Activation of cancer cell migration and invasion by ectopic synthesis of coagulation factor VII.
Blood coagulation factor VII (fVII) is physiologically synthesized in the liver and released into the blood. Binding of fVII to tissue factor (TF) at sites of vascular injury triggers coagulation and hemostasis. TF/fVIIa complex formation on the surface of cancer cells plays important roles in cancer biology. Although fVII is synthesized by hepatocellular carcinoma, it remained unclear how TF/fVIIa complex formation and promigratory signaling can occur for most other cancers in extravascular locations. Here, we show by reverse transcription-PCR analysis that nonhepatic cancer cell lines constitutively express fVII mRNA and that endogenously synthesized fVIIa triggers coagulation activation on these cells. fVIIa expression in cancer cells is inducible under hypoxic conditions and hypoxia-inducible factor-2 alpha bound the promoter region of the FVII gene in chromatin immunoprecipitation analyses. Constitutive fVII expression in an ovarian cancer cell line enhanced both migration and invasion. Enhanced motility was blocked by anti-TF antibodies, factor Xa inhibition, and anti-protease-activated receptor-1 antibody treatment, confirming that TF/fVIIa stimulated migration by triggering cell signaling. This study shows that ectopic synthesis of fVII by cancer cells is sufficient to support proinvasive factor Xa-mediated protease-activated receptor-1 signaling and that this pathway is inducible under hypoxia.
Koizume
Shiro
S
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Asahi-ku, Yokohama 241-0815, Japan.
Jin
Ming-Shou
MS
Miyagi
Etsuko
E
Hirahara
Fumiki
F
Nakamura
Yoshiyasu
Y
Piao
Jin-Hua
JH
Asai
Akio
A
Yoshida
Akira
A
Tsuchiya
Eiju
E
Ruf
Wolfram
W
Miyagi
Yohei
Y
D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D001777:Blood Coagulation; D019735:Carbon-Carbon Ligases / Q000096:biosynthesis / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D005167:Factor VII / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015951:Factor Xa / Q000502:physiology; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009369:Neoplasms / Q000097:blood / Q000473:pathology; D010051:Ovarian Neoplasms / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D044463:Receptor, PAR-1 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013925:Thromboplastin / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D019735:Carbon-Carbon Ligases; D005167:Factor VII; D015951:Factor Xa; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D044463:Receptor, PAR-1; D011993:Recombinant Fusion Proteins; D013925:Thromboplastin; D000099162:Endothelial PAS Domain-Containing Protein 1; C020660:glutamyl carboxylase