Wu Shuang, Yu Wenjun, Qu Xiaoyan, Wang Rong, Xu Ji, Zhang Qiguo, Xu Jiaren, Li Jianyong, Chen Lijuan
Department of Hematology, First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing 210029, China.
J Hematol Oncol. 2014 May 7;7:40. doi: 10.1186/1756-8722-7-40.
Dysregulated microRNA (miRNA) expression contributes to cancer cell proliferation, apoptosis and angiogenesis. Angiogenesis is a hallmark of multiple myeloma (MM) development and progression. Argonaute 2 (AGO2) protein, a core component of the RNA-induced silencing complex (RISC), can directly bind to miRNAs and mediate target messenger RNA (mRNA) degradation. A previous study showed that AGO2 knockdown suppressed human umbilical vein endothelial cell (HUVEC) growth and tube formation. However, the roles and molecular mechanisms of AGO2-induced myeloma angiogenesis are not yet fully understood. The aim of this study was to characterize these roles and effects and their associated mechanisms.
Supernatants from AGO2-overexpressing MM lines induced HUVEC migration and accelerated tube formation. Conversely, supernatants from AGO2-knockdown MM lines suppressed HUVEC cell migration and tube formation. Moreover, a chick chorioallantoic membrane (CAM) assay was used to demonstrate that AGO2 could drive neovessel formation in MM lines in vivo. Using an miRNA microarray, we observed that 25 miRNAs were upregulated and 7 were downregulated in response to AGO2. Most let-7 family members and 2 miR-17/92 cluster members (miR-17a and miR-92-1), all known pro-angiogenic miRNAs, were positively regulated by AGO2 whereas anti-angiogenic miRNAs such as miR-145 and miR-361 were negatively regulated by AGO2.
We conclude that AGO2 can drive neovessel formation in vitro and in vivo by dysregulating the expression of some angiogenic miRNAs. The pro-angiogenic miRNAs of the let-7 family and the miR-17/92 cluster, along with the anti-angiogenic miRNA miR-145, play crucial roles in AGO2-mediated angiogenesis by targeting angiogenesis-related genes.
微小RNA（miRNA）表达失调促进癌细胞增殖、凋亡和血管生成。血管生成是多发性骨髓瘤（MM）发生发展的一个标志。AGO2蛋白是RNA诱导沉默复合体（RISC）的核心成分，可直接与miRNA结合并介导靶信使核糖核酸（mRNA）降解。先前的一项研究表明，敲低AGO2可抑制人脐静脉内皮细胞（HUVEC）生长和管腔形成。然而，AGO2诱导骨髓瘤血管生成的作用和分子机制尚未完全明确。本研究旨在明确这些作用、影响及其相关机制。
AGO2过表达的MM细胞系培养上清液可诱导HUVEC迁移并加速管腔形成。相反，AGO2敲低的MM细胞系培养上清液可抑制HUVEC细胞迁移和管腔形成。此外，采用鸡胚绒毛尿囊膜（CAM）试验证明AGO2可在体内驱动MM细胞系中的新血管形成。通过miRNA微阵列，我们观察到响应AGO2时，25种miRNA上调，7种miRNA下调。大多数let-7家族成员以及2种miR-17/92簇成员（miR-17a和miR-92-1），均为已知的促血管生成miRNA，受AGO2正向调控，而抗血管生成miRNA如miR-145和miR-361受AGO2负向调控。
我们得出结论，AGO2可通过调节一些血管生成相关miRNA的表达，在体外和体内驱动新血管形成。let-7家族和miR-17/92簇的促血管生成miRNA，以及抗血管生成miRNA miR-145，通过靶向血管生成相关基因，在AGO2介导的血管生成中发挥关键作用。
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