Deregulation of the activin/follistatin system in hepatocarcinogenesis.
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.
Grusch
Michael
M
Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria. michael.grusch@meduniwien.ac.at
Drucker
Claudia
C
Peter-Vörösmarty
Barbara
B
Erlach
Natascha
N
Lackner
Andreas
A
Losert
Annemarie
A
Macheiner
Doris
D
Schneider
Wolfgang J
WJ
Hermann
Marcela
M
Groome
Nigel P
NP
Parzefall
Wolfram
W
Berger
Walter
W
Grasl-Kraupp
Bettina
B
Schulte-Hermann
Rolf
R
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
D038681:Follistatin; D038702:Follistatin-Related Proteins; C103008:inhibin beta A subunit; D004247:DNA; D028322:Inhibin-beta Subunits