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.

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
investigated the effect of FVIIa on IL-8
expression and cell migration in a breast
carcinoma cell line, MDA-MB-231, a cell
line that constitutively expresses abundant
TF. Expression of IL-8 mRNA in
MDA-MB-231 cells was markedly upregulated
by plasma concentrations of
FVII or an equivalent concentration of
FVIIa (10 nM). Neither thrombin nor other
proteases involved in hemostasis were
effective in stimulating IL-8 in these cells.
Increased transcriptional activation of the
IL-8 gene is responsible for increased
expression of IL-8 in FVIIa-treated cells.
PAR-2–specific antibodies fully attenuated
TF-FVIIa–induced IL-8 expression.
Additional in vitro experiments showed
that TF-FVIIa promoted tumor cell migration
and invasion, active site–inactivated
FVIIa, and specific antibodies against
TF, PAR-2, and IL-8 inhibited TF-FVIIa–
induced cell migration. In summary, the
studies described herein provide insight
into how TF may contribute to tumor
invasion.