Transcriptional program induced by factor VIIa‐tissue factor, PAR1 and PAR2 in MDA‐MB‐231 cells

Abstract

Summary. Background: Factor VIIa (FVIIa) binding to tissue factor (TF) induces cell signaling via the protease activity of FVIIa and protease-activated receptor 2 (PAR2). Objective: We examined how the gene-expression profile induced by FVIIa corresponds to the profiles induced by protease-activated receptor 1 (PAR1) or PAR2 agonists using MDA-MB-231 breast carcinoma cells that constitutively express TF, PAR1 and PAR2. Results and conclusions: Out of 8500 genes, FVIIa stimulation induced differential regulation of 39 genes most of which were not previously recognized as FVIIa regulated. All genes regulated by FVIIa were similarly regulated by a PAR2 agonist peptide confirming FVIIa signaling via PAR2. An appreciable fraction of the PAR2-regulated genes was also regulated by a PAR1 agonist peptide suggesting extensive redundancy between FVIIa/PAR2 signaling and thrombin/ PAR1 signaling. The FVIIa regulated genes encode cytokines, chemokines and growth factors, and the gene repertoire induced by FVIIa in MDA-MB-231 cells is consistent with a role for TF-FVIIa signaling in regulation of a wound healing type of response. Interestingly, a number of genes regulated exclusively by FVIIa/PAR2-mediated cell signaling in MDA-MB-231 cells were regulated by thrombin and a PAR1 agonist, but not by FVIIa, in the TF-expressing glioblastoma U373 cell line.

Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

“…Evidence for this relationship has been strengthened in vivo in the mouse wound-healing model reported here. In addition, FVIIa-mediated inflammatory signaling via PAR-2 has been proposed to occur in a breast carcinoma cell line (48,49). In the current study, the cellular mechanism of FVIIa-mediated inflammatory signaling in keratinocytes was investigated using keratinocytes isolated from mice with gene deficiencies that have been implicated in FVIIa-induced cellular signaling.…”

The Endothelial Protein C Receptor Supports Tissue Factor Ternary Coagulation Initiation Complex Signaling through Protease-activated Receptors

“…signaling has been demonstrated in both murine and human cells (23,48,49), little is known about signaling of the ternary complex in primary cells isolated from mice. Because TF is not typically expressed by endothelial cells in the absence of proangiogenic or inflammatory stimuli, we focused on murine SMCs that constitutively express EPCR and TF (50,51).…”

Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

“…This includes tissue factor (TF), thrombin receptor (PAR-1) along with other protease activated receptors (PARs), urokinase receptor (uPAR), thrombomodulin (TM), endothelial protein C receptor (EPCR), receptors for protein S (TAM group), integrins, and growth factor receptors that can be transactivated by the coagulation system [10][11][12][13][14]. These molecular interactions activate intracellular signalling pathways and change the expression of several genes [15,16], including mediators of angiogenesis, inflammation and other processes relevant to cancer [10,[17][18][19]. In this manner, the various components of the haemostatic circuitry, such as factor VIIa, Xa, thrombin, fibrin, proteins C and S and others, in conjunction…”