Cancer Institute A national cancer institute
designated cancer center

Dean W. Felsher

Publication Details

  • Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas LEUKEMIA Dejean, E., Renalier, M. H., Foisseau, M., Agirre, X., Joseph, N., De Paiva, G. R., Al Saati, T., Soulier, J., Desjobert, C., Lamant, L., Prosper, F., Felsher, D. W., Cavaille, J., Prats, H., Delsol, G., Giuriato, S., Meggetto, F. 2011; 25 (12): 1882-1890

    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 1? (HIF1?) 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.

    View details for DOI 10.1038/leu.2011.168

    View details for Web of Science ID 000298405500012

    View details for PubMedID 21778999

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