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: Elena González-Gugel, María Villa-Morales, Javier Santos, Maria José Bueno, Marcos Malumbres, Socorro María Rodríguez-Pinilla, Miguel Ángel Piris, José Fernández-Piqueras
• Journal: Carcinogenesis (Carcinogenesis) Vol. 34 Issue 4 Pg. 902-8 (Apr 2013) ISSN: 1460-2180 [Electronic] England
• PMID: 23288923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gli1 protein, mouse
• Hedgehog Proteins
• Kruppel-Like Transcription Factors
• MIRN193 microRNA, human
• MicroRNAs
• Mirn141 microRNA, mouse
• Mirn30d microRNA, mouse
• RNA, Small Interfering
• Receptors, G-Protein-Coupled
• Smo protein, mouse
• Smoothened Receptor
• Veratrum Alkaloids
• Zinc Finger Protein GLI1
• cyclopamine

Topics

• 3T3 Cells
• Animals
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Down-Regulation
• Hedgehog Proteins (genetics, metabolism)
• Humans
• Jurkat Cells
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Lymphoma, T-Cell (genetics)
• Mice
• Mice, Inbred C57BL
• MicroRNAs (genetics)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics)
• RNA Interference
• RNA, Small Interfering
• Receptors, G-Protein-Coupled (biosynthesis, genetics)
• Signal Transduction (genetics)
• Smoothened Receptor
• Up-Regulation
• Veratrum Alkaloids (pharmacology)
• Zinc Finger Protein GLI1