Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model

Sook In Chung, Hyuk Moon, Hye Lim Ju, Kyung Joo Cho, Do Young Kim, Kwang Hyub Han, Jung Woo Eun, Suk Woo Nam, Silvia Ribback, Frank Dombrowski, Diego F. Calvisi, Simon Weonsang Ro

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background & Aims Liver fibrosis is an increasing health concern worldwide and a major risk factor for hepatocellular carcinoma (HCC). Although the involvement of Hedgehog signaling in hepatic fibrosis has been known for some time, the causative role of activated Hedgehog signaling in liver fibrosis has not been verified in vivo. Methods Using hydrodynamics-based transfection, a transgenic mouse model has been developed that expresses Sonic Hedgehog (SHH), a ligand for Hedgehog signaling, in the liver. Levels of hepatic fibrosis and fibrosis-related gene expression were assessed in the model. Hepatic expression of SHH was induced in a murine model for hepatocellular adenoma (HCA) and tumor development was subsequently investigated. Results The transgenic mice revealed SHH expression in 2-5% of hepatocytes. Secreted SHH activated Hedgehog signaling in numerous cells of various types in the tissues. Hepatic expression of SHH led to fibrosis, activation of hepatic stellate cells, and an upregulation of various fibrogenic genes. Liver injury and hepatocyte apoptosis were observed in SHH mice. Persistent expression of SHH for up to 13 months failed to induce tumors in the liver; however, it promoted liver tumor development induced by other oncogenes. By employing a HCA model induced by P53R172H and KRASG12D, we found that the SHH expression promoted the transition from HCA to HCC. Conclusions SHH expression in the liver induces liver fibrosis with concurrent activation of hepatic stellate cells and fibrogenic genes. It can also enhance hepatocarcinogenesis induced by other oncogenes.

Original languageEnglish
Pages (from-to)618-627
Number of pages10
JournalJournal of Hepatology
Volume64
Issue number3
DOIs
Publication statusPublished - 2016 Mar 1

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Hedgehogs
Liver Cirrhosis
Transgenic Mice
Liver
Liver Cell Adenoma
Fibrosis
Hepatic Stellate Cells
Oncogenes
Hepatocytes
Hepatocellular Carcinoma
Neoplasms
Hydrodynamics
Genes
Transfection
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Chung, Sook In ; Moon, Hyuk ; Ju, Hye Lim ; Cho, Kyung Joo ; Kim, Do Young ; Han, Kwang Hyub ; Eun, Jung Woo ; Nam, Suk Woo ; Ribback, Silvia ; Dombrowski, Frank ; Calvisi, Diego F. ; Ro, Simon Weonsang. / Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model. In: Journal of Hepatology. 2016 ; Vol. 64, No. 3. pp. 618-627.
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title = "Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model",
abstract = "Background & Aims Liver fibrosis is an increasing health concern worldwide and a major risk factor for hepatocellular carcinoma (HCC). Although the involvement of Hedgehog signaling in hepatic fibrosis has been known for some time, the causative role of activated Hedgehog signaling in liver fibrosis has not been verified in vivo. Methods Using hydrodynamics-based transfection, a transgenic mouse model has been developed that expresses Sonic Hedgehog (SHH), a ligand for Hedgehog signaling, in the liver. Levels of hepatic fibrosis and fibrosis-related gene expression were assessed in the model. Hepatic expression of SHH was induced in a murine model for hepatocellular adenoma (HCA) and tumor development was subsequently investigated. Results The transgenic mice revealed SHH expression in 2-5{\%} of hepatocytes. Secreted SHH activated Hedgehog signaling in numerous cells of various types in the tissues. Hepatic expression of SHH led to fibrosis, activation of hepatic stellate cells, and an upregulation of various fibrogenic genes. Liver injury and hepatocyte apoptosis were observed in SHH mice. Persistent expression of SHH for up to 13 months failed to induce tumors in the liver; however, it promoted liver tumor development induced by other oncogenes. By employing a HCA model induced by P53R172H and KRASG12D, we found that the SHH expression promoted the transition from HCA to HCC. Conclusions SHH expression in the liver induces liver fibrosis with concurrent activation of hepatic stellate cells and fibrogenic genes. It can also enhance hepatocarcinogenesis induced by other oncogenes.",
author = "Chung, {Sook In} and Hyuk Moon and Ju, {Hye Lim} and Cho, {Kyung Joo} and Kim, {Do Young} and Han, {Kwang Hyub} and Eun, {Jung Woo} and Nam, {Suk Woo} and Silvia Ribback and Frank Dombrowski and Calvisi, {Diego F.} and Ro, {Simon Weonsang}",
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Chung, SI, Moon, H, Ju, HL, Cho, KJ, Kim, DY, Han, KH, Eun, JW, Nam, SW, Ribback, S, Dombrowski, F, Calvisi, DF & Ro, SW 2016, 'Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model', Journal of Hepatology, vol. 64, no. 3, pp. 618-627. https://doi.org/10.1016/j.jhep.2015.10.007

Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model. / Chung, Sook In; Moon, Hyuk; Ju, Hye Lim; Cho, Kyung Joo; Kim, Do Young; Han, Kwang Hyub; Eun, Jung Woo; Nam, Suk Woo; Ribback, Silvia; Dombrowski, Frank; Calvisi, Diego F.; Ro, Simon Weonsang.

In: Journal of Hepatology, Vol. 64, No. 3, 01.03.2016, p. 618-627.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model

AU - Chung, Sook In

AU - Moon, Hyuk

AU - Ju, Hye Lim

AU - Cho, Kyung Joo

AU - Kim, Do Young

AU - Han, Kwang Hyub

AU - Eun, Jung Woo

AU - Nam, Suk Woo

AU - Ribback, Silvia

AU - Dombrowski, Frank

AU - Calvisi, Diego F.

AU - Ro, Simon Weonsang

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Background & Aims Liver fibrosis is an increasing health concern worldwide and a major risk factor for hepatocellular carcinoma (HCC). Although the involvement of Hedgehog signaling in hepatic fibrosis has been known for some time, the causative role of activated Hedgehog signaling in liver fibrosis has not been verified in vivo. Methods Using hydrodynamics-based transfection, a transgenic mouse model has been developed that expresses Sonic Hedgehog (SHH), a ligand for Hedgehog signaling, in the liver. Levels of hepatic fibrosis and fibrosis-related gene expression were assessed in the model. Hepatic expression of SHH was induced in a murine model for hepatocellular adenoma (HCA) and tumor development was subsequently investigated. Results The transgenic mice revealed SHH expression in 2-5% of hepatocytes. Secreted SHH activated Hedgehog signaling in numerous cells of various types in the tissues. Hepatic expression of SHH led to fibrosis, activation of hepatic stellate cells, and an upregulation of various fibrogenic genes. Liver injury and hepatocyte apoptosis were observed in SHH mice. Persistent expression of SHH for up to 13 months failed to induce tumors in the liver; however, it promoted liver tumor development induced by other oncogenes. By employing a HCA model induced by P53R172H and KRASG12D, we found that the SHH expression promoted the transition from HCA to HCC. Conclusions SHH expression in the liver induces liver fibrosis with concurrent activation of hepatic stellate cells and fibrogenic genes. It can also enhance hepatocarcinogenesis induced by other oncogenes.

AB - Background & Aims Liver fibrosis is an increasing health concern worldwide and a major risk factor for hepatocellular carcinoma (HCC). Although the involvement of Hedgehog signaling in hepatic fibrosis has been known for some time, the causative role of activated Hedgehog signaling in liver fibrosis has not been verified in vivo. Methods Using hydrodynamics-based transfection, a transgenic mouse model has been developed that expresses Sonic Hedgehog (SHH), a ligand for Hedgehog signaling, in the liver. Levels of hepatic fibrosis and fibrosis-related gene expression were assessed in the model. Hepatic expression of SHH was induced in a murine model for hepatocellular adenoma (HCA) and tumor development was subsequently investigated. Results The transgenic mice revealed SHH expression in 2-5% of hepatocytes. Secreted SHH activated Hedgehog signaling in numerous cells of various types in the tissues. Hepatic expression of SHH led to fibrosis, activation of hepatic stellate cells, and an upregulation of various fibrogenic genes. Liver injury and hepatocyte apoptosis were observed in SHH mice. Persistent expression of SHH for up to 13 months failed to induce tumors in the liver; however, it promoted liver tumor development induced by other oncogenes. By employing a HCA model induced by P53R172H and KRASG12D, we found that the SHH expression promoted the transition from HCA to HCC. Conclusions SHH expression in the liver induces liver fibrosis with concurrent activation of hepatic stellate cells and fibrogenic genes. It can also enhance hepatocarcinogenesis induced by other oncogenes.

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