RRC ID 42779
Author Koizume S, Jin MS, Miyagi E, Hirahara F, Nakamura Y, Piao JH, Asai A, Yoshida A, Tsuchiya E, Ruf W, Miyagi Y.
Title Activation of cancer cell migration and invasion by ectopic synthesis of coagulation factor VII.
Journal Cancer Res
Abstract 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.
Volume 66(19)
Pages 9453-60
Published 2006-10-1
DOI 10.1158/0008-5472.CAN-06-1803
PII 66/19/9453
PMID 17018600
MeSH Basic Helix-Loop-Helix Transcription Factors / physiology Blood Coagulation Carbon-Carbon Ligases / biosynthesis Carbon-Carbon Ligases / genetics Cell Hypoxia / genetics Cell Line, Tumor / metabolism Cell Movement / physiology Factor VII / biosynthesis* Factor VII / genetics Factor VII / physiology Factor Xa / physiology Female Humans Neoplasm Invasiveness / physiopathology* Neoplasm Proteins / biosynthesis* Neoplasm Proteins / genetics Neoplasm Proteins / physiology Neoplasms / blood Neoplasms / pathology Ovarian Neoplasms / pathology RNA, Messenger / biosynthesis RNA, Messenger / genetics RNA, Neoplasm / biosynthesis RNA, Neoplasm / genetics Receptor, PAR-1 / physiology Recombinant Fusion Proteins / physiology Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Thromboplastin / biosynthesis Thromboplastin / genetics Transfection
IF 9.727
Times Cited 104
Human and Animal Cells OCUB-M(RCB0881) MDA-MB-453(RCB1192)