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

Abstract

BackgroundCancer-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.MethodsNIH/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.ResultsIn 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0911-3) contains supplementary material, which is available to authorized users.

miR‐155 overexpression is followed by downregulation of its target gene, NFE2L2, and altered pattern of VEGFA expression in the liver of melanoma B16‐bearing mice at the premetastatic stage

“…Altered expression of miR‐155, miR‐21 and miR‐205 has been observed in various types of cancer . The results of the present study demonstrated that the levels of miR‐155 and miR‐21 were increased, whereas those of miR‐205 were decreased in the liver tissue of melanoma B16‐bearing mice at the premetastatic stage.…”

“…The miR-155 molecule induces the proangiogenic switch of cancer-associated fibroblasts in melanoma; this microRNA downregulates suppressor of cytokine signalling 1, which leads to the activation of the JAK2/STAT3 signalling pathway and increases VEGFA, fibroblast growth factor 2 and matrix metallopeptidase 9 expression levels in cancer-associated fibroblasts. 23 MicroRNA miR-21 enhances oxidative stress and angiogenesis during melanoma development through modulation of the expression of critical target genes, such as forkhead Box O1, phosphatase and tensin homologue, hypoxia-inducible factor 1α and tissue inhibitor of metallopeptidase 3. 24 The molecule miR-205 acts as an oncosuppressor; this microRNA diminishes angiogenesis by targeting VEGFA and its downstream products.…”

Tumoral microvesicle–activated glycometabolic reprogramming in fibroblasts promotes the progression of oral squamous cell carcinoma

“…As a novel marker of CAFs, CAV1 was associated with metabolic reprogramming (18, 22, 39). In our previous study, tumoral EVs were capable tof inducing the transition of normal fibroblasts to CAFs (11, 40). In the present study, the up‐regulation of FAP and Tn‐c and down‐regulation of CAV1 suggest that TMV‐treated HGFs enable a phenotype switch to CAFs.…”

Salidroside inhibits migration and invasion of poorly differentiated thyroid cancer cells

“…Studies have demonstrated that salidroside inhibited JAK2/STAT3 signaling pathway in many cancers and downregulated MMP‐2 and MMP‐9 proteins . It has also been demonstrated that MMP‐2 and MMP‐9 are associated with the JAK2/STAT3 signaling pathway . MMP2 and MMP9 are important effector molecules in JAK2/STAT3 pathway, and activation of JAK2/STAT3 can increase expression of MMP2 and MMP9, resulting in degradation of extracellular matrix .…”