title: Down-regulation of specific miRNAs enhances the expression of the gene Smoothened and contributes to T-cell lymphoblastic lymphoma development.
abstract: Inappropriate activation of the GLI/hedgehog (GLI/Hh) signalling occurs in several human cancers, including haematological neoplasms. However, little is known about its relevance in precursor T-cell lymphoblastic lymphomas (T-LBL) development. Moreover, the mechanisms whereby GLI/Hh 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-LBL. 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/Hh signalling. Activation of the GLI/Hh signalling in T-LBL 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-LBL development and advocate the use of specific SMO inhibitors or microRNAs-based therapies as an attractive possibility to treat an important subset of T-LBL.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: González-Gugel
authors.forename: María
authors.initials: M
authors.lastname: Villa-Morales
authors.forename: Javier
authors.initials: J
authors.lastname: Santos
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Bueno
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.forename: Socorro María
authors.initials: SM
authors.lastname: Rodríguez-Pinilla
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Piris
authors.forename: José
authors.initials: J
authors.lastname: Fernández-Piqueras
mesh_terms: D016475:3T3 Cells; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D000072086:Smoothened Receptor; D015854:Up-Regulation; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C546818:MIRN193 microRNA, human; D035683:MicroRNAs; C543718:Mirn141 microRNA, mouse; C534715:Mirn30d microRNA, mouse; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine