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 factor (HGF), a potent epithelial cell mitogen with scattering activity. In this study, we first screened c-met expression in human gastric carcinomas. 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-met in cultured gastric carcinoma cells, using an antisense 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 response to HGF, whereas TMK-1 cells had an ability to invade in an HGF-dependent 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-45 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 oligonucleotides also effectively inhibited the migration of TMK-1 cells. These results indicate that c-met gene products may be causally related to the proliferation or invasion of gastric cancer cells, and that antisense c-met DNA has the potential to help circumvent the progression of gastric cancers.
Kaji
M
M
Department of Biochemistry, Kanazawa University School of Medicine, Japan.
Yonemura
Y
Y
Harada
S
S
Liu
X
X
Terada
I
I
Yamamoto
H
H
D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D016373:DNA, Antisense / Q000494:pharmacology*; D004587:Electrophoresis, Agar Gel; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D016373:DNA, Antisense; D009838:Oligodeoxyribonucleotides; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases