SNAIL Promotes Metastatic Behavior of Rhabdomyosarcoma by Increasing EZRIN and AKT Expression and Regulