The muscle-specific microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation
Riccardo Taulli, … , Thomas Tuschl, Carola Ponzetto
Riccardo Taulli, … , Thomas Tuschl, Carola Ponzetto
Published July 20, 2009
Citation Information: J Clin Invest. 2009;119(8):2366-2378. https://doi.org/10.1172/JCI38075.
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Research Article

The muscle-specific microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation

Abstract

Many microRNAs (miRNAs), posttranscriptional regulators of numerous cellular processes and developmental events, are downregulated in tumors. However, their role in tumorigenesis remains largely unknown. In this work, we examined the role of the muscle-specific miRNAs miR-1 and miR-206 in human rhabdomyosarcoma (RMS), a soft tissue sarcoma thought to arise from skeletal muscle progenitors. We have shown that miR-1 was barely detectable in primary RMS of both the embryonal and alveolar subtypes and that both miR-1 and miR-206 failed to be induced in RMS cell lines upon serum deprivation. Moreover, reexpression of miR-206 in RMS cells promoted myogenic differentiation and blocked tumor growth in xenografted mice by switching the global mRNA expression profile to one that resembled mature muscle. Finally, we showed that the product of the MET proto-oncogene, the Met tyrosine-kinase receptor, which is overexpressed in RMS and has been implicated in RMS pathogenesis, was downregulated in murine satellite cells by miR-206 at the onset of normal myogenesis. Thus, failure of posttranscriptional modulation may underlie Met overexpression in RMS and other types of cancer. We propose that tissue-specific miRNAs such as miR-1 and miR-206, given their ability to modulate hundreds of transcripts and to act as nontoxic differentiating agents, may override the genomic heterogeneity of solid tumors and ultimately hold greater therapeutic potential than single gene–directed drugs.

Authors

Riccardo Taulli, Francesca Bersani, Valentina Foglizzo, Alessandra Linari, Elisa Vigna, Marc Ladanyi, Thomas Tuschl, Carola Ponzetto

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Figure 6

Met is posttranscriptionally downregulated by miR-206 by direct targeting of its 3′UTR.

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Met is posttranscriptionally downregulated by miR-206 by direct targetin...
(A) Western blot of Met, GFP, and tubulin on protein extracts (30 μg/lane) of murine satellite cells transfected with the Met 3′UTR reporter construct along with a scrambled or miR-206–directed LNA (400 nM) and then switched to differentiation medium for 1 to 2 days. The difference in the kinetics of Met and EGFP downmodulation is most likely due to the long half-life of this form of GFP (stabilized). (B) GFP quantification by FACS analysis on RD18 cells transfected with either a miR-1/miR-206 sensor vector (see Methods) or a point-mutated (MUT) sensor vector along with a scrambled or miR-206–directed LNA (400 nM). The GFP level of control cells was set at 100%. Mean values (± SD) are from 3 independent experiments. (C and D) Western blot on protein extracts of noninduced and induced RD18 and RH4 (C) cells probed for Met, myogenin, and tubulin and (D) RMS xenografts probed for Met and tubulin. Thirty micrograms of protein extracts were loaded in each lane.