title: Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sook In
authors.initials: SI
authors.lastname: Chung
authors.affiliation: Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Hyuk
authors.initials: H
authors.lastname: Moon
authors.affiliation: Liver Cirrhosis Clinical Research Center, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Hye-Lim
authors.initials: HL
authors.lastname: Ju
authors.affiliation: Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Kyung Joo
authors.initials: KJ
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Kwang-Hyub
authors.initials: KH
authors.lastname: Han
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Jung Woo
authors.initials: JW
authors.lastname: Eun
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
authors.affiliation: Institute of Pathology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ribback
authors.affiliation: Institute of Pathology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.affiliation: Institute of Pathology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.affiliation: Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea; Liver Cirrhosis Clinical Research Center, Yonsei University College of Medicine, Seoul, South Korea. Electronic address: simonr@yuhs.ac.
authors.forename: Simon Weonsang
authors.initials: SW
authors.lastname: Ro
mesh_terms: D000818:Animals; D017209:Apoptosis; D058750:Epithelial-Mesenchymal Transition; D053823:Hedgehog Proteins / Q000032:analysis / Q000502:physiology*; D008106:Liver Cirrhosis, Experimental / Q000209:etiology* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000502:physiology
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D053773:Transforming Growth Factor beta1
keywords: Hepatic stellate cell; Hepatocellular carcinoma; Hydrodynamic transfection; Liver fibrosis; Sonic Hedgehog