Effect of hepatocyte growth factor on methionine adenosyltransferase genes and growth is cell density‐dependent in HepG2 cells

Abstract Hepatocyte growth factor (HGF) is a potent hepatocyte mitogen but its effect in liver cancer is conflicting. Methionine adenosyltransferase (MAT) is an essential enzyme encoded by two genes ( MAT1A and MAT2A ), while a third gene ( MAT2β ) encodes for a subunit that regulates the MAT2A ‐encoded isoenzyme. MAT1A is silenced while MAT2A and MAT2β are induced in hepatocellular carcinoma (HCC). The current work examined expression of HGF/c‐met in HCC and whether HGF regulates MAT genes and growth in HepG2 cells. We found the mRNA levels of HGF and c‐ met are markedly increased in HCC. To study the influence of cell density, HepG2 cells were plated under high‐density (HD) or low‐density (LD) and treated with HGF (10 ng/ml). Cell density had a dramatic effect on MAT1A expression, being nearly undetectable at LD to a ninefold induction under HD. Cell density also determined the effect of HGF. At HD, HGF increased the mRNA levels of p21 and p27 , while lowering the levels of MAT genes, cyclin A , and c‐ met . At LD, HGF increased the mRNA levels of cyclin A , MAT2A , MAT2β , and c‐ met . Consistently, HGF inhibits growth under HD but stimulates growth under LD. HGF induced sustained high ERK activation under HD as compared to LD. In summary, HGF induces genes favoring growth and is mitogenic when HepG2 cells are plated under LD; however, the opposite occurs under HD. This involves cell density‐dependent differences in HGF‐induced ERK activation. This may explain why HGF is mitogenic only when there is loss of cell‐cell contact in vivo. J. Cell. Physiol. 210: 766–773, 2007. © 2006 Wiley‐Liss, Inc.