14,15-EET induces the infiltration and tumor-promoting function of neutrophils to trigger the growth of minimal dormant metastases.
Infiltrating neutrophils are known to promote in the development of tumor. However, it is unclear whether and how neutrophils are involved in triggering the growth of dormant metastases. Here we show that 14,15-epoxyeicosatrienoic acid (14,15-EET) can trigger the growth of dormant micrometastases by inducing neutrophilic infiltration and converting neutrophil function. 14,15-EET triggered neutrophil infiltration in metastatic lesions by activating STAT3 and JNK pathways to induce the expression of human IL-8 and murine CXCL15 in corresponding tumor cells. The continuous expression of hIL-8/mCXCL15 was maintained by the sustained and enhanced activation of JNK pathway. 14,15-EET up-regulated miR-155 expression by activating STAT3 and JNK pathways. miR-155 in turn down-regulated the expression of SHIP1 and DET1, thus augmenting the activation of JNK and c-Jun. Moreover, the function of neutrophils was converted from tumor-suppressing to tumor-promoting by 14,15-EET in vivo. By inducing the production of G-CSF/IL-6 in vivo, 14,15-EET induced the enhancement of STAT3 activation in neutrophils to increase MMP-9 expression and decrease TRAIL expression. Neutrophil-derived MMP-9 was required for 14,15-EET to induce angiogenesis during the growth of dormant micrometastases. Depleting neutrophils or inhibiting hIL-8/mCXCL15 up-regulation resulted in the failure of 14,15-EET to promote the development of micrometastases. These findings reveal a mechanism through which the infiltration and tumor-promoting function of neutrophils could be induced to trigger the growth of dormant metastases, which might be a driving force for the tumor recurrence based on dormant metastases.
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Wuhan 430030, People's Republic of China.
Jing
J
Luo
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030,  People's Republic of China.
Xin-Xia
XX
Feng
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Wuhan 430030, People's Republic of China.
Chao
C
Luo
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Wuhan 430030, People's Republic of China.
Yu
Y
Wang
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Wuhan 430030, People's Republic of China.
Dong
D
Li
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Wuhan 430030, People's Republic of China.
Yu
Y
Shu
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Wuhan 430030, People's Republic of China.
Shan-Shan
SS
Wang
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Wuhan 430030, People's Republic of China.
Jian
J
Qin
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Wuhan 430030, People's Republic of China.
Yong-Chao
YC
Li
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Wuhan 430030, People's Republic of China.
Jiu-Ming
JM
Zou
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030,  People's Republic of China.
De-An
DA
Tian
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Wuhan 430030, People's Republic of China.
Gui-Mei
GM
Zhang
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Wuhan 430030, People's Republic of China.
Zuo-Hua
ZH
Feng
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D061206:Neoplasm Micrometastasis / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
C508606:CXCL8 protein, human; D019743:Chemokines, CXC; C118893:Cxcl15 protein, mouse; D015850:Interleukin-6; D016209:Interleukin-8; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D016179:Granulocyte Colony-Stimulating Factor; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D020780:Matrix Metalloproteinase 9; D015126:8,11,14-Eicosatrienoic Acid
dormancy; epoxyeicosatrienoic acids; metastases; neutrophils; recruitment