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Development of a transgenic mouse model of hepatocellular carcinoma with a liver fibrosis background

 Sook In Chung  ;  Hyuk Moon  ;  Dae Yeong Kim  ;  Kyung Joo Cho  ;  Hye-Lim Ju  ;  Do Young Kim  ;  Sang Hoon Ahn  ;  Kwang-Hyub Han  ;  Simon Weonsang Ro 
 BMC GASTROENTEROLOGY, Vol.16(13) : 1-9, 2016 
Journal Title
Issue Date
Animals ; Carbon Tetrachloride ; Carcinogenesis/metabolism ; Carcinoma, Hepatocellular/etiology* ; Carcinoma, Hepatocellular/metabolism ; Disease Models, Animal ; Genes, myc/genetics ; Genes, p53 ; Hepatic Stellate Cells/metabolism ; Liver/metabolism ; Liver/pathology ; Liver Cirrhosis, Experimental/chemically induced ; Liver Cirrhosis, Experimental/complications* ; Liver Neoplasms/etiology* ; Liver Neoplasms/metabolism ; Liver Neoplasms, Experimental/etiology* ; Liver Neoplasms, Experimental/metabolism ; Mice ; Mice, Transgenic ; RNA, Small Interfering ; Transposases/metabolism
Transgenic mouse ; Hepatocellular carcinoma ; Fibrosis ; Hydrodynamic transfection ; Liver injury
BACKGROUND: Liver fibrosis and its end-stage disease, cirrhosis, are major risk factors for hepatocellular carcinoma (HCC) and present in 80 to 90 % of patients with HCC. Current genetically engineered mouse models for HCC, however, generally do not feature liver fibrosis, which is a critical discrepancy between human HCC and murine models thereof. In this study, we developed a simple transgenic mouse model of HCC within the context of a fibrotic liver.
METHODS: Employing hydrodynamic transfection (HT), coupled with the Sleeping Beauty (SB) transposon system, liver was stably transfected with transposons expressing cMyc and a short hairpin RNA down-regulating p53 (shp53). A chronic liver injury model, induced by hepatotoxic carbon tetrachloride (CCl4), was applied to the transgenic mice, allowing cells expressing cMyc plus shp53 to become malignant in the background of liver fibrosis.
RESULTS: Livers harvested about 3 months after HT had excessive collagen deposition and activated hepatic stellate cells surrounding the tumors. Hepatocarcinogenesis was significantly accelerated in the fibrotic livers compared to those of the control, significantly decreasing the life span of the mice. The tumor incidence and average number of tumors per mouse were significantly higher in the group treated with CCl4 compared to the vehicle-treated control mice, following HT (p < 0.01).
CONCLUSIONS: Considering the simplicity and efficiency in generating HCC for fibrotic livers, the transgenic HCC model has the potential to be effectively used in preclinical testing of HCC anticancer therapy and in studies of hepatocarcinogenesis in fibrotic livers.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Do Young(김도영)
Ro, Simon Weonsang(노원상) ORCID logo https://orcid.org/0000-0003-2187-3698
Ahn, Sang Hoon(안상훈) ORCID logo https://orcid.org/0000-0002-3629-4624
Chung, Sook In(정숙인) ORCID logo https://orcid.org/0000-0002-7915-9203
Han, Kwang-Hyub(한광협) ORCID logo https://orcid.org/0000-0003-3960-6539
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