Membrane-anchored heparin-binding epidermal growth factor-like growth factor acts as a tumor survival factor in a hepatoma cell line.

Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), which belongs to the EGF family, is produced as a membrane-anchored form (pro-HB-EGF) and later processed to a soluble form (sHB-EGF). It is known that high expression of pro-HB-EGF occurs in hepatoma tissues, although its biological meaning remains unknown. We established two types of hepatoma cell lines (AH66tc), which stably produce pro-HB-EGF and sHB-EGF, respectively. While sHB-EGF-producing cells (sHB-AH) showed rapid growth, pro-HB-EGF-producing cells (pHB-AH) showed markedly suppressed cell growth as compared with the parental cells. Transforming growth factor beta or serum-starved conditions induced apoptosis of mock and sHB-AH as well as the parental cells, but not of pHB-AH. The resistance to apoptosis upon serum-starved treatment was correlated with an increase in the rate of the G1 phase in the cell cycle due to up-regulation of the cyclin-dependent kinase inhibitor p21. The mechanism underlying this resistance of pHB-AH to apoptosis was thought to be related to the prolonged half-life of the EGF receptor followed by continuous phosphorylation of the tyrosine residues. These observations demonstrate a unique function of pro-HB-EGF that is not observed for the mature form and show that pro-HB-EGF may act as a tumor survival factor in hepatoma cells.