Detalle Publicación


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

Autores: Dejean, E.; Renalier, M. H. ; Foisseau, M.; Aguirre Ena, Xabier; Joseph, N. ; de Paiva, G. R.; Al Saati, T.; Soulier, J. ; Desjobert, C. ; Lamant, L.; Prosper Cardoso, Felipe; Felsher, D. W.; Cavaille, J. ; Prats, H.; Delsol, G.; Giuriato, S. ; Meggetto, F.
Título de la revista: LEUKEMIA
ISSN: 0887-6924
Volumen: 25
Número: 12
Páginas: 1882 - 1890
Fecha de publicación: 2011
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 1 alpha (HIF1 alpha) 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. Leukemia (2011) 25, 1882-1890; doi:10.1038/leu.2011.168; published online 22 July 2011