PARTICIPATION OF C-MET IN THE PROGRESSION OF HUMAN GASTRIC CANCERS - ANTI-C-MET OLIGONUCLEOTIDES INHIBIT PROLIFERATION OR INVASIVENESS OF GASTRIC-CANCER CELLS

The protooncogene c-met encodes the receptor for hepatocyte growth fac tor (HGF), a potent epithelial cell mitogen with scattering activity. In this study, we first screened c-met expression in human gastric car cinomas. Twenty-eight of 154 tumors (18%) were positively stained for MET proteins. The incidence of c-met expression increased with higher histopathological stages of the cancer. Second, we examined functional roles of c mel in cultured gastric carcinoma cells, using an antisens e strategy. Cell lines used were MKN-45, TMK-1, and MKN-28. Among them , MKN-45 cells exhibited the highest c-met expression and grew in resp onse to HGF, whereas TMK-1 cells had an ability to invade in an HGF-de pendent manner. When antisense oligodeoxyribonucleotides complementary to c-met messenger RNA (mRNA) were administered to the culture medium , the content of MET protein was selectively decreased in either MKN-4 5 or TMK-1 cells, indicating that the antisense molecules did inhibit the translation of c-met mRNA. The growth of MKN-45 cells was markedly inhibited by the antisense c-met oligonucleotides in a dose-dependent manner, but not by sense or scrambled controls. The antisense oligonu cleotides also effectively inhibited the migration of TMK-1 cells. The se result indicate that c-met gene products may be causally related to the proliferation or invasion of gastric cancer cells, and that antis ense c-met DNA has the potential to help circumvent the progression of gastric cancers.