Expression of tissue factor signaling pathway elements correlates with the production of vascular endothelial growth factor and interleukin-8 in human astrocytoma patients

Tatiana Lobo, Marina T. Lima, Andréa Mariano-Oliveira, Angélica Dutra-Oliveira, Sueli M. Oba-Shinjo, Suely K.N. Marie, Mari C. Sogayar, Robson Q. Monteiro

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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 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.

Original languageEnglish
Pages (from-to)679-686
Number of pages8
JournalOncology Reports
Volume31
Issue number2
DOIs
Publication statusPublished - 1 Feb 2014
Externally publishedYes

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Keywords

  • Astrocytoma
  • Blood coagulation
  • Glioblastoma
  • Interleukin-8
  • Protease-activated receptor
  • Tissue factor
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lobo, T., Lima, M. T., Mariano-Oliveira, A., Dutra-Oliveira, A., Oba-Shinjo, S. M., Marie, S. K. N., Sogayar, M. C., & Monteiro, R. Q. (2014). Expression of tissue factor signaling pathway elements correlates with the production of vascular endothelial growth factor and interleukin-8 in human astrocytoma patients. Oncology Reports, 31(2), 679-686. https://doi.org/10.3892/or.2013.2880