Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment
| Autor: | Jun Ji, Jingxuan Shan, Bing Ya Liu, Sara Tomei, Qu Cai, Zheng Gang Zhu, Xiu Ying Huang, Li Ping Su, Ying Yan Yu, Lotfi Chouchane, Qiao Ming Zhi, Jian Fang Li, Di Zhang, Chenglong Li, Zhiheng Xu, Fang Zhen Sun, Bei Qin Yu, Ya Qing Wang, Xue Hua Chen, Pu Li |
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| Rok vydání: | 2015 |
| Předmět: |
Stromal cell
Prostaglandin E2 receptor Tumor initiation Biology Dinoprostone Cell Line Epigenesis Genetic microRNA Humans Molecular Biology IL-6 Tumor microenvironment Helicobacter pylori Interleukin-6 Interleukin Cell Biology Fibroblasts epigenetic silencing Cell biology MicroRNAs Crosstalk (biology) Cyclooxygenase 2 Cancer-Associated Fibroblasts Original Article PGE2 microRNA-149 cancer-associated fibroblasts Signal Transduction |
| Zdroj: | Cell Research |
| ISSN: | 1748-7838 1001-0602 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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