MiRNAs as Players in Rhabdomyosarcoma Development

Patrizia Gasparini,Orazio Fortunato,Francesca Limido,Andrea Ferrari,Maura Massimino,Michela Casanova,Gabriella Sozzi

doi:10.3390/ijms20225818

Abstract

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood and adolescence, is a rare but aggressive malignancy that originates from immature mesenchymal cells committed to skeletal muscle differentiation. Although RMS is, generally, responsive to the modern multimodal therapeutic approaches, the prognosis of RMS depends on multiple variables and for some patients the outcome remains dismal. Further comprehension of the molecular and cellular biology of RMS would lead to identification of novel therapeutic targets. MicroRNAs (miRNAs) are small non-coding RNAs proved to function as key regulators of skeletal muscle cell fate determination and to play important roles in RMS pathogenesis. The purpose of this review is to better delineate the role of miRNAs as a biomarkers or functional leaders in RMS development, so to possibly elucidate some of RMS molecular mechanisms and potentially therapeutically target them to improve clinical management of pediatric RMS.

Highlights

Soft tissue sarcoma (STS) are rare malignant tumors that arise in connective tissues
MicroRNAs are small non-coding RNAs proved to function as key regulators of skeletal muscle cell fate determination and to play important roles in RMS pathogenesis
Myogenic transcriptor factors such as MyoD, MEF2 and serum response factor (SRF) directly regulate the expression of miR-1 and miR-133a in skeletal muscle during myogenesis, while the expression of miR-206 is controlled by MyoD and MyoG [38,39]

Summary

Molecular Cytogenetic Characterization of RMS

Genetic factors play an important role in the development and progression of RMS and the majority of cases are sporadic and not associated with hereditary syndromes, there is yet a small proportion that are linked to congenital anomalies (Beckwith-Wiedemann syndrome), or are associated with particular familial syndromes (neurofibromatosis type I and Li-Fraumeni syndrome) [11,12,13]. The malignant transformation of RMS occurs cytogenetically due to the accumulation of somatic mutations by the acquisition of tumor-specific chromosomal aberrations [2]. As for chromosomal rearrangements, the embryonal subtype is mainly characterized by the presence of loss of heterozygosity (LOH) of the short arm of chromosome 11 (11p15.5) and 16q [14,15]. It has been demonstrated that the most common rearrangements in ERMS are the inactivation of the parental bias of chromosome 11p15 [16] (Figure 1). Novel complex chromosomal rearrangements in PAX3 were rarely reported [17]

Loss of heterozygosity LOH complex translocation Rearrangements

Genes Involved

Induction of myoblasts differentiation

Inhibition of RMS cell migration

Findings

Conclusions