title: R-spondin1 arguments hepatic fibrogenesis in vivo and in vitro.
abstract: BACKGROUND
  The development of liver fibrosis is the key stage toward a number of mortal complications of liver diseases, including cirrhosis and hepatocellular carcinoma. Canonical Wnt pathway is crucial in diverse biological processes and mediates the progression and regression of liver fibrosis. As a potent Wnt pathway agonist, roof plate-specific spondin-1 (R-spondin1) protein's role in the hepatic fibrosis has not been well elucidated. The purpose of this study was to investigate whether R-spondin1 contributed to hepatic stellate cells (HSC) activation, the key event in liver fibrogenesis.
  
  
  METHODS
  Tissue microarrays of human fibrotic liver samples, hepatocellular carcinoma samples, and normal hepatic tissue samples were constructed and immunostained for R-spondin1. Protein expression and transcriptional level of freshly isolated mice HSC were analyzed by Western blot assay and real-time polymerase chain reaction, respectively. Exogenous stimulation with recombinant R-spondin1 and Dickkopf-1 was performed to investigate the functionality. Nuclear β-catenin level and T-cell specific transcription factor activity were analyzed, and HSC proliferation was tested by Methyl-Thiazol-Tetrazolium bromide assay.
  
  
  RESULTS
  Overexpression of R-spondin1 was observed in both fibrotic liver tissues and culture-activated HSC. Coculture with recombinant R-spondin1 induced a dose-dependent increase in both the transcription factor activity and the protein level of α-smooth muscle actin, collagen I, and nuclear β-catenin. Additionally, Dickkopf-1 repressed R-spondin1's effect on HSC.
  
  
  CONCLUSIONS
  These findings suggested that R-spondin1 might argument liver fibrogenesis by enhancing the canonical Wnt pathway.
authors.affiliation: Centre for Gastroenterology and Hepatology, The First Affiliated Hospital of Jiaxing College, Jiaxing, Zhejiang Province, PR China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Xinguang
authors.affiliation: Intensive Care Unit, The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang Province, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huixing
authors.affiliation: Deparment of Pathology, The First Affiliated Hospital of Jiaxing College, Jiaxing, Zhejiang Province, PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Xiaowei
authors.affiliation: Centre for Gastroenterology and Hepatology, The First Affiliated Hospital of Jiaxing College, Jiaxing, Zhejiang Province, PR China.
authors.forename: Wu
authors.initials: W
authors.lastname: Xiaojun
authors.affiliation: Centre for Gastroenterology and Hepatology, The First Affiliated Hospital of Jiaxing College, Jiaxing, Zhejiang Province, PR China. Electronic address: yu.lh70s@gmail.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Linghua
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D019699:Thrombospondins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000098907:R-Spondins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D019699:Thrombospondins; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C501126:DKK1 protein, human; C503243:RSPO1 protein, human; D000098907:R-Spondins; C518903:RSPO1 protein, mouse
keywords: HSC; Liver fibrosis; Nuclear β-catenin; R-spondin1; TCF; Wnt pathway