Volume 25, No 5, May 2015

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 25 Issue 5, May 2015: 588-603   |  Open Access

ORIGINAL ARTICLES

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

Pu Li^1,*, Jing-Xuan Shan^3,*, Xue-Hua Chen^1,*, Di Zhang^2,*, Li-Ping Su¹, Xiu-Ying Huang², Bei-Qin Yu¹, Qiao-Ming Zhi¹, Cheng-Long Li¹, Ya-Qing Wang², Sara Tomei³, Qu Cai¹, Jun Ji¹, Jian-Fang Li¹, Lotfi Chouchane³, Ying-Yan Yu¹, Fang-Zhen Sun², Zhi-Heng Xu², Bing-Ya Liu¹ and Zheng-Gang Zhu¹

¹Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Ruijin Er Rd, Shanghai 200025, China
²State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Rd, Beijing 100101, China
³Laboratory of Genetic Medicine and Immnology, Weill Cornell Medical College in Qatar, Education City, P.O. Box 24144, Doha, Qatar Correspondence: Zheng-Gang Zhu,Bing-Ya Liu,Zhi-Heng Xu(zhenggang.zhu@yahoo.com; byliu@sjtu.edu.cn;zhxu@genetics.ac.cn)

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.

10.1038/cr.2015.51

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