Journal
CELL RESEARCH
Volume 25, Issue 5, Pages 588-603Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cr.2015.51
Keywords
microRNA-149; epigenetic silencing; cancer-associated fibroblasts; PGE2; IL-6
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Funding
- National Natural Science Foundation of China [81172324, 81300290, 81372187, 91229106, 81272749]
- Science and Technology Commission of Shanghai Municipality [12XD1403700]
- Key Projects in the National Science & Technology Pillar Program of China [2014BAI09B03]
- Key Project of Shanghai Education Committee [12ZZ105, 12ZZ102]
- China Postdoctoral Science Foundation [2011M500796]
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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.
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