title: Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas.
abstract: The anaplastic lymphoma kinase (ALK), tyrosine kinase oncogene is implicated in a wide variety of cancers. In this study we used conditional onco-ALK (NPM-ALK and TPM3-ALK) mouse MEF cell lines (ALK+ fibroblasts) and transgenic models (ALK+ B-lymphoma) to investigate the involvement and regulation of angiogenesis in ALK tumor development. First, we observed that ALK expression leads to downregulation of miR-16 and increased Vascular Endothelial Growth Factor (VEGF) levels. Second, we found that modification of miR-16 levels in TPM3-ALK MEF cells greatly affected VEGF levels. Third, we demonstrated that miR-16 directly interacts with VEGF mRNA at the 3'-untranslated region and that the regulation of VEGF by miR-16 occurs at the translational level. Fourth, we showed that expression of both the ALK oncogene and hypoxia-induced factor 1α (HIF1α) is a prerequisite for miR-16 downregulation. Fifth, in vivo, miR-16 gain resulted in reduced angiogenesis and tumor growth. Finally, we highlighted an inverse correlation between the levels of miR-16 and VEGF in human NPM-ALK+ Anaplastic Large Cell Lymphomas (ALCL). Altogether, our results demonstrate, for the first time, the involvement of angiogenesis in ALK+ ALCL and strongly suggest an important role for hypoxia-miR-16 in regulating VEGF translation.
authors.affiliation: Centre de Recherches en Cancérologie de Toulouse, INSERM-UMR 1037-Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: E
authors.initials: E
authors.lastname: Dejean
authors.forename: M H
authors.initials: MH
authors.lastname: Renalier
authors.forename: M
authors.initials: M
authors.lastname: Foisseau
authors.forename: X
authors.initials: X
authors.lastname: Agirre
authors.forename: N
authors.initials: N
authors.lastname: Joseph
authors.forename: G R
authors.initials: GR
authors.lastname: de Paiva
authors.forename: T
authors.initials: T
authors.lastname: Al Saati
authors.forename: J
authors.initials: J
authors.lastname: Soulier
authors.forename: C
authors.initials: C
authors.lastname: Desjobert
authors.forename: L
authors.initials: L
authors.lastname: Lamant
authors.forename: F
authors.initials: F
authors.lastname: Prósper
authors.forename: D W
authors.initials: DW
authors.lastname: Felsher
authors.forename: J
authors.initials: J
authors.lastname: Cavaillé
authors.forename: H
authors.initials: H
authors.lastname: Prats
authors.forename: G
authors.initials: G
authors.lastname: Delsol
authors.forename: S
authors.initials: S
authors.lastname: Giuriato
authors.forename: F
authors.initials: F
authors.lastname: Meggetto
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D016022:Case-Control Studies; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D019175:DNA Methylation; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; C522604:Mirn16 microRNA, mouse; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases