title: Argonaute 2 promotes myeloma angiogenesis via microRNA dysregulation.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wu
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yu
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Qu
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Ji
authors.initials: J
authors.lastname: Xu
authors.forename: Qiguo
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jiaren
authors.initials: J
authors.lastname: Xu
authors.forename: Jianyong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hematology, First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing 210029, China. Chenljb@126.com.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000235:genetics*; D009101:Multiple Myeloma / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome / Q000235:genetics
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D017077:Culture Media, Conditioned; D035683:MicroRNAs