Sook In Chung1, Hyuk Moon1, Hye-Lim Ju2, Kyung Joo Cho1, Do Young Kim3, Kwang-Hyub Han3, Jung Woo Eun4, Suk Woo Nam4, Silvia Ribback5, Frank Dombrowski5, Diego F Calvisi5, Simon Weonsang Ro6. 1. Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea. 2. Liver Cirrhosis Clinical Research Center, Yonsei University College of Medicine, Seoul, South Korea. 3. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea. 4. Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea. 5. Institute of Pathology, University Medicine Greifswald, Greifswald, Germany. 6. 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.
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.
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 SHHmice. 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.
Authors: Kyungjoo Cho; Nam Hee Kim; Sang Hyun Seo; Sang Hyun Song; Chul Hee Jeong; Hyun Sil Kim; Jo Eun Um; Minhee Ku; Jaemoon Yang; Jun Yong Park; Sang Hoon Ahn; Jong In Yook; Seung Up Kim Journal: Am J Cancer Res Date: 2022-02-15 Impact factor: 6.166
Authors: M Granato; C Zompetta; E Vescarelli; C Rizzello; A Cardi; S Valia; G Antonelli; C Marchese; M R Torrisi; A Faggioni; M Cirone Journal: Sci Rep Date: 2016-08-01 Impact factor: 4.379