GC factor represses transcription of several growth factor/receptor genes and causes growth inhibition of human gastric carcinoma cell lines.
The GC factor (GCF) binds to specific GC-rich sequences in the epidermal growth factor receptor (EGFR) gene promoter and represses its transcription. In this study, by the use of GCF transfection, we examined whether GCF represses the gene expression of several other growth factors and receptors and causes growth inhibition of cancer cells. The transfection of GCF expression vector into gastric carcinoma cell lines (TMK-1 and MKN-28) decreased the mRNA levels of transforming growth factor (TGF) alpha, insulin-like growth factor II, and c-met. The reduction of TGF-alpha expression was confirmed at the protein level by enzyme-linked immunosorbent assay. Transfection of GCF expression vector interfered with the mRNA accumulation for EGFR and TGF-beta induced by epidermal growth factor in gastric carcinoma cell lines. The carcinoma cells transfected with GCF expression vector did not grow in a serum-free medium, whereas the control cells did grow under serum-free conditions. When the growth of the gastric carcinoma cell lines was studied in nude mice, GCF-transfected carcinoma cells showed a significantly slower growth compared to the control tumor. Transient cotransfection analysis with NIH3T3 cells revealed that GCF repressed the promoter activity of TGF-alpha in addition to EGFR. These findings indicate that GCF negatively regulates gene expression of not only the EGFR but also several other growth factor and receptor genes and can inhibit the growth of gastric carcinomas in immunodeficient mice.
Kitadai
Y
Y
First Department of Pathology, Hiroshima University, School of Medicine, Japan.
Yamazaki
H
H
Yasui
W
W
Kyo
E
E
Yokozaki
H
H
Kajiyama
G
G
Johnson
A C
AC
Pastan
I
I
Tahara
E
E
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics*; D005822:Genetic Vectors; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014407:Tumor Cells, Cultured
C072278:GCFC2 protein, human; D006133:Growth Substances; D012097:Repressor Proteins; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors