title: Stem cell and hepatocyte proliferation in hepatitis C cirrhosis and hepatocellular carcinoma: transplant implications.
abstract: BACKGROUND. The liver possesses two distinct mechanisms for healing. Wound healing via hepatic stem cells recapitulates early development (hepatoblast proliferation), while liver regeneration resembles late embryonic growth (hepatocyte proliferation). Loss of control over both of these processes have been proposed as mechanisms that may contribute to poor outcomes in HCC. MATERIAL AND METHODS. We used microarray gene expression profiles to examine the involvement of hepatic stem cell and hepatocyte proliferation markers and regulators in HCV-induced cirrhosis and HCC. We compared 30 cirrhosis and 49 HCC samples to 12 disease-free control livers. RESULTS. Cirrhosis and HCC expressed markers of stem cell. Inhibitors of hepatocyte proliferation (HP) were highly expressed in cirrhosis. Loss of these HP inhibitors in HCC patients was associated poor prognosis (94 vs. 38% 2-year recurrence- free survival, p = 0.0003). Principal Components Analysis discriminated cirrhotic and HCC tissues, and HCC patients with poor (< 2 year) vs. good (> 2 year) recurrence-free survival. Loss of CDH1 expression correlated with up-regulation of hepatocyte proliferation promoters MET and YAP1. CDH1, MET, and YAP1 were independent predictors of recurrence-free survival by Cox regression when corrected for tumor stage (p < 0.0001). CONCLUSION. HCV-cirrhosis is characterized by proliferation of liver stem cells and inhibition of hepatocyte proliferation. HCC tumors in which this pattern persists have superior outcomes to those which acquire a hepatocyte proliferation signature. Genes in this signature should be studied further for potential as tissue or serum biomarkers for patient risk stratification. CDH1 and MET are candidates for personalized therapies with targeted pharmaceutical agents.
authors.affiliation: Transplant Program Administration, Virginia Commonwealth University Health System, 1200 E. Broad St., Richmond, VA 23298, USA.
authors.forename: Martha K
authors.initials: MK
authors.lastname: Behnke
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, 800 E Leigh St., Richmond, VA 23298, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Reimers
authors.affiliation: Department of Surgery, Virginia Commonwealth University, 1200 E. Broad St., Richmond, VA 23298, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fisher
mesh_terms: D000071916:AC133 Antigen; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D018572:Disease-Free Survival; D000071858:Epithelial Cell Adhesion Molecule; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D016031:Liver Transplantation; D046228:Microarray Analysis; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D016016:Proportional Hazards Models; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D000071916:AC133 Antigen; D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C513384:CDH1 protein, human; D015820:Cadherins; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D006023:Glycoproteins; D010455:Peptides; D010750:Phosphoproteins; C499380:TACSTD2 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met