Melanoma cell-secreted exosomal miR-155-5p induce proangiogenic switch of cancer-associated fibroblasts via SOCS1/JAK2/STAT3 signaling pathway

Cancer-associated fibroblasts (CAFs) have been widely reported to promote tumor angiogenesis. However, the underlying mechanisms of the proangiogenic switch of CAFs remain poorly understood. This study aims to clarify the mechanisms underlying the proangiogenic switch of CAFs. NIH/3T3 cells were tre...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of experimental & clinical cancer research 2018-10, Vol.37 (1), p.242-242, Article 242
Main Authors:	Zhou, Xiaocheng, Yan, Tinglin, Huang, Chunming, Xu, Zhi, Wang, Lin, Jiang, Erhui, Wang, Hui, Chen, Yang, Liu, Ke, Shao, Zhe, Shang, Zhengjun
Format:	Article
Language:	eng
Subjects:	Angiogenesis Animals Cancer Cancer-associated fibroblasts Cancer-Associated Fibroblasts - metabolism Cancer-Associated Fibroblasts - pathology Cell adhesion & migration Cell growth Cell Proliferation - physiology Cytokines Enzymes Exosomes Exosomes - genetics Exosomes - metabolism Fibroblasts Gene expression Investigations JAK2/STAT3 signaling pathway Janus Kinase 2 - metabolism Kinases Male Melanoma Melanoma, Experimental - blood supply Melanoma, Experimental - genetics Melanoma, Experimental - metabolism Melanoma, Experimental - pathology Metastasis Mice Mice, Inbred C57BL MicroRNA MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism Mmu-miR-155-5p Neovascularization Neovascularization, Pathologic - genetics Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - pathology NIH 3T3 Cells Physiological aspects Proteins Signal Transduction STAT3 Transcription Factor - metabolism Suppressor of Cytokine Signaling 1 Protein - metabolism Transfection Tumors Vascular endothelial growth factor
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Cancer-associated fibroblasts (CAFs) have been widely reported to promote tumor angiogenesis. However, the underlying mechanisms of the proangiogenic switch of CAFs remain poorly understood. This study aims to clarify the mechanisms underlying the proangiogenic switch of CAFs. NIH/3T3 cells were treated with B16 and B16F10-derived exosomes. Then the CAFs markers and proangiogenic factors were detected by RT-PCR and Western blot. CCK-8 assay, transwell migration assay, tube formation assay, and in vivo Matrigel plug assay were conducted to determine the proangiogenic capability of CAFs. Western blot and AG490 were used to investigate the role of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in the proangiogenic switch of CAFs. Bioinformatics analysis, luciferase reporter assay, microRNA mimic and inhibitor, and xenograft models were used to investigate the role of mmu-miR-155-5p (miR-155) in the proangiogenic switch of CAFs. In this study, we show that melanoma cell-secreted exosomes can induce reprogramming of fibroblasts into CAFs and that exosomal miR-155 can trigger the proangiogenic switch of CAFs. Mechanistically exosomal miR-155 can be delivered into fibroblasts and promote the expression of proangiogenic factors, including vascular endothelial growth factor A (VEGFa), fibroblast growth factor 2 (FGF2), and matrix metalloproteinase 9 (MMP9), by directly targeting suppressor of cytokine signaling 1 (SOCS1). Downregulation of SOCS1 activates JAK2/STAT3 signaling pathway and elevates the expression levels of VEGFa, FGF2, and MMP9 in fibroblasts. Treatment with exosomes containing overexpressed miR-155 can promote angiogenesis, and the reduction of miR-155 in melanoma cell-secreted exosomes alleviates angiogenesis in vitro and in vivo. These results demonstrate that by promoting the expression of proangiogenic factors in recipient fibroblasts via SOCS1/JAK2/STAT3 signaling pathway, melanoma cell-secreted exosomal miR-155 can induce the proangiogenic switch of CAFs. Although tumor angiogenesis is modulated by various factors, exosomal miR-155 may be a potential target for controlling melanoma angiogenesis and used to set up novel strategies to treat melanoma.
ISSN:	1756-9966 0392-9078 1756-9966