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

Pu Li, Jingxuan Shan, Xue Hua Chen, Di Zhang, Li Ping Su, Xiu Ying Huang, Bei Qin Yu, Qiao Ming Zhi, Cheng Long Li, Ya Qing Wang, Sara Tomei, Qu Cai, Jun Ji, Jian Fang Li, Lotfi Chouchane, Ying Yan Yu, Fang Zhen Sun, Zhi Heng Xu, Bing Ya Liu, Zheng Gang Zhu

Research output: Contribution to journalArticle

74 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)588-603
Number of pages16
JournalCell Research
Volume25
Issue number5
DOIs
Publication statusPublished - 7 May 2015

Keywords

  • cancer-associated fibroblasts
  • epigenetic silencing
  • IL-6
  • microRNA-149
  • PGE2

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Li, P., Shan, J., Chen, X. H., Zhang, D., Su, L. P., Huang, X. Y., Yu, B. Q., Zhi, Q. M., Li, C. L., Wang, Y. Q., Tomei, S., Cai, Q., Ji, J., Li, J. F., Chouchane, L., Yu, Y. Y., Sun, F. Z., Xu, Z. H., Liu, B. Y., & Zhu, Z. G. (2015). Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment. Cell Research, 25(5), 588-603. https://doi.org/10.1038/cr.2015.51