14,15-EET induces the infiltration and tumor-promoting function of neutrophils to trigger the growth of minimal dormant metastases

// Jing Luo 1, * , Xin-Xia Feng 2, * , Chao Luo 1 , Yu Wang 1 , Dong Li 1 , Yu Shu 1 , Shan-Shan Wang 1 , Jian Qin 1 , Yong-Chao Li 1 , Jiu-Ming Zou 1 , De-An Tian 2 , Gui-Mei Zhang 1 , Zuo-Hua Feng 1 1 Department of Biochemistry and Molecular Biology, School of Basic Medicine, Wuhan 430030, People’s Republic of China 2 Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China * These authors contributed equally to this work Correspondence to: Zuo-Hua Feng, email: fengzhg_tj@163.com Gui-Mei Zhang, email: zhanggm58@163.com Keywords: neutrophils, recruitment, metastases, dormancy, epoxyeicosatrienoic acids Received: January 06, 2016      Accepted: May 13, 2016      Published: May 30, 2016 ABSTRACT 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.