title: Hepatic IGF-1R overexpression combined with the activation of GSK-3β and FOXO3a in the development of liver cirrhosis.
abstract: OBJECTIVE
  Liver cirrhosis is the common pathological histology manifest among a number of chronic liver diseases and liver cancer. Circulating levels of insulin growth factor-1 (IGF-1) have been recently linked to liver cirrhosis and the development of liver cancer. Herein, we hypothesized that IGF-1R overexpression combining the activation of GSK-3β and FOXO3a were involved in the development of human and murine chronic liver cirrhosis.
  
  
  METHODS
  Liver samples of patients were screened from the Tissue Bank of the China-Japan Union Hospital of Jilin University. Mice liver fibrosis model was performed using intraperitoneal injection of carbon tetrachloride (CCl4) for 12weeks. Serum IGF-1 levels were detected by enzyme-linked immunosorbent assays (ELISA). Microscopical examination of liver parenchyma was performed using conventional H&E and Masson's staining. Moreover, we investigated the IGF-1 receptor (IGF-1R) signaling pathway at different period after CCl4 administration.
  
  
  RESULTS
  Serum IGF-1 levels were significantly decreased in patients with liver cirrhosis, which is concomitant with the declined circulating levels of IGF-1 in 8 to 12weeks CCl4-treated mice. Furthermore, the expression of IGF-1R was significantly higher at 12w compared with control group. In addition, activation of the GSK-3β and FOXO3a were activated during the process of murine chronic liver injury.
  
  
  CONCLUSIONS
  The present study demonstrates that decreased circulating IGF-1 levels are involved in human and murine chronic liver disease. Interestingly, overexpression of the IGF-1R, and activation of GSK3β and FOXO3a might be the molecular mechanisms underlying the development of liver cirrhosis.
authors.affiliation: Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Hospital of Stomatology, Jilin University, Changchun, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Pathology, China-Japan Union Hospital of Jilin University, People's Republic of China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, People's Republic of China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China. Electronic address: zxw515@sohu.com.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China. Electronic address: edmond19811981@163.com.
authors.forename: Changyong
authors.initials: C
authors.lastname: E
mesh_terms: D000368:Aged; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D016022:Case-Control Studies; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008875:Middle Aged; D017526:Receptor, IGF Type 1 / Q000235:genetics*
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D007334:Insulin-Like Growth Factor I; D002251:Carbon Tetrachloride; D017526:Receptor, IGF Type 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: AKT; FoxO3a; GSK-3β; IGF-1; IGF-1R; Liver cirrhosis