15-Deoxy-Δ12,14-prostaglandin J2 Upregulates VEGF Expression via NRF2 and Heme Oxygenase-1 in Human Breast Cancer Cells.
Eun-Hee KimSu-Jung KimHye-Kyung NaWonshik HanNam-Jung KimYoung-Ger SuhYoung-Joon SurhPublished in: Cells (2021)
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.
Keyphrases
- endothelial cells
- vascular endothelial growth factor
- oxidative stress
- breast cancer cells
- poor prognosis
- high glucose
- inflammatory response
- nuclear factor
- induced pluripotent stem cells
- induced apoptosis
- toll like receptor
- diabetic rats
- binding protein
- signaling pathway
- long non coding rna
- pi k akt
- machine learning
- young adults
- transcription factor
- immune response
- nitric oxide
- electronic health record
- cell death
- data analysis
- cell cycle arrest
- nitric oxide synthase