Taulli Riccardo, Bersani Francesca, Foglizzo Valentina, Linari Alessandra, Vigna Elisa, Ladanyi Marc, Tuschl Thomas, Ponzetto Carola
Department of Anatomy, Pharmacology and Forensic Medicine, and Center for Experimental Research and Medical Studies, University of Torino, Torino, Italy.
J Clin Invest. 2009 Aug;119(8):2366-78. doi: 10.1172/JCI38075. Epub 2009 Jul 20.
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.
许多微小RNA（miRNA）作为众多细胞过程和发育事件的转录后调节因子，在肿瘤中表达下调。然而，它们在肿瘤发生中的作用仍 largely未知。在本研究中，我们检测了肌肉特异性miRNA miR-1和miR-206在人横纹肌肉瘤（RMS）中的作用，RMS是一种被认为起源于骨骼肌祖细胞的软组织肉瘤。我们发现，在胚胎型和肺泡型两种原发性RMS中几乎检测不到miR-1，并且在血清剥夺后，RMS细胞系中miR-1和miR-206均未被诱导表达。此外，在RMS细胞中重新表达miR-206可促进肌源性分化，并通过将整体mRNA表达谱转变为类似于成熟肌肉的表达谱来阻断异种移植小鼠中的肿瘤生长。最后，我们表明，在正常肌生成开始时，miR-206可下调小鼠卫星细胞中MET原癌基因的产物——Met酪氨酸激酶受体，该受体在RMS中过表达并与RMS发病机制有关。因此，转录后调节功能的缺失可能是RMS和其他类型癌症中Met过表达的基础。我们提出，诸如miR-1和miR-206等组织特异性miRNA，鉴于它们调节数百种转录本的能力以及作为无毒分化剂的作用，可能会克服实体瘤的基因组异质性，并最终比单基因导向药物具有更大的治疗潜力。
