Down-regulation of specific miRNAs enhances the expression of the gene Smoothened and contributes to T-cell lymphoblastic lymphoma development
Menée à l'aide d'échantillons prélevés sur des patients atteints d'un lymphome lymphoblastique T, sur des lignées cellulaires et à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, via divers micro-ARNs spécifiques, la surexpression du gène Smoothened favorise le développement de la maladie
Inappropriate activation of the GLI/Hedgehog signalling occurs in several human cancers, including haematological neoplasms. However, little is known about its relevance in precursor T-cell lymphoblastic lymphomas development. Moreover, the mechanisms whereby GLI/Hedgehog signalling is activated in haematological malignancies are not fully clear. Here we show that the gene Smoothened (SMO), the only non-redundant gene of this pathway, is up-regulated in mouse and human T-cell lymphoblastic lymphomas. Interestingly, down-regulation of micro-RNAs mmu-miR-30a and mmu-miR-141 as well as hsa-miR-193b clearly contributes to enhance the expression of this gene in mouse and human lymphomas and, subsequently, to activate the GLI/Hedgehog signalling. Activation of the GLI/Hedgehog signalling in T-cell lymphoblastic lymphomas promotes cell survival and proliferation, since inhibition of the pathway using short-hairpin-RNA-mediated SMO knockdown, or cyclopamine as a specific antagonist, significantly reduces these cellular processes. These findings suggest that sustained SMO up-regulation may contribute to T-cell lymphoblastic lymphoma development, and advocate the use of specific SMO inhibitors or microRNAs-based therapies as an attractive possibility to treat an important subset of T-cell lymphoblastic lymphomas.
http://carcin.oxfordjournals.org/content/early/2013/01/02/carcin.bgs404.abstract