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.

MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma

“…The numerous reported roles of miR122 include regulation of cholesterol biosynthesis 19,20 , hepatitis C virus replication 49 and maintenance of the adult liver phenotype 21 . Specific miRNAs are often involved in the differentiation of specific cells and tissues 50 . As miR122 is liver-specific, we reasoned that this miRNA may have a role in the differentiation of normal hepatocytes.…”

MET signalling: principles and functions in development, organ regeneration and cancer

“…Although the regulatory molecules are the same and the biological outcomes share unifying principles, the precise mechanisms that dictate the final execution of one or another response are far from being elucidated. The regulation of the different outcomes of MET activation, as well as the definition of their biological specificity, could depend on signal modifiers that are endowed with a tissue-restricted distribution (including, as recently demonstrated, microRNAs 149,150,151,152,153 ) or on dedicated protein interaction networks, and could be further tuned by transcriptional modulation. The ongoing development of new technologies is certainly one prerequisite for unravelling the complexity of these issues.…”

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

“…Clinical data show that MET overexpression, in the absence of gene amplifi cation, is the most frequent cause of constitutive MET activation in human tumors and often correlates with poor prognosis. Overexpression can be caused by several factors, such as hypoxia ( 19 ), activation of upstream oncogenes ( 20,21 ), inactivation of tumor suppressor genes ( 22 ), or loss of miRNAs ( 23,24 ). MET gene amplifi cation, which drives increased expression and constitutive receptor activation, has been described in selected histotypes such as gastroesophageal, colorectal, endometrial, and lung carcinomas, glioblastomas, and medulloblastomas (reviewed in ref.…”