Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene.
Hypoxia unleashes the invasive and metastatic potential of tumor cells by largely unknown mechanisms. The Met tyrosine kinase, a high affinity receptor for hepatocyte growth factor (HGF), plays a crucial role in controlling invasive growth and is often overexpressed in cancer. Here we show that: (1) hypoxia activates transcription of the met protooncogene, resulting in higher levels of Met; (2) hypoxic areas of tumors overexpress Met; (3) hypoxia amplifies HGF signaling; (4) hypoxia synergizes with HGF in inducing invasion; (5) the proinvasive effects of hypoxia are mimicked by Met overexpression; and (6) inhibition of Met expression prevents hypoxia-induced invasive growth. These data show that hypoxia promotes tumor invasion by sensitizing cells to HGF stimulation, providing a molecular basis to explain Met overexpression in cancer.
Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy.
Selma
S
Pennacchietti
Paolo
P
Michieli
Maria
M
Galluzzo
Massimiliano
M
Mazzone
Silvia
S
Giordano
Paolo M
PM
Comoglio
D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D018014:Gene Transfer Techniques; D017228:Hepatocyte Growth Factor / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met