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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 
 JOURNAL OF HEPATOLOGY, Vol.64(3) : 618-627, 2016 
Journal Title
Issue Date
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
Hepatic stellate cell ; Hepatocellular carcinoma ; Hydrodynamic transfection ; Liver fibrosis ; Sonic Hedgehog
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.
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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
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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