Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment

Abstract

Tumor initiation and growth depend on its microenvironment in which cancer-associated fibroblasts (CAFs) in tumor stroma play an important role. Prostaglandin E2 (PGE2) and interleukin (IL)-6 signal pathways are involved in the crosstalk between tumor and stromal cells. However, how PGE2-mediated signaling modulates this crosstalk remains unclear. Here, we show that microRNA (miR)-149 links PGE2 and IL-6 signaling in mediating the crosstalk between tumor cells and CAFs in gastric cancer (GC). miR-149 inhibited fibroblast activation by targeting IL-6 and miR-149 expression was substantially suppressed in the CAFs of GC. miR-149 negatively regulated CAFs and their effect on GC development both in vitro and in vivo. CAFs enhanced epithelial-to-mesenchymal transition (EMT) and the stem-like properties of GC cells in a miR-149-IL-6-dependent manner. In addition to IL-6, PGE2 receptor 2 (PTGER2/EP2) was revealed as another potential target of miR-149 in fibroblasts. Furthermore, H. pylori infection, a leading cause of human GC, was able to induce cyclooxygenase-2 (COX-2)/PGE2 signaling and to enhance PGE2 production, resulting in the hypermethylation of miR-149 in CAFs and increased IL-6 secretion. Our findings indicate that miR-149 mediates the crosstalk between tumor cells and CAFs in GC and highlight the potential of interfering miRNAs in stromal cells to improve cancer therapy.

Epigenetic Control of the Tumor Microenvironment

“…An example showing the regulation of miRNAs by DNA methylation was presented by Li et al [103], who studied the interaction between gastric cancer cells and CAFs. They found that prostaglandin PGE2 secreted by tumor cells triggered DNA hypermethylation of the miRNA-149 (miR-149) promoter in CAFs.…”

Effect of the Diabetic Environment On the Expression of MiRNAs in Endothelial Cells: Mir-149-5p Restoration Ameliorates the High Glucose-Induced Expression of TNF-α and ER Stress Markers

“…In endothelial cells, NO is mainly produced by eNOS [29-30]) and decrease the levels of ET-1 (which damages VECs by strongly contracting vascular smooth muscles [31-33]), vWF (a marker of vascular injury or vascular functional disturbances [34-36]) and ICAM-1 (a marker of inflammation in endothelial cells [37-38]) in HG-treated HUVECs. Recent studies have also shown that miR-149 not only participates in the anticancer mechanism [39-42] but also acts as an important new regulator of endothelial function [43]. In addition, TNF-α was importance in tumorigenesis [44-45] and the initiation and progression of vascular disorders by modulating the expression of molecules that are involved in vascular tone, inflammation and remodeling, thus inducing endothelial inflammation and dysfunction [46-49].…”

Molecular mechanisms of gastric cancer initiation and progression by Helicobacter pylori

“…DNA methylation also impacts micro-RNA (miRNA) regulation in chronic inflammatory diseases and in cancers [15**, 21]. In H. pylori positive patients with gastric disease, aberrant methylation of the CpG island in the miR-210 promoter occurs.…”

“…This methylation results in a decrease in miR-210, which leads to an increase in expression of miR-210 pro-proliferation targets such as stathmin1 (STMN1) and demethyladensosine transferase 1 (DIMT1) [15**]. H. pylori also stimulates miRNA promoter hypermethylation via cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) activation [21]. PGE2 promotes methylation in tumor cells, and in the case of H. pylori infection, miR-149 is a target of PGE2 induced DNA methylation.…”

“…Thus, methylation of miR-149 results in a decrease in miR-149 and an increase in IL-6. Downstream consequences of IL-6 induction include EMT, stem-like traits, and invasive properties [21]. Interestingly, IL-6 regulates the cancer cell environment by activating the COX-2/PGE2 pathway and by regulating miRNAs [21].…”