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

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number13
JournalBMC Gastroenterology
Volume16
Issue number1
DOIs
Publication statusPublished - 2016 Jan 29

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Liver Cirrhosis
Transgenic Mice
Hepatocellular Carcinoma
Liver
Hydrodynamics
Transfection
Beauty
Hepatic Stellate Cells
Neoplasms
Carbon Tetrachloride
Small Interfering RNA
Fibrosis
Collagen
Incidence
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Chung, Sook In ; Moon, Hyuk ; Kim, Dae Yeong ; Cho, Kyung Joo ; Ju, Hye Lim ; Kim, Do Young ; Ahn, Sang Hoon ; Han, Kwang Hyub ; Ro, Simon Weonsang. / Development of a transgenic mouse model of hepatocellular carcinoma with a liver fibrosis background. In: BMC Gastroenterology. 2016 ; Vol. 16, No. 1.
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abstract = "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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Development of a transgenic mouse model of hepatocellular carcinoma with a liver fibrosis background. / Chung, Sook In; Moon, Hyuk; Kim, Dae Yeong; Cho, Kyung Joo; Ju, Hye Lim; Kim, Do Young; Ahn, Sang Hoon; Han, Kwang Hyub; Ro, Simon Weonsang.

In: BMC Gastroenterology, Vol. 16, No. 1, 13, 29.01.2016.

Research output: Contribution to journalArticle

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T1 - Development of a transgenic mouse model of hepatocellular carcinoma with a liver fibrosis background

AU - Chung, Sook In

AU - Moon, Hyuk

AU - Kim, Dae Yeong

AU - Cho, Kyung Joo

AU - Ju, Hye Lim

AU - Kim, Do Young

AU - Ahn, Sang Hoon

AU - Han, Kwang Hyub

AU - Ro, Simon Weonsang

PY - 2016/1/29

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N2 - 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.

AB - 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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