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

Authors
 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 
Citation
 Journal of Hepatology, Vol.64(3) : 618-627, 2016 
Journal Title
 Journal of Hepatology 
ISSN
 0168-8278 
Issue Date
2016
MeSH
Animals ; Apoptosis ; Epithelial-Mesenchymal Transition ; Hedgehog Proteins/analysis ; Hedgehog Proteins/physiology* ; Liver Cirrhosis, Experimental/etiology* ; Liver Cirrhosis, Experimental/pathology ; Liver Neoplasms, Experimental/etiology* ; Liver Neoplasms, Experimental/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Signal Transduction ; Transforming Growth Factor beta1/physiology
Keywords
Hepatic stellate cell ; Hepatocellular carcinoma ; Hydrodynamic transfection ; Liver fibrosis ; Sonic Hedgehog
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 13months failed to induce tumors in the liver; however, it promoted liver tumor development induced by other oncogenes. By employing a HCA model induced by P53(R172H) and KRAS(G12D), 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.
Full Text
http://www.sciencedirect.com/science/article/pii/S0168827815006789
DOI
10.1016/j.jhep.2015.10.007
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Liver Cirrhosis Clinical Research Center (간경변증임상연구센터) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
김도영(Kim, Do Young)
노원상(Ro, Simon Weonsang) ORCID logo https://orcid.org/0000-0003-2187-3698
정숙인(Chung, Sook In) ORCID logo https://orcid.org/0000-0002-7915-9203
한광협(Han, Kwang-Hyub) ORCID logo https://orcid.org/0000-0003-3960-6539
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/146642
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