.03.022. 夏巍, 赖永静, 杜龙, 等. 树鼩在人类肿瘤疾病动物模型中的应用进展[J]. 动物医学进展, 2019, 40(3): 109-113. DOI: 10.3969/j.issn.1007-5038.2019.03.022.
[10]	ZHANG X, YU D, WU Y, et al. Establishment and transcriptomic features of an immortalized hepatic cell line of the Chinese tree shrew[J]. Appl Microbiol Biotechnol, 2020, 104(20): 8813-8823. DOI: 10.1007/s00253-020-10855-x.
[11]	TANG B, WU T, XIAO SF, et al. Using tree shrews (Tupaia belangeri) as a novel animal model of liver transplantation[J]. Curr Med Sci, 2018, 38(6): 1069-1074. DOI: 10.1007/s11596-018-1985-z.
[12]	SHI Z, XING H, QI C, et al. Chinese tree shrews as a primate experimental animal eligible for the study of alcoholic liver disease: characterization and confirmation by MRI[J]. Exp Anim, 2020, 69(1): 110-118. DOI: 10.1538/expanim.19-0073.
[13]	LARSON-CASEY JL, HE C, CHE P, et al. Technical advance: The use of tree shrews as a model of pulmonary fibrosis[J]. PLoS One, 2020, 15(11): e0241323. DOI: 10.1371/journal.pone.0241323.
[14]	SURESH M, CZERWINSKI S, MURREDDU MG, et al. Innate and adaptive immunity associated with resolution of acute woodchuck hepatitis virus infection in adult woodchucks[J]. PLoS Pathog, 2019, 15(12): e1008248. DOI: 10.1371/journal.ppat.1008248.
[15]	MICHALAK TI. Diverse virus and host-dependent mechanisms influence the systemic and intrahepatic immune responses in the woodchuck model of hepatitis B[J]. Front Immunol, 2020, 11: 853. DOI: 10.3389/fimmu.2020.00853.
[16]	NAKAYAMA J, GONG ZY. Transgenic zebrafish for modeling hepatocellular carcinoma[J]. MedComm, 2020, 1(2): 17. DOI: 1a1002/mc02.29.
[17]	AFALONIATI H, ANGELOPOULOU K, GIAKOUSTIDIS A, et al. HDAC1/2 inhibitor romidepsin suppresses DEN-induced hepatocellular carcinogenesis in mice[J]. Onco Targets Ther, 2020, 13: 5575-5588. DOI: 10.2147/OTT.S250233.
[18]	LEE S, WON KY, JOO S. Protective effect of polydeoxyribonucleotide against CCl₄-induced acute liver injury in mice[J]. Int Neurourol J, 2020, 24(Suppl 2): 88-95. DOI: 10.5213/inj.2040430.215.
[19]	WANG PP, WANG YH, WANG LS, et al. Anti-tumor effect and its related mechanisms of cinobufotalin combined with cisplatin on H22 liver cancer mice[J]. China J Clin Mater Med, 2020, 45(16): 3945-3951. DOI: 10.19540/j.cnki.cjcmm.20200224.401. 王培培, 王永辉, 王丽森, 等. 华蟾素辅助顺铂化疗对H22肝癌小鼠的抑瘤作用及其相关机制研究[J]. 中国中药杂志, 2020, 45(16): 3945-3951. DOI: 10.19540/j.cnki.cjcmm.20200224.401.
[20]	FRIEMEL J, FRICK L, UNGER K, et al. Characterization of HCC mouse models: Towards an etiology-oriented subtyping approach[J]. Mol Cancer Res, 2019, 17(7): 1493-1502. DOI: 10.1158/1541-7786.MCR-18-1045.
[21]	ANFUSO B, EL-KHOBAR KE, IE SI, et al. Activation of hepatic stem cells compartment during hepatocarcinogenesis in a HBsAg HBV-transgenic mouse model[J]. Sci Rep, 2018, 8(1): 13168. DOI: 10.1038/s41598-018-31406-5.
