Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSPCARNEIRO-LOBO, Tatiana C.LIMA, Marina T.MARIANO-OLIVEIRA, AndreaDUTRA-OLIVEIRA, AngelicaOBA-SHINJO, Sueli M.MARIE, Suely K. N.SOGAYAR, Mari C.MONTEIRO, Robson Q.2014-09-302014-09-302014ONCOLOGY REPORTS, v.31, n.2, p.679-686, 20141021-335Xhttps://observatorio.fm.usp.br/handle/OPI/7548The 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.engrestrictedAccessblood coagulationtissue factorprotease-activated receptorvascular endothelial growth factorinterleukin-8astrocytomaglioblastomahighly procoagulant patterncentral-nervous-systemhuman gliomatumor angiogenesisblood-coagulationcell-linescancerglioblastomaprogressionthrombosisarticleCopyright SPANDIDOS PUBL LTD10.3892/or.2013.2880Oncology1791-2431