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

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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

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Tumor Microenvironment
MicroRNAs
Dinoprostone
Epigenomics
Interleukin-6
Stomach Neoplasms
Neoplasms
Stromal Cells
Fibroblasts
Prostaglandin Receptors
Cancer-Associated Fibroblasts
Epithelial-Mesenchymal Transition
Pylorus
Cyclooxygenase 2
Signal Transduction

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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

In: Cell Research, Vol. 25, No. 5, 07.05.2015, p. 588-603.

Research output: Contribution to journalArticle

Li, P, Shan, J, Chen, XH, Zhang, D, Su, LP, Huang, XY, Yu, BQ, Zhi, QM, Li, CL, Wang, YQ, Tomei, S, Cai, Q, Ji, J, Li, JF, Chouchane, L, Yu, YY, Sun, FZ, Xu, ZH, Liu, BY & Zhu, ZG 2015, 'Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment', Cell Research, vol. 25, no. 5, pp. 588-603. https://doi.org/10.1038/cr.2015.51
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. / Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment. In: Cell Research. 2015 ; Vol. 25, No. 5. pp. 588-603.
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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.",
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T1 - Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment

AU - Li, Pu

AU - Shan, Jingxuan

AU - Chen, Xue Hua

AU - Zhang, Di

AU - Su, Li Ping

AU - Huang, Xiu Ying

AU - Yu, Bei Qin

AU - Zhi, Qiao Ming

AU - Li, Cheng Long

AU - Wang, Ya Qing

AU - Tomei, Sara

AU - Cai, Qu

AU - Ji, Jun

AU - Li, Jian Fang

AU - Chouchane, Lotfi

AU - Yu, Ying Yan

AU - Sun, Fang Zhen

AU - Xu, Zhi Heng

AU - Liu, Bing Ya

AU - Zhu, Zheng Gang

PY - 2015/5/7

Y1 - 2015/5/7

N2 - 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.

AB - 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.

KW - cancer-associated fibroblasts

KW - epigenetic silencing

KW - IL-6

KW - microRNA-149

KW - PGE2

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