[22]	SHI J, HAN X, WANG J, et al. Matrine prevents the early development of hepatocellular carcinoma like lesions in rat liver[J]. Exp Ther Med, 2019, 18(4): 2583-2591. DOI: 10.3892/etm.2019.7875.
[23]	CAI Y, ZHANG C, ZHAN L, et al. Anticancer effects of gleditsia sinensis extract in rats transplanted with hepatocellular carcinoma cells[J]. Oncol Res, 2019, 27(8): 889-899. DOI: 10.3727/096504018X15482423944678.
[24]	LUO MT, FAN Y, MU D, et al. Molecular cloning and characterization of APOBEC3 family in tree shrew[J]. Gene, 2018, 646: 143-152. DOI: 10.1016/j.gene.2017.12.060.
[25]	DENG LJ, LEI YH, QUAN JY, et al. 1β-OH-arenobufagin induces mitochondrial apoptosis in hepatocellular carcinoma through the suppression of mTOR signaling pathway[J]. J Ethnopharmacol, 2021, 266: 113443. DOI: 10.1016/j.jep.2020.113443.
[26]	YANG Q, YAN C, WANG X, et al. Leptin induces muscle wasting in a zebrafish kras-driven hepatocellular carcinoma(HCC) model[J]. Dis Model Mech, 2019, 12(2): dmm038240. DOI: 10.1242/dmm.038240.
[27]	ZHENG W, LI Z, NGUYEN AT, et al. Xmrk, kras and myc transgenic zebrafish liver cancer models share molecular signatures with subsets of human hepatocellular carcinoma[J]. PLoS One, 2014, 9(3): e91179. DOI: 10.1371/journal.pone.0091179.
[28]	WU SY, YANG WY, CHENG CC, et al. Low molecular weight fucoidan inhibits hepatocarcinogenesis and nonalcoholic fatty liver disease in zebrafish via ASGR/STAT3/HNF4A signaling[J]. Clin Transl Med, 2020, 10(8): e252. DOI: 10.1002/ctm2.252.
[29]	NOIJ DP, van der LINDEN PW. Spontaneous regression of hepatocellular carcinoma in a Caucasian male patient: A case report and review of the literature[J]. Mol Clin Oncol, 2017, 6(2): 225-228. DOI: 10.3892/mco.2016.1115.
[30]	ROMUALDO GR, GRASSI TF, GOTO RL, et al. An integrative analysis of chemically-induced cirrhosis-associated hepatocarcinogenesis: Histological, biochemical and molecular features[J]. Toxicol Lett, 2017, 281: 84-94. DOI: 10.1016/j.toxlet.2017.09.015.
[31]	ZHANG HE, HENDERSON JM, GORRELL MD. Animal models for hepatocellular carcinoma[J]. Biochim Biophys Acta Mol Basis Dis, 2019, 1865(5): 993-1002. DOI: 10.1016/j.bbadis.2018.08.009.
[32]	FUENTES-HERNÁNDEZ S, ALARCÓN-SÁNCHEZ BR, GUERRERO-ESCALERA D, et al. Chronic administration of diethylnitrosamine to induce hepatocarcinogenesis and to evaluate its synergistic effect with other hepatotoxins in mice[J]. Toxicol Appl Pharmacol, 2019, 378: 114611. DOI: 10.1016/j.taap.2019.114611.
[33]	ZHANG SM, WANG Y, LI SL. Discontinuous low-dose Diethylnitrosamine induced C57BL/6J mouse liver cancer animal models[J]. J Henan Univ (Medical Science), 2019, 38(2): 110-112. 张舒曼, 王源, 李淑莲. 间断低剂量二乙基亚硝胺诱导C57BL/6J小鼠肝癌模型[J]. 河南大学学报(医学版), 2019, 38(2): 110-112.
[34]	CHEN Q, YOU X, YANG W, et al. Survival of endogenous hepatic stem/progenitor cells in liver tissues during liver cirrhosis[J]. Life Sci, 2020, 241: 117121. DOI: 10.1016/j.lfs.2019.117121.
[35]	SEYDI E, RAHIMPOUR Z, SALIMI A, et al. Selective toxicity of chrysin on mitochondria isolated from liver of a HCC rat model[J]. Bioorg Med Chem, 2019, 27(24): 115163. DOI: 10.1016/j.bmc.2019.115163.
[36]	FRANK D, SAVIR S, GRUENBAUM BF, et al. Inducing acute liver injury in rats via carbon tetrachloride (CCl₄) exposure through an orogastric tube[J]. J Vis Exp, 2020, (158). DOI: 10.3791/60695.
[37]	UNSAL V, CICEK M, SABANCILAR . Toxicity of carbon tetrachloride, free radicals and role of antioxidants[J]. Rev Environ Health, 2020. DOI: 10.1515/reveh-2020-0048.[Onlineaheadofprint]
[38]	WEI QY, ZHUGE F, SU LY, et al. Study on the anti-CCL₄ rat liver fibrosis mechanism of Xiangsiteng total flavonoid based on FAK/PI3K/Akt signaling pathway[J]. J Guangxi Med Univ, 2020, 37(10): 1816-1823. DOI: 10.16190/j.cnki.45-1211/r.2020.10.010. 韦淇元, 诸葛芳, 粟莲玉, 等. 相思藤总黄酮基于FAK/PI3K/Akt信号通路抗CCl₄大鼠肝纤维化作用机制的研究[J]. 广西医科大学学报, 2020, 37(10): 1816-1823. DOI: 10.16190/j.cnki.45-1211/r.2020.10.010.
[39]	WU LY, ZHANG YH, XUE G, et al. LC-MS/MS for the determination of six enzyme metabolites by cytochrome P450 in cell culture fluid[J]. Chin J Pharm Anal, 2020, 40(9): 1565-1574. DOI: 10.16155/j.0254-1793.2020.09.06. 吴丽颖, 张运好, 薛改, 等. LC-MS/MS法测定细胞培养液中6个细胞色素P450酶代谢产物的浓度[J]. 药物分析杂志, 2020, 40(9): 1565-1574. DOI: 10.16155/j.0254-1793.2020.09.06.
[40]	BROL MJ, RÖSCH F, SCHIERWAGEN R, et al. Combination of CCl(4) with alcoholic and metabolic injuries mimics human liver fibrosis[J]. Am J Physiol Gastrointest Liver Physiol, 2019, 317(2): g182-g194. DOI: 10.1152/ajpgi.00361.2018.
[41]	WEI XJ, LIU DP, SHENG YL, et al. A comparative study of CCl₄ intraperitoneal injection and common bile duct ligation induced liver injury in rats[J]. Guangdong Chem Industry, 2020, 47(17): 280-281, 279. DOI: 10.3969/j.issn.1007-1865.2020.17.130. 位小杰, 刘东璞, 盛延良, 等. CCL₄腹腔注射和胆总管结扎致大鼠肝损伤对比的实验性研究[J]. 广东化工, 2020, 47(17): 280-281, 279. DOI: 10.3969/j.issn.1007-1865.2020.17.130.
[42]	YANG CL, HUANG S, MO LM, et al. Expression of protein phosphatase 2A catalytic subunit in hepatoma cells after acute and chronic injury induced by hydrogen peroxide and aflatoxin B1 and its influence on hepatoma cells[J]. J Clin Hepatol, 2019, 35(12): 2730-2735. DOI: 10.3969/j.issn.1001-5256.2019.12.018. 杨成雷, 黄燊, 莫来铭, 等. 肝癌细胞蛋白磷酸酶2 A催化亚基在过氧化氢和黄曲霉毒素B1诱导急慢性肝癌细胞损伤模型中的表达及其对肝癌细胞的影响[J]. 临床肝胆病杂志, 2019, 35(12): 2730-2735. DOI: 10.3969/j.issn.1001-5256.2019.12.018.
[43]	WANG Q, WEI S, ZHOU S, et al. Hyperglycemia aggravates acute liver injury by promoting liver-resident macrophage NLRP3 inflammasome activation via the inhibition of AMPK/mTOR-mediated autophagy induction[J]. Immunol Cell Biol, 2020, 98(1): 54-66. DOI: 10.1111/imcb.12297.
[44]	HELMY SA, EL-MESERY M, EL-KAREF A, et al. Thymoquinone upregulates TRAIL/TRAILR2 expression and attenuates hepatocellular carcinoma in vivo model[J]. Life Sci, 2019, 233: 116673. DOI: 10.1016/j.lfs.2019.116673.
[45]	PATHAK S, CATANZARO R, VASAN D, et al. Benefits of aged garlic extract in modulating toxicity biomarkers against p-dimethylaminoazobenzene and phenobarbital induced liver damage in Rattus norvegicus[J]. Drug Chem Toxicol, 2020, 43(5): 454-467. DOI: 10.1080/01480545.2018.1499773.
[46]	DUAN X, WANG M, HAN X, et al. Combined use of microwave ablation and cell immunotherapy induces nonspecific immunity of hepatocellular carcinoma model mice[J]. Cell Cycle, 2020, 19(24): 3595-3607. DOI: 10.1080/15384101.2020.1853942.
[47]	XU ZT, DING H, FU TT, et al. A nude mouse model of orthotopic liver transplantation of human hepatocellular carcinoma HCCLM3 cell xenografts and the use of imaging to evaluate tumor progression[J]. Med Sci Monit, 2019, 25: 8694-8703. DOI: 10.12659/MSM.917648.
[48]	BARMAN A, DEB B, CHAKRABORTY S. A glance at genome editing with CRISPR-Cas9 technology[J]. Curr Genet, 2020, 66(3): 447-462. DOI: 10.1007/s00294-019-01040-3.
[49]	FRIEMEL J, FRICK L, UNGER K, et al. Characterization of HCC mouse models: Towards an etiology-oriented subtyping approach[J]. Mol Cancer Res, 2019, 17(7): 1493-1502. DOI: 10.1158/1541-7786.MCR-18-1045.
[50]	GABA RC, ELKHADRAGY L, BOAS FE, et al. Development and comprehensive characterization of porcine hepatocellular carcinoma for translational liver cancer investigation[J]. Oncotarget, 2020, 11(28): 2686-2701. DOI: 10.18632/oncotarget.27647.
[51]	HASSAN SA, SCHMITHALS C, VON HARTEN M, et al. Time-dependent changes in proliferation, DNA damage and clock gene expression in hepatocellular carcinoma and healthy liver of a transgenic mouse model[J]. Int J Cancer, 2021, 148(1): 226-237. DOI: 10.1002/ijc.33228.
[52]	STONE D, LONG KR, LOPRIENO MA, et al. CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice[J]. Mol Ther Methods Clin Dev, 2021, 20: 258-275. DOI: 10.1016/j.omtm.2020.11.014.
[53]	DENG LJ, LEI YH, QUAN JY, et al. 1β-OH-arenobufagin induces mitochondrial apoptosis in hepatocellular carcinoma through the suppression of mTOR signaling pathway[J]. J Ethnopharmacol, 2021, 266: 113443. DOI: 10.1016/j.jep.2020.113443.
[54]	CHEN S, GONG Z, LETCHER RJ, et al. Promotion effect of liver tumor progression in male kras transgenic zebrafish induced by tris (1, 3-dichloro-2-propyl) phosphate[J]. Ecotoxicol Environ Saf, 2020, 191: 110220. DOI: 10.1016/j.ecoenv.2020.110220.