Hirohito Tsubouchi

Effects of Simultaneous Treatment with Growth Factors on DNA Synthesis, MAPK Activity, and G1 Cyclins in Rat Hepatocytes

Several growth factors act in concert during liver regeneration in vivo. Once hepatic injury occurs, liver regeneration is stimulated by hepatocyte growth factor (HGF), transforming growth factor (TGF)-α, and heparin-binding epidermal growth factor-like growth factor (HB-EGF), whereas TGF-s1 terminates liver regeneration. Treatment with a combination of HGF and epidermal growth factor (EGF), in comparison with that with either HGF or EGF, was found to additively stimulate mitogen-activated protein kinase (MAPK) activity and cyclin D1 expression additively, resulting in additive stimulation of DNA synthesis. In contrast, TGF-s1 treatment completely inhibited DNA synthesis through a marked decrease in cyclin E expression, although growth factor-induced MAPK activity and cyclin D1 expression were not affected by TGF-s1. These results indicate that potent mitogens such as HGF, TGF-α, and HB-EGF can cooperatively induce the additive enhancement ofliver regeneration through an increase in Ras/MAPK activity followed by cyclin D1 expression, and that TGF-s1 suppresses the growth factor-induced signals between cyclin D1 and cyclin E, resulting in inhibition of DNA synthesis.

HGF-Related Proteins in Hepatocellular Carcinoma (HCC)

Hepatocyte growth factor (HGF) is secreted as a single-chain form (proHGF) from mesenchymal cells of the liver, and proHGF is converted to heterodimeric HGF (mature HGF) by serine proteases, including hepatocyte growth factor activator (HGFA), in response to tissue injury. Hepatocyte growth factor activator inhibitor type 1 (HAI-1) and type 2 (HAI-2) have recently been purified from the conditioned medium of a gastric cancer cell line, and their cDNAs have been successfully cloned. The hepatocytes of patients with chronic liver diseases including hepatocellular carcinoma (HCC) were stained with anti-HGFA. HAI-1 was detected in tumorous tissues of HCC, but not in liver tissues of patients with chronic liver diseases. Tumorous tissues in HCC were positive for HAI-1 mRNA. HAI-1 may play an important role in the development or invasiveness of HCC through the mechanism regulating HGF activation.