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 1

miR-1 is poorly expressed in primary tumors, and RMS cells switched to differentiating conditions fail to induce miR-1/miR-206.

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miR-1 is poorly expressed in primary tumors, and RMS cells switched to d...
(A) Quantitative real-time PCR analysis of mature miR-1 and miR-206 in primary human RMS (A–R) and control muscles (no. 1–4). Mean values (± SD) are from 3 replicates. (B) Increase of expression of mature miR-1/miR-206 in RMS cells and control hMBs in differentiation medium (D, medium with low levels of serum) relative to proliferation medium (P, medium with high levels of serum), measured by real-time PCR. Mean values (± SD) are from 3 independent experiments. (C) Northern blot with miR-206– and miR-1–specific probes on total RNA (5 μg/lane) obtained from the indicated RMS cells grown for 3 days in differentiation medium and from proliferating and differentiating murine satellite cells. Increasing amounts of synthetic miRNAs were used as standards for quantification.