Melanoma cell-secreted exosomal miR-155-5p induce proangiogenic switch of cancer-associated fibroblasts via SOCS1/JAK2/STAT3 signaling pathway.
Melanoma cell-secreted exosomal miR-155-5p induce proangiogenic switch of cancer-associated fibroblasts via SOCS1/JAK2/STAT3 signaling pathway.
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黑色素瘤细胞分泌的外泌体 miR-155-5p 通过 SOCS1/JAK2/STAT3 信号通路诱导癌症相关成纤维细胞的促血管生成开关
DOI：
10.1186/s13046-018-0911-3
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发表时间：
2018-10-03
期刊：
影响因子：
--
通讯作者：
Shang Z
中科院分区：
文献类型：
--
作者：
Zhou X;Yan T;Huang C;Xu Z;Wang L;Jiang E;Wang H;Chen Y;Liu K;Shao Z;Shang Z
癌症相关成纤维细胞（CAF）已被广泛报道，以促进肿瘤血管生成。然而，CAFs的促血管生成开关的潜在机制仍然知之甚少。本研究旨在阐明CAFs促血管生成转换的机制。用B16和B16 F10衍生的外泌体处理NIH/3 T3细胞。RT-PCR和Western blot检测CAFs标志物和促血管生成因子。通过CCK-8测定、transwell迁移测定、管形成测定和体内Matrigel塞测定来确定CAF的促血管生成能力。Western blot和AG 490检测JAK 2/STAT 3信号通路在CAFs促血管生成转换中的作用。采用生物信息学分析、荧光素酶报告基因分析、microRNA模拟物和抑制剂以及异种移植模型研究mmu-miR-155- 5 p（miR-155）在CAFs促血管生成开关中的作用。在这项研究中，我们发现黑色素瘤细胞分泌的外泌体可以诱导成纤维细胞重编程为CAFs，并且外泌体miR-155可以触发CAFs的促血管生成开关。外泌体miR-155可通过直接靶向细胞因子信号转导抑制因子1（SOCS 1），机制性地递送到成纤维细胞中并促进促血管生成因子（包括血管内皮生长因子A（VEGFa）、成纤维细胞生长因子2（FGF 2）和基质金属蛋白酶9（MMP 9））的表达。SOCS 1的下调激活JAK 2/STAT 3信号通路并提高成纤维细胞中VEGFa、FGF 2和MMP 9的表达水平。用含有过表达的miR-155的外泌体治疗可以促进血管生成，并且黑色素瘤细胞分泌的外泌体中miR-155的减少在体外和体内促进血管生成。这些结果表明，通过SOCS 1/JAK 2/STAT 3信号通路促进受体成纤维细胞中促血管生成因子的表达，黑色素瘤细胞分泌的外泌体miR-155可以诱导CAFs的促血管生成开关。尽管肿瘤血管生成受多种因素调节，但外泌体miR-155可能是控制黑色素瘤血管生成的潜在靶点，并用于建立治疗黑色素瘤的新策略。本文的在线版本（10.1186/s13046-018-0911-3）包含补充材料，可供授权用户使用。
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. The online version of this article (10.1186/s13046-018-0911-3) contains supplementary material, which is available to authorized users.
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针对JAK/STAT3信号传导的靶向封锁抑制了卵巢癌的生长。
影响因子：
5.7
作者：
Gritsina G;Xiao F;O'Brien SW;Gabbasov R;Maglaty MA;Xu RH;Thapa RJ;Zhou Y;Nicolas E;Litwin S;Balachandran S;Sigal LJ;Huszar D;Connolly DC
通讯作者：
Connolly DC
JAK/STAT3 信号通路调节内皮细胞/脂肪源性基质细胞共培养 3D 凝胶模型中的血管生成。
影响因子：
8.5
作者：
Xue, Changyue;Xie, Jiamin;Cai, Xiaoxiao
通讯作者：
Cai, Xiaoxiao
DOI：
10.1007/978-94-007-5590-1_6
发表时间：
2013-01-01
期刊：
MICRORNA CANCER REGULATION: ADVANCED CONCEPTS, BIOINFORMATICS AND SYSTEMS BIOLOGY TOOLS
影响因子：
--
作者：
Kunz, Manfred
通讯作者：
Kunz, Manfred
影响因子：
45.3
作者：
Ugurel, S;Rappl, G;Reinhold, U
通讯作者：
Reinhold, U
影响因子：
8.8
作者：
Grignol, V.;Fairchild, E. T.;Zimmerer, J. M.;Lesinski, G. B.;Walker, M. J.;Magro, C. M.;Kacher, J. E.;Karpa, V. I.;Clark, J.;Nuovo, G.;Lehman, A.;Volinia, S.;Agnese, D. M.;Croce, C. M.;Carson, W. E., III
通讯作者：
Carson, W. E., III