Down-regulation of specific miRNAs enhances the expression of the gene Smoothened and contributes to T-cell lymphoblastic lymphoma development

Carcinogenesis. 2013 Apr;34(4):902-8. doi: 10.1093/carcin/bgs404. Epub 2013 Jan 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Down-Regulation
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Humans
  • Jurkat Cells
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / 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
  • Receptors, G-Protein-Coupled / genetics*
  • Signal Transduction / genetics
  • Smoothened Receptor
  • Up-Regulation
  • Veratrum Alkaloids / pharmacology
  • Zinc Finger Protein GLI1


  • 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