Inherent growth advantage of (pre)malignant hepatocytes associated with nuclear translocation of pro-transforming growth factor alpha.
The pro-peptide of transforming growth factor alpha (proTGFalpha) was recently found in hepatocyte nuclei preparing for DNA replication, which suggests a role of nuclear proTGFalpha for mitogenic signalling. This study investigates whether the nuclear occurrence of the pro-peptide is involved in the altered growth regulation of (pre)malignant hepatocytes. In human hepatocarcinogenesis, the incidence of proTGFalpha-positive and replicating nuclei gradually increased from normal liver, to dysplastic nodules, to hepatocellular carcinoma. ProTGFalpha-positive nuclei almost always were in DNA synthesis. Also, in rat hepatocarcinogenesis, proTGFalpha-positive nuclei occurred in (pre)malignant hepatocytes at significantly higher incidences than in unaltered hepatocytes. For functional studies unaltered (GSTp(-)) and premalignant (GSTp(+)) rat hepatocytes were isolated by collagenase perfusion and cultivated. Again, DNA synthesis occurred almost exclusively in proTGFalpha-positive nuclei. GSTp(+) hepatocytes showed an approximately 3-fold higher frequency of proTGFalpha-positive nuclei and DNA replication than GSTp(-) cells. Treatment of cultures with the mitogen cyproterone acetate (CPA) elevated the incidence of proTGFalpha-positive nuclei and DNA synthesis in parallel. Conversely, transforming growth factor beta1 (TGFbeta1) lowered both. These effects of CPA and TGFbeta1 were significantly more pronounced in GSTp(+) than in GSTp(-) hepatocytes. In conclusion, nuclear translocation of proTGFalpha increases in the course of hepatocarcinogenesis and appears to be involved in the inherent growth advantage of (pre)malignant hepatocytes.
Schausberger
E
E
Institute for Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
Hufnagl
K
K
Parzefall
W
W
Gerner
C
C
Kandioler-Eckersberger
D
D
Wrba
F
F
Klimpfinger
M
M
Schulte-Hermann
R
R
Grasl-Kraupp
B
B
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism*; D017373:Cyproterone Acetate / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004261:DNA Replication; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D000970:Antineoplastic Agents; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017373:Cyproterone Acetate; D004247:DNA; D005982:Glutathione Transferase