title: TWEAK-stimulated macrophages inhibit metastasis of epithelial ovarian cancer via exosomal shuttling of microRNA.
abstract: Exosomal-miRNAs are emerging as mediators of crosstalk between tumor cells and macrophages. In this study, we observed that exosomes derived from TWEAK-stimulated macrophages (TMs) could be internalized by epithelial ovarian cancer (EOC) cells and inhibit cell metastasis. Through a miRNA microarray analysis, we identified 19 miRNAs that are differentially expressed in exosomes derived from macrophages treated with or without TWEAK. The study validated that TWEAK not only increased the levels of microRNA-7 (miR-7) in macrophages and its secreted exosomes but also resulted in an elevated level of miR-7 in recipient EOC cells, which eventually reduced the activity of the EGFR/AKT/ERK1/2 pathway. Pre-transfection of antagomiR-7 in TMs substantially decreased the levels of miR-7 in macrophages, its secreted exosomes and the recipient EOC cells with a concomitant enhancement of EOC metastasis, suggesting an involvement of exosomal miR-7 from TMs in modulating the metastasis of EOC cells. Finally, the exosomes from TMs significantly blocked EOC metastasis in a xenograft mouse model. These findings provide a novel model in which TMs inhibit the metastasis of EOC cells via shuttling of exosomal miR-7 to EOC cells, thereby inhibiting the EGFR/AKT/ERK1/2 pathway.
authors.affiliation: Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China.
authors.forename: Anyue
authors.initials: A
authors.lastname: Wu
authors.affiliation: Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China.
authors.forename: Xingdi
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Di
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: leihuang@shsmu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China. Electronic address: lilyqiulh@126.com.
authors.forename: Lihua
authors.initials: L
authors.lastname: Qiu
mesh_terms: D000818:Animals; D000070416:Antagomirs / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002465:Cell Movement; D018920:Coculture Techniques; D066246:ErbB Receptors / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D048069:Tumor Necrosis Factors / Q000494:pharmacology*
chemical_list: D000070416:Antagomirs; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D035683:MicroRNAs; D051057:Proto-Oncogene Proteins c-akt; D048069:Tumor Necrosis Factors; C549242:MIRN7-1 microRNA, human; C512478:EGFR protein, human
keywords: Epithelial ovarian cancer; Exosomes; Macrophages; Metastasis; MiR-7; TWEAK