Inherent growth advantage of (pre)malignant hepatocytes associated with nuclear translocation of pro-transforming growth factor α

The pro-peptide of transforming growth factor α (proTGFα) was recently found in hepatocyte nuclei preparing for DNA replication, which suggests a role of nuclear proTGFα 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 proTGFα-positive and replicating nuclei gradually increased from normal liver, to dysplastic nodules, to hepatocellular carcinoma. ProTGFα-positive nuclei almost always were in DNA synthesis. Also, in rat hepatocarcinogenesis, proTGFα-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 proTGFα-positive nuclei. GSTp(+) hepatocytes showed an ∼3-fold higher frequency of proTGFα-positive nuclei and DNA replication than GSTp(−) cells. Treatment of cultures with the mitogen cyproterone acetate (CPA) elevated the incidence of proTGFα-positive nuclei and DNA synthesis in parallel. Conversely, transforming growth factor β1 (TGFβ1) lowered both. These effects of CPA and TGFβ1 were significantly more pronounced in GSTp(+) than in GSTp(−) hepatocytes. In conclusion, nuclear translocation of proTGFα increases in the course of hepatocarcinogenesis and appears to be involved in the inherent growth advantage of (pre)malignant hepatocytes.