Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment.
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.
Department 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.
Pu
P
Li
Laboratory of Genetic Medicine and Immnology, Weill Cornell Medical College in Qatar, Education City, P.O. Box 24144, Doha, Qatar.
Jing-Xuan
JX
Shan
Department 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.
Xue-Hua
XH
Chen
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Rd, Beijing 100101, China.
Di
D
Zhang
Department 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.
Li-Ping
LP
Su
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Rd, Beijing 100101, China.
Xiu-Ying
XY
Huang
Department 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.
Bei-Qin
BQ
Yu
Department 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.
Qiao-Ming
QM
Zhi
Department 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.
Cheng-Long
CL
Li
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Rd, Beijing 100101, China.
Ya-Qing
YQ
Wang
Laboratory of Genetic Medicine and Immnology, Weill Cornell Medical College in Qatar, Education City, P.O. Box 24144, Doha, Qatar.
Sara
S
Tomei
Department 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.
Qu
Q
Cai
Department 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.
Jun
J
Ji
Department 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.
Jian-Fang
JF
Li
Laboratory of Genetic Medicine and Immnology, Weill Cornell Medical College in Qatar, Education City, P.O. Box 24144, Doha, Qatar.
Lotfi
L
Chouchane
Department 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.
Ying-Yan
YY
Yu
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Rd, Beijing 100101, China.
Fang-Zhen
FZ
Sun
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Rd, Beijing 100101, China.
Zhi-Heng
ZH
Xu
Department 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.
Bing-Ya
BY
Liu
Department 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.
Zheng-Gang
ZG
Zhu
D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism*; D016480:Helicobacter pylori / Q000472:pathogenicity; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D015850:Interleukin-6; C551557:MIRN149 microRNA, human; D035683:MicroRNAs; D051546:Cyclooxygenase 2; D015232:Dinoprostone