title: Expression of tissue factor signaling pathway elements correlates with the production of vascular endothelial growth factor and interleukin-8 in human astrocytoma patients.
abstract: The expression levels of tissue factor (TF), the clotting initiator protein, have been correlated with angiogenesis and the histological grade of malignancy in glioma patients. The pro-tumor function of TF is linked to a family of G protein-coupled receptors known as protease-activated receptors (PARs), which may be activated by blood coagulation proteases. Activation of PARs elicits a number of responses, including the expression of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). In the present study, we analyzed the expression of TF signaling pathway elements (TF, PAR1 and PAR2) and evaluated their correlation with the expression of downstream products (VEGF and IL-8) in human astrocytoma patients. Quantitative PCR (qPCR) showed a significant increase in TF expression in grade IV (glioblastoma) tumors, which was inversely correlated with the expression of the tumor-suppressor PTEN. Immunohistochemistry and qPCR analyses demonstrated a highly significant elevation in the expression of PAR1, but not PAR2, in tumor samples from high-grade astrocytoma patients. The elevated VEGF expression levels detected in the high-grade astrocytoma samples were positively correlated with TF, PAR1 and PAR2 expression. In addition, IL-8 was significantly increased in glioblastoma patients and positively correlated with TF and PAR2 expression. Further in vitro assays employing the human glioma cell lines U87-MG and HOG demonstrated that a synthetic peptide PAR2 agonist stimulated VEGF and IL-8 production. Our findings suggest a role for TF signaling pathway elements in astrocytoma progression, particularly in glioblastoma. Therefore, TF/PAR signaling elements may be suitable targets for the development of new therapies for the treatment of aggressive glioma.
authors.affiliation: Institute of Medical Biochemistry, Federal University of Rio de Janeiro, RJ, Brazil.
authors.forename: Tatiana C
authors.initials: TC
authors.lastname: Carneiro-Lobo
authors.affiliation: Biochemistry Department, Chemistry Institute, Cell and Molecular Therapy Center (NUCEL), University of São Paulo, SP, Brazil.
authors.forename: Marina T
authors.initials: MT
authors.lastname: Lima
authors.affiliation: Institute of Medical Biochemistry, Federal University of Rio de Janeiro, RJ, Brazil.
authors.forename: Andréa
authors.initials: A
authors.lastname: Mariano-Oliveira
authors.affiliation: Institute of Medical Biochemistry, Federal University of Rio de Janeiro, RJ, Brazil.
authors.forename: Angélica
authors.initials: A
authors.lastname: Dutra-Oliveira
authors.affiliation: Department of Neurology, School of Medicine, University of São Paulo, SP, Brazil.
authors.forename: Sueli M
authors.initials: SM
authors.lastname: Oba-Shinjo
authors.affiliation: Department of Neurology, School of Medicine, University of São Paulo, SP, Brazil.
authors.forename: Suely K N
authors.initials: SK
authors.lastname: Marie
authors.affiliation: Biochemistry Department, Chemistry Institute, Cell and Molecular Therapy Center (NUCEL), University of São Paulo, SP, Brazil.
authors.forename: Mari C
authors.initials: MC
authors.lastname: Sogayar
authors.affiliation: Institute of Medical Biochemistry, Federal University of Rio de Janeiro, RJ, Brazil.
authors.forename: Robson Q
authors.initials: RQ
authors.lastname: Monteiro
mesh_terms: D001932:Brain Neoplasms / Q000473:pathology; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000378:metabolism; D009389:Neovascularization, Pathologic; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D044463:Receptor, PAR-1 / Q000096:biosynthesis*; D044464:Receptor, PAR-2 / Q000819:agonists / Q000096:biosynthesis*; D015398:Signal Transduction; D013925:Thromboplastin / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors / Q000096:biosynthesis*
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D042442:Vascular Endothelial Growth Factors; D013925:Thromboplastin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human