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- Title
Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment.
- Authors
Li, Pu; Shan, Jing-Xuan; Chen, Xue-Hua; Zhang, Di; Su, Li-Ping; Huang, Xiu-Ying; Yu, Bei-Qin; Zhi, Qiao-Ming; Li, Cheng-Long; Wang, Ya-Qing; Tomei, Sara; Cai, Qu; Ji, Jun; Li, Jian-Fang; Chouchane, Lotfi; Yu, Ying-Yan; Sun, Fang-Zhen; Xu, Zhi-Heng; Liu, Bing-Ya; Zhu, Zheng-Gang
- 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.
- Subjects
TUMOR growth; GENE silencing; MICRORNA; FIBROBLASTS; CANCER cells; CELLULAR signal transduction; PROSTAGLANDINS
- Publication
Cell Research, 2015, Vol 25, Issue 5, p588
- ISSN
1001-0602
- Publication type
Article
- DOI
10.1038/cr.2015.51