Regulatory Role of the MicroRNA-29b-IL-6 Signaling in the Formation of Vascular Mimicry.
Regulatory Role of the MicroRNA-29b-IL-6 Signaling in the Formation of Vascular Mimicry.
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MicroRNA-29b-IL-6 信号传导在血管拟态形成中的调节作用。
DOI：
10.1016/j.omtn.2017.06.009
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发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Zhuang SM
中科院分区：
文献类型：
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作者：
Fang JH;Zheng ZY;Liu JY;Xie C;Zhang ZJ;Zhuang SM
血管拟态（VM）是微循环的关键补充，并与肿瘤进展有关。我们发现来源于肿瘤细胞和基质细胞的IL-6促进肿瘤细胞形成VM结构，而通过RNA干扰、IL-6中和抗体或STAT 3抑制剂阻断IL-6信号传导抑制肿瘤细胞的VM形成。IL-6通过激活STAT 3，上调VE-钙粘蛋白表达和MMP-2活性，促进VM形成。进一步的分析发现IL-6-STAT 3信号传导的激活与人肝癌组织中VM结构的形成之间存在正相关性。而miR-29 b通过直接与STAT 3和MMP 2 mRNA的3′ UTR结合而抑制其表达。一致地，功能获得和功能丧失分析均显示miR-29 b抑制肿瘤细胞在体外形成管状结构。体内研究进一步揭示，肿瘤内注射表达miR-29 b的病毒显著抑制小鼠异种移植物中IL-6促进的VM形成，并且miR-29 b的下调与人HCC组织中VM的存在相关。这项研究阐明了miR-29 b-IL-6信号级联及其在VM形成中的作用，这为癌症治疗提供了潜在的靶点。
Vascular mimicry (VM) is a critical complement for microcirculation and is implicated in tumor progression. We showed that IL-6 derived from tumor cells and stroma cells promoted tumor cells to form a VM structure, whereas blocking the IL-6 signaling by RNA interference, IL-6-neutralizing antibody, or STAT3 inhibitor suppressed the VM formation of tumor cells. Mechanism investigations revealed that IL-6 stimulated VM formation by activating STAT3, in turn upregulating VE-cadherin expression and MMP2 activity. Further analyses identified a positive association between the activation of IL-6-STAT3 signaling and the formation of the VM structure in human HCC tissues. However, miR-29b repressed the expression of STAT3 and MMP2 by directly binding to the 3′ UTRs of their mRNAs. Consistently, both gain- and loss-of-function analyses showed that miR-29b suppressed tumor cells to form tube structures in vitro. The in vivo studies further disclosed that intratumoral injection of the miR-29b-expressing viruses significantly inhibited the IL-6-promoted VM formation in mouse xenografts, and downregulation of miR-29b was correlated with the presence of VM in human HCC tissues. This study elucidates a miR-29b-IL-6 signaling cascade and its role in VM formation, which provide potential targets for cancer therapy.