There is a plethora of evidence to support that
inflammation is causally linked to
carcinogenesis.
Cyclooxygenase-2 (COX-2), a rate-limiting
enzyme in the biosynthesis of
prostaglandins, is inappropriately overexpressed in various
cancers and hence recognized as one of the hallmarks of chronic
inflammation-associated
malignancies. However, the mechanistic role of COX-2 as a link between
inflammation and
cancer remains largely undefined. In this study, we found that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the final products of COX-2, induced upregulation of
vascular endothelial growth factor (
VEGF) and capillary formation and migration through nuclear factor erythroid 2-related factor 2 (NRF2)-dependent
heme oxygenase-1 (HO-1) induction in MCF-7 cells. Analysis of the publicly available TCGA data set showed that high
mRNA levels of both COX-2 and NRF2 correlated with the poor clinical outcomes in
breast cancer patients. Moreover, human tissue analysis showed that the levels of
15d-PGJ2 as well the expression of COX-2, NRF2, and HO-1 were found to be increased in human
breast cancer tissues. In conclusion, the elevated levels of
15d-PGJ2 during inflammatory response activate
VEGF expression through NRF2-driven induction of HO-1 in human
breast cancer cells, proposing a novel mechanism underlying the oncogenic function of
15d-PGJ2.