Tissue factor-factor VIIa–specific up-regulation of IL-8 expression in MDA-MB-231 cells is mediated by PAR-2 and results in increased cell migration

Abstract

Tissue factor (TF), the cellular receptor for factor VIIa (FVIIa), besides initiating blood coagulation, is believed to play an important role in tissue repair, inflammation, angiogenesis, and tumor metastasis. Like TF, the chemokine interleukin-8 (IL-8) is shown to play a critical role in these processes. To elucidate the potential mechanisms by which TF contributes to tumor invasion and metastasis, we IntroductionCells that express tissue factor (TF) are usually not exposed to the blood. However, in normal response to vessel injury, TF exposure is an initial event of a strictly regulated process resulting in fibrin deposition, inflammation, angiogenesis, and tissue repair. Carcinomas exploit a normal physiologic response in a way that allows tumor growth and dissemination. It has long been presumed that tumors may take advantage of the hemostatic system. A relationship between increased clotting and malignancy was recognized more than a century ago. 1 Numerous clinical observations suggest that the hemostatic system is frequently activated in cancer patients. 2-5 Many tumor types have been shown to express TF. 6,7 Further, the level of TF expression in various tumor types has been shown to correlate with their metastatic potential. [8][9][10] Studies carried out with mouse tumor metastasis models establish that TF plays a critical role in tumor metastasis. 11,12 TF is the cellular receptor for coagulation factor VIIa (FVIIa). TF-induced metastasis requires participation of the cytoplasmic tail of TF and assembly of an active TF-FVIIa complex, 13,14 indicating a dual function for TF in tumor metastasis. The TF cytoplasmic domain, through its specific interaction with ABP-280, has been shown to support cell adhesion and migration. 15 At present it is unclear how TF on tumor cells contributes to tumor metastasis and whether the TF-FVIIa complex plays a direct role or whether its sole requirement is for the downstream generation of active coagulation factors, particularly thrombin, which have been implicated in tumor metastasis. [16][17][18] Recent studies show that proteolytic hydrolysis mediated by the TF-FVIIa complex induces cell signaling through G-proteincoupled receptors in a number of cell types (for reviews, see Prydz et al, 19 Pendurthi and Rao, 20 Ruf et al 21 ). TF-FVIIa-induced signaling in various cell types was shown to alter the expression of specific genes that encode transcription factors, growth factors, and proteins related to cellular reorganization. [22][23][24][25][26][27] These studies suggest that TF-FVIIa-induced signaling may play a role in growthpromoting settings, such as wound healing and cancer. However, it has yet to be shown how TF-FVIIa-induced regulation of gene expression actually affects cell phenotype or pathophysiologic processes. Moreover, a considerable overlap in signaling induced by TF-FVIIa and various other proteases, especially a highmagnitude response generated by thrombin, raises a valid question about the potential significance of TF-FVIIa-induced signaling in path...

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

“…The mRNA of both cytokines showed significant up-regulation in HAD brains compared with ND HIV/AIDS patients, similar to previous studies (53,54). Although PAR-2 may modulate inflammation in certain circumstances (6,(55)(56)(57), little is known about its role in neuroinflammation, particularly in the CNS. To investigate PAR-2 expression in the brain, PAR-2 mRNA levels were evaluated, in addition to its activating protease, trypsinogen IV (32) in the same brain samples.…”

ORAI1-Mediated Calcium Influx in Lactation and in Breast Cancer

“…Despite the presence of other ORAI isoforms, selective inhibition of ORAI1 is sufficient to alter breast cancer cell properties and the nature of the calcium influx associated with growth factors and proinvasiveness stimuli associated with calcium store mobilization, such as seen in our studies with a PAR-2 activator. PAR-2 is a G-protein coupled receptor activated by specific proteases including trypsin (30), and its activation mobilizes calcium from internal stores and promotes the proliferation and invasion of MDA-MB-231 breast cancer cells (31)(32)(33)(34). The ability of ORAI1 inhibition to modify the nature of calcium responses elicited by growth factors and proinvasion factors points to the need for further exploration of mechanism and potential differences between stimuli, specifically the effects on gene transcription via NFAT, which seems particularly sensitive to changes in sustained calcium influx (5).…”

Effects of Tissue Factor, PAR-2 and MMP-9 Expression on Human Breast Cancer Cell Line MCF-7 Invasion

“…Thus, MMP-9 may be the effector molecule of TF. A study on TF signaling pathways revealed that a TF-FVII complexes directly or indirectly pass through the downstream product and activate PAR-2 (Hjortoe et al, 2004;Wilson et al, 2004;Disse et al, 2011).…”

“…TF is also closely related to tumor growth, invasion, and metastasis (Förster et al, 2006;Kasthuri et al, 2009;Ruf et al, 2010). The combination of TF with factor VIIa, as well the combination of TF with factor VII and protease activated receptor-2 (PAR-2) (Hjortoe et al, 2004; induces tumor cells to form new blood vessels and promote metastasis. In addition, TF changes the expression of cancer extracellular matrix proteins through a variety of signaling pathways.…”