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

Overview

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.

authors

  • Li, Pu
  • Shan, Jingxuan
  • 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

publication date

  • April 28, 2015

Research

keywords

  • Dinoprostone
  • Epigenesis, Genetic
  • Fibroblasts
  • Interleukin-6
  • MicroRNAs

Identity

PubMed Central ID

  • PMC4423088

Scopus Document Identifier

  • 84928927906

Digital Object Identifier (DOI)

  • 10.1038/cr.2015.51

PubMed ID

  • 25916550

Additional Document Info

volume

  • 25

issue

  • 5