MiR-205/YAP1 in Activated Fibroblasts of Breast Tumor Promotes VEGF-independent Angiogenesis through STAT3 Signaling.
MiR-205/YAP1 in Activated Fibroblasts of Breast Tumor Promotes VEGF-independent Angiogenesis through STAT3 Signaling.
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乳腺肿瘤激活的成纤维细胞中的 MiR-205/YAP1 通过 STAT3 信号转导促进不依赖于 VEGF 的血管生成
作者：
Du YE;Tu G;Yang G;Li G;Yang D;Lang L;Xi L;Sun K;Chen Y;Shu K;Liao H;Liu M;Hou Y
肿瘤微环境对肿瘤血管生成有重要作用。然而，激活的肿瘤相关成纤维细胞(CAF)在血管生成中的作用仍不清楚。在此，我们报道了激活的间质成纤维细胞中的miR-205/YAP1信号在血管内皮生长因子非依赖性的乳腺肿瘤血管生成中起关键作用。方法：用实时定量聚合酶链式反应(qRT-PCR)检测MIR-205的表达，用qRT-PCR、Western blotting和免疫组织化学方法检测YAP1的表达，用qRT-PCR、westernblotting和ELISA法检测IL11和IL15的表达。分别进行体外血管形成实验、三维发芽实验和体内异种移植血管生成实验。通过过表达实验和shRNA、siRNA或抗体中和实验，分析miR-205/YAP1介导的肿瘤血管生成机制。结果：MIR-205/YAP1信号轴激活乳腺正常成纤维细胞向CAF分化，促进人脐静脉内皮细胞(HUVECs)的小管形成和萌发。在CAF中抢救miR-205会钝化血管生成过程。YAP1是miR-205的靶标，它不调节血管内皮生长因子的表达，而是特异性地增强白介素11和白介素15的表达，通过中和血管内皮生长因子抗体来维持肿瘤血管生成，即使在阿西替尼存在的情况下或在血管内皮生长因子耗尽后也是如此。CAF释放的IL11和IL15激活HUVECs中的STAT3信号。阻断CAF中IL11和IL15的表达导致血管内皮细胞STAT3信号失活，抑制CAF诱导的血管生成。钝化的血管生成抑制了乳腺癌细胞的体内侵袭和转移。结论：这些结果为以非血管内皮生长因子的方式诱导乳腺肿瘤血管生成提供了一个新的视角。
Tumor microenvironment contributes to tumor angiogenesis. However, the role of the activated cancer associated-fibroblasts (CAFs) in angiogenesis is still unclear. Here we report that miR-205/YAP1 signaling in the activated stromal fibroblasts plays a critical role in VEGF-independent angiogenesis in breast tumor. Methods: miR-205 expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR); YAP1 expression by qRT-PCR, western blotting and immunohistochemistry; IL11 and IL15 expression by qRT-PCR, western blotting and ELISA. Tube formation and three-dimensioned sprouting assays in vitro, and orthotopic Xenografts in vivo were conducted as angiogenesis experiments. The mechanism of miR-205/YAP1-mediated tumor angiogenesis was analyzed via overexpression and shRNA, siRNA, or antibody neutralization experiments in combination with anti-VEGF antibody or Axitinib. Results: miR-205/YAP1 signaling axis activates breast normal fibroblasts (NFs) into CAFs, promotes tubule formation and sprouting of Human Umbilical Vein Endothelial Cells (HUVECs). Rescue of miR-205 in CAFs blunts angiogenesis processes. YAP1, a target of miR-205, does not regulate VEGF expression but specifically enhances IL11 and IL15 expressions, maintaining tumor angiogenesis even in the presence of Axitinib or after exhaustion of VEGF by neutralizing VEGF antibody. IL11 and IL15 released from CAFs activate STAT3 signaling in HUVECs. Blockage of IL11 and IL15 expression in CAFs results in the inactivation of STAT3-signaling in HUVECs and repression of the CAF-induced angiogenesis. The blunt angiogenesis halts the invasion and metastasis of breast cancer cells in vivo. Conclusions: These results provide a novel insight into breast CAF-induced tumor angiogenesis in a VEGF-independent manner.
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