title: Deregulation of the activin/follistatin system in hepatocarcinogenesis.
abstract: OBJECTIVE
  Activins A and E negatively regulate hepatic cell number by inhibiting cell replication and inducing apoptosis. Follistatin and follistatin-like 3 bind activins and antagonise their biological activities. Aim of our study was to investigate, whether activins and follistatins may play a role in hepatocarcinogenesis.
  
  
  METHODS
  Expression levels of follistatin, follistatin-like 3, and activin subunits beta(A) as well as beta(E) were investigated in chemically induced rat and human liver tumours by real-time PCR and immunohistochemistry. In addition, the effects of follistatin and activin A on DNA synthesis of normal as well as preneoplastic hepatocytes and hepatoma cells were analysed.
  
  
  RESULTS
  Follistatin was overexpressed while both activin subunits were downregulated in the majority of rat and human liver tumours. Follistatin-like 3 expression was low in normal but enhanced in malignant rat liver. In human normal liver, in contrast, it was abundantly expressed but downregulated in liver cancer. Administration of follistatin to normal and preneoplastic hepatocytes stimulated DNA synthesis preferentially in preneoplastic rat hepatocytes, whereas activin A repressed it.
  
  
  CONCLUSIONS
  The balanced expression of follistatins and activins becomes deregulated during hepatocarcinogenesis. The sensitivity of preneoplastic hepatocytes to activin signals suggests the activin/follistatin system as promising target for therapeutic intervention.
authors.affiliation: Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria. michael.grusch@meduniwien.ac.at
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.forename: Claudia
authors.initials: C
authors.lastname: Drucker
authors.forename: Barbara
authors.initials: B
authors.lastname: Peter-Vörösmarty
authors.forename: Natascha
authors.initials: N
authors.lastname: Erlach
authors.forename: Andreas
authors.initials: A
authors.lastname: Lackner
authors.forename: Annemarie
authors.initials: A
authors.lastname: Losert
authors.forename: Doris
authors.initials: D
authors.lastname: Macheiner
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Schneider
authors.forename: Marcela
authors.initials: M
authors.lastname: Hermann
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Groome
authors.forename: Wolfram
authors.initials: W
authors.lastname: Parzefall
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
authors.forename: Rolf
authors.initials: R
authors.lastname: Schulte-Hermann
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000503:physiopathology; D004247:DNA / Q000096:biosynthesis; D015536:Down-Regulation / Q000502:physiology; D038681:Follistatin / Q000378:metabolism*; D038702:Follistatin-Related Proteins / Q000378:metabolism*; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D028322:Inhibin-beta Subunits / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D023421:Models, Animal; D016133:Polymerase Chain Reaction / Q000379:methods; D051381:Rats; D015854:Up-Regulation / Q000502:physiology
chemical_list: D038681:Follistatin; D038702:Follistatin-Related Proteins; C103008:inhibin beta A subunit; D004247:DNA; D028322:Inhibin-beta Subunits