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Journal of Gastrointestinal Cancer
Published in: Journal of Gastrointestinal Cancer 4/2021

01-12-2021 | Metastasis | Invited Reviews

Zebrafish Xenotransplantation Models for Studying Gene Function and Drug Treatment in Hepatocellular Carcinoma

Authors: Seniye Targen, Ozlen Konu

Published in: Journal of Gastrointestinal Cancer | Issue 4/2021

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Abstract

Introduction

Zebrafish is a promising model organism for human disease including hepatocellular cancer (HCC). Recently, zebrafish has emerged also as a host for xenograft studies of liver cancer cell lines and patient derived tumors of HCC. Zebrafish embryos enable drug screening and gene function studies of xenografted cells via ease of microinjection and visualization of tumor growth and metastasis.

Objectives

In this review, we aimed to overview zebrafish HCC and liver cancer xenotransplantation studies focusing on ‘gene functional analysis’ and ‘drug/chemical screening’.

Methods

Herein, a comprehensive literature search was performed for liver and HCC xenografts in zebrafish on PubMed using different key words and filters for molecular modifications or drug exposure.

Results

Our literature search revealed around 250 studies which were filtered and summarized in a table (Table 1) revealing comprehensive collection of experimental and technical details on microinjection, injected cell lines, molecular modifications of injected cells, types and doses of drug treatments as well as biological assessments.

