Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas

E Dejean; M H Renalier; M Foisseau; X Agirre; N Joseph; G R de Paiva; T Al Saati; J Soulier; C Desjobert; L Lamant; F Prósper; D W Felsher; J Cavaillé; H Prats; G Delsol; S Giuriato; F Meggetto

doi:10.1038/leu.2011.168

Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas

Leukemia. 2011 Dec;25(12):1882-90. doi: 10.1038/leu.2011.168. Epub 2011 Jul 22.

Authors

E Dejean¹, M H Renalier, M Foisseau, X Agirre, N Joseph, G R de Paiva, T Al Saati, J Soulier, C Desjobert, L Lamant, F Prósper, D W Felsher, J Cavaillé, H Prats, G Delsol, S Giuriato, F Meggetto

Affiliation

¹ Centre de Recherches en Cancérologie de Toulouse, INSERM-UMR 1037-Université Toulouse III Paul Sabatier, Toulouse, France.

PMID: 21778999
DOI: 10.1038/leu.2011.168

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Anaplastic Lymphoma Kinase
Animals
Blotting, Northern
Blotting, Western
Case-Control Studies
Cell Adhesion
Cell Movement
Cells, Cultured
DNA Methylation
Down-Regulation
Embryo, Mammalian / cytology
Embryo, Mammalian / metabolism
Enzyme-Linked Immunosorbent Assay
Female
Fibroblasts / cytology
Fibroblasts / metabolism
Gene Expression Regulation, Neoplastic*
Humans
Hypoxia / genetics
Hypoxia / metabolism*
Hypoxia / pathology
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Immunoenzyme Techniques
Lymphoma, Large-Cell, Anaplastic / genetics*
Lymphoma, Large-Cell, Anaplastic / metabolism*
Lymphoma, Large-Cell, Anaplastic / pathology
Mice
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / genetics*
MicroRNAs / metabolism
Neovascularization, Pathologic
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Receptor Protein-Tyrosine Kinases / genetics
Receptor Protein-Tyrosine Kinases / metabolism*
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism*

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
MIRN16 microRNA, human
MicroRNAs
Mirn16 microRNA, mouse
RNA, Messenger
Vascular Endothelial Growth Factor A
ALK protein, human
Alk protein, mouse
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases