J Cancer Prev.  2020 Sep;25(3):152-163. 10.15430/JCP.2020.25.3.152.

15-Deoxy-Δ12,14 -prostaglandin J2 Induces Epithelial-tomesenchymal Transition in Human Breast Cancer Cells and Promotes Fibroblast Activation

Affiliations
  • 1Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University,Seoul,, Korea
  • 2Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University,Seoul, Korea
  • 3Cancer Research Institute, Seoul National University, Seoul, Korea
  • 4Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon, Korea
  • 5Department of Food Science and Biotechnology, College of Knowledge-based Services Engineering, Sungshin Women’s University, Seoul, Korea

Abstract

In inflammation-associated carcinogenesis, COX-2 is markedly overexpressed, resulting in accumulation of various prostaglandins. 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ2 ) is one of the terminal products of COX-2-catalyzed arachidonic acid catabolism with oncogenic potential. Epithelial-to-mesenchymal transition (EMT) is a process by which epithelial cells lose their polarity and adhesiveness, and thereby gain migratory and invasive properties. Treatment of human breast cancer MCF-7 cells with 15d-PGJ2 induced EMT as evidenced by increased expression of Snail and ZEB1, with concurrent down-regulation of E-cadherin. Nuclear extract from 15d-PGJ2 -treated MCF-7 cells showed the binding of Snail and ZEB1 to E-box sequences present in the E-cadherin promoter, which accounts for repression of E-catherin expression. Unlike 15d-PGJ2 , its non-electrophilic analogue 9,10-dihydro-15d-PGJ2 failed to induce EMT, suggesting that the α,β-unsaturated carbonyl group located in the cyclopentenone ring of 15d-PGJ2 is essential for its oncogenic function. Notably, the mRNA level of interleukin-8 (IL-8)/CXCL8 was highly elevated in 15d-PGJ 2 -stimulated MCF-7 cells. 15d-PGJ2 -induced up-regulation of IL-8/CXCL8 expression was abrogated by silencing of Snail short interfering RNA. Treatment of normal fibroblast with conditioned medium obtained from cultures of MCF-7 cells undergoing EMT induced the expression of activated fibroblast marker proteins, α-smooth muscle actin and fibroblasts activation protein-α.Co-culture of normal fibroblasts with 15d-PGJ2 -stimulated MCF-7 cells also activated normal fibroblast cells to cancer associated fibroblasts. Taken together, above findings suggest that 15d-PGJ2 induces EMT through up-regulation of Snail expression and subsequent production of CXCL8 as a putative activator of fibroblasts, which may contribute to tumor-stroma interaction in inflammatory breast cancer microenvironment.

Keyword

15-Deoxy-Δ12,14 -prostaglandin J2; Breast cancer; Cancer-associated fibroblasts; Epithelial-to-mesenchymal transition; Tumor microenvironment
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