Conclusion

This review provides a platform for HCC and liver xenografts and highlights studies performed to understand gene functionality and drug efficacy in vivo in zebrafish.
Literature
1.
Fazio M, Ablain J, Chuan Y, Langenau DM, Zon LI. Zebrafish patient avatars in cancer biology and precision cancer therapy. Nat Rev Cancer. 2020.
2.
Drabsch Y, Snaar-Jagalska BE, Ten Dijke P. Fish tales: the use of zebrafish xenograft human cancer cell models. Histol Histopathol. 2017.
3.
Targen S, Kaya T, Ender Avci M, Gunes D, Keskus AG, Konu O. ZenoFishDb v1.1: a database for xenotransplantation studies in zebrafish. Zebrafish. 2020;17.
4.
Tonon F, Farra R, Zennaro C, Pozzato G, Truong N, Parisi S, Rizzolio F, Grassi M, Scaggiante B, Zanconati F, Bonazza D. Xenograft zebrafish models for the development of novel anti-hepatocellular carcinoma molecules. Pharmaceuticals. 2021;14(8):803. https://​doi.​org/​10.​3390/​ph14080803.
5.
Tonon F, Zennaro C, Dapas B, Carraro M, Mariotti M, Grassi G. Rapid and cost-effective xenograft hepatocellular carcinoma model in zebrafish for drug testing. Int J Pharm. 2016;515.
6.
Karkampouna S, van der Helm D, Gray PC, Chen L, Klima I, Grosjean J, et al. CRIPTO promotes an aggressive tumour phenotype and resistance to treatment in hepatocellular carcinoma. J Pathol. 2018.
7.
Li Y, Wu Q, Yu G, Li L, Zhao X, Huang X, et al. Polypyridyl ruthenium(II) complex-induced mitochondrial membrane potential dissipation activates DNA damage-mediated apoptosis to inhibit liver cancer. Eur J Med Chem. 2019;164.
8.
Bartucci M, Hussein MS, Huselid E, Flaherty K, Patrizii M, Laddha SV, et al. Synthesis and characterization of novel BMI1 inhibitors targeting cellular self-renewal in hepatocellular carcinoma. Target Oncol. 2017;12.
9.
Wu L, Chen P, Ying J, Zhang Q, Liu F, Lv B, et al. MAT2B mediates invasion and metastasis by regulating EGFR signaling pathway in hepatocellular carcinoma. Clin Exp Med. 2019;19.
10.
Nakayama J, Lu JW, Makinoshima H, Gong Z. A novel zebrafish model of metastasis identifies the HSD11b1 inhibitor adrenosterone as a suppressor of epithelial-mesenchymal transition and metastatic dissemination. Mol Cancer Res. 2020;18.
11.
Yang J, Pei H, Luo H, Fu A, Yang H, Hu J, et al. Non-toxic dose of liposomal honokiol suppresses metastasis of hepatocellular carcinoma through destabilizing EGFR and inhibiting the downstream pathways. Oncotarget. 2017;8.
12.
Poté N, Cros J, Laouirem S, Raffenne J, Negrão M, Albuquerque M, et al. The histone acetyltransferase hMOF promotes vascular invasion in hepatocellular carcinoma. Liver Int. 2020;40.
13.
Sie ZL, Li RY, Sampurna BP, Hsu PJ, Liu SC, Wang HD, et al. WNK1 kinase stimulates angiogenesis to promote tumor growth and metastasis. Cancers. 2020;12.
14.
Avci ME, Keskus AG, Targen S, Isilak ME, Ozturk M, Atalay RC, et al. Development of a novel zebrafish xenograft model in ache mutants using liver cancer cell lines. Sci Rep. Springer US; 2018;8:1570.
15.
Khan N, Mahajan NK, Sinha P, Jayandharan GR. An efficient method to generate xenograft tumor models of acute myeloid leukemia and hepatocellular carcinoma in adult zebrafish. Blood Cells Mol Dis. 2019.
16.
Kim EA, Lee JH, Heo SJ, Jeon YJ. Saringosterol acetate isolated from Hizikia fusiforme, an edible brown alga, suppressed hepatocellular carcinoma growth and metastasis in a zebrafish xenograft model. Chem Biol Interact. 2021;335.
17.
Tu H-C, Hsiao Y-C, Yang W-Y, Tsai S-L, Lin H-K, Liao C-Y, et al. Up-regulation of golgi α-mannosidase IA and down-regulation of golgi α-mannosidase IC activates unfolded protein response during hepatocarcinogenesis. Hepatol Commun. 2017;1.
18.
Iscan E, Ekin U, Yildiz G, Oz O, Keles U, Suner A, et al. TAp73β can promote hepatocellular carcinoma dedifferentiation. Cancers. 2021;13.
19.
Topel H, Bagirsakci E, Comez D, Bagci G, Cakan-Akdogan G, Atabey N. lncRNA HOTAIR overexpression induced downregulation of c-Met signaling promotes hybrid epithelial/mesenchymal phenotype in hepatocellular carcinoma cells. Cell Communication and Signaling. 2020;18.
20.
Akbari S, Kunter I, Azbazdar Y, Ozhan G, Atabey N, Firtina Karagonlar Z, et al. LGR5/R-Spo1/Wnt3a axis promotes stemness and aggressive phenotype in hepatoblast-like hepatocellular carcinoma cell lines. Cell Signal. 2021;82.
21.
Huang D, Yang B, Yao Y, Liao M, Zhang Y, Zeng Y, et al. Autophagic inhibition of caveolin-1 by compound Phyllanthus urinaria L. activates ubiquitination and proteasome degradation of β-catenin to suppress metastasis of hepatitis B-associated hepatocellular carcinoma. Front Pharmacol. 2021;12.
22.
Chou YT, Chen LY, Tsai SL, Tu HC, Lu JW, Ciou SC, et al. Ribose-5-phosphate isomerase A overexpression promotes liver cancer development in transgenic zebrafish via activation of ERK and β-catenin pathways. Carcinogenesis. 2019;40.
23.
Liu JS, Huo CY, Cao HH, Fan CL, Hu JY, Deng LJ, et al. Aloperine induces apoptosis and G2/M cell cycle arrest in hepatocellular carcinoma cells through the PI3K/Akt signaling pathway. Phytomedicine. 2019;61.
24.
Wei PL, Huang CY, Chang YJ. Propyl gallate inhibits hepatocellular carcinoma cell growth through the induction of ROS and the activation of autophagy. PLoS ONE. 2019;14.
25.
Zhao LJ, Zhao HY, Wei XL, Guo FF, Wei JY, Wang HJ, et al. The lipid homeostasis regulation study of arenobufagin in zebrafish HepG2 xenograft model and HepG2 cells using integrated lipidomics-proteomics approach. J Ethnopharmacol. 2020;260.
26.
Gao J, Yin Z, Wu Z, Sheng Z, Ma C, Chen R, et al. Probing synergistic targets by natural compounds for hepatocellular carcinoma. Front Cell Dev Biol. 2021;9.
27.
Xu J, Yan B, Zhang L, Zhou L, Zhang J, Yu W, et al. Theabrownin induces apoptosis and tumor inhibition of hepatocellular carcinoma HUH7 cells through ask1-jnk-c-jun pathway. OncoTargets and Therapy. 2020;13.
28.
Meehan TF, Conte N, Goldstein T, Inghirami G, Murakami MA, Brabetz S, et al. PDX-MI: minimal information for patient-derived tumor xenograft models. Cancer Res. 2017;77.
29.
Conte N, Mason JC, Halmagyi C, Neuhauser S, Mosaku A, Yordanova G, et al. PDX Finder: a portal for patient-derived tumor xenograft model discovery. Nucleic Acids Res. 2019;47.
30.
He S, Hu B, Li C, Lin P, Tang WG, Sun YF, et al. PDXliver: a database of liver cancer patient derived xenograft mouse models. BMC Cancer. 2018;
31.
Lin HS, Huang YL, Wang YR, Hsiao E, Hsu TA, Shiao HY, et al. Identification of novel anti-liver cancer small molecules with better therapeutic index than sorafenib via zebrafish drug screening platform. Cancers. 2019;
32.
Usai A, Di Franco G, Colucci P, Pollina LE, Vasile E, Funel N, et al. A model of a zebrafish avatar for co-clinical trials. Cancers. 2020;12.
33.
Di Franco G, Usai A, Funel N, Palmeri M, Rosamaria Montesanti IE, Bianchini M, et al. Use of zebrafish embryos as avatar of patients with pancreatic cancer: a new xenotransplantation model towards personalized medicine. World J Gastroenterol. 2020;26.
34.
Ikonomopoulou MP, Fernandez-Rojo MA, Pineda SS, Cabezas-Sainz P, Winnen B, Morales RAV, et al. Gomesin inhibits melanoma growth by manipulating key signaling cascades that control cell death and proliferation. Sci Rep. 2018;8.
35.
Yuan Y, Zhang Y, Yao S, Shi H, Huang X, Li Y, et al. The translation initiation factor eIF3i up-regulates vascular endothelial growth factor A, accelerates cell proliferation, and promotes angiogenesis in embryonic development and tumorigenesis. J Biol Chem. 2014;289.
36.
Zhang H, Song Y, Li L, Zhang SY, Wu Q, Mei WJ, et al. Phenanthroimidazole derivatives act as potent inducer of autophagy by activating DNA damage pathway. Bioinorg Chem. 2019;88.
37.
Dawood M, Hegazy MEF, Elbadawi M, Fleischer E, Klinger A, Bringmann G, et al. Vitamin K3 chloro derivative (VKT-2) inhibits HDAC6, activates autophagy and apoptosis, and inhibits aggresome formation in hepatocellular carcinoma cells. Biochem Pharmacol. 2020;180.
38.
Deng LJ, Lei YH, Quan JY, Li BJ, Zhang DM, Tian HY, et al. 1β–OH–arenobufagin induces mitochondrial apoptosis in hepatocellular carcinoma through the suppression of mTOR signaling pathway. J Ethnopharmacol. 2021;266.
39.
Huang CY, Chang YJ, Wei PL, Hung CS, Wang W. Methyl gallate, gallic acid-derived compound, inhibit cell proliferation through increasing ROS production and apoptosis in hepatocellular carcinoma cells. PLoS ONE. 2021;16.
40.
Chen Y, Yang W, Chen Q, Liu Q, Liu J, Zhang Y, et al. Prediction of hepatocellular carcinoma risk in patients with chronic liver disease from dynamic modular networks. J Transl Med. 2021;19.
41.
Zhang C, Li Q, Qin G, Zhang Y, Li C, Han L, et al. Anti-angiogenesis and anti-metastasis effects of polyphyllin VII on hepatocellular carcinoma cells in vitro and in vivo. Chinese Medicine (United Kingdom). 2021;16.
42.
Hou Y, Chu M, Du FF, Lei JY, Chen Y, Zhu RY, et al. Recombinant disintegrin domain of ADAM15 inhibits the proliferation and migration of Bel-7402 cells. Biochem Biophys Res Commun. 2013;435.
43.
Zhu XY, Guo DW, Lao QC, Xu YQ, Meng ZK, Xia B, et al. Sensitization and synergistic anti-cancer effects of furanodiene identified in zebrafish models. Sci Rep. 2019;9.
44.
Gunes A, Bagirsakci E, Iscan E, Cakan-Akdogan G, Aykutlu U, Senturk S, et al. Thioredoxin interacting protein promotes invasion in hepatocellular carcinoma. Oncotarget 2018;9.
45.
Tseng CH, Chen YR, Tzeng CC, Liu W, Chou CK, Chiu CC, et al. Discovery of indeno[1,2-b]quinoxaline derivatives as potential anticancer agents. Euro J Medicinal Chem. 2016;108.
46.
Tian L, Xie K, Sheng D, Wan X, Zhu G. Antiangiogenic effects of oridonin. BMC Complemen Altern Med. 2017;17.
47.
Chang WT, Liu W, Chiu YH, Chen BH, Chuang SC, Chen YC, et al. A 4-phenoxyphenol derivative exerts inhibitory effects on human hepatocellular carcinoma cells through regulating autophagy and apoptosis accompanied by downregulating α-tubulin expression. Molecules 2017;22. 
Metadata
Title
Zebrafish Xenotransplantation Models for Studying Gene Function and Drug Treatment in Hepatocellular Carcinoma
Authors
Seniye Targen
Ozlen Konu
Publication date
01-12-2021
Publisher
Springer US
Published in
Journal of Gastrointestinal Cancer / Issue 4/2021
Print ISSN: 1941-6628
Electronic ISSN: 1941-6636
DOI
https://doi.org/10.1007/s12029-021-00782-z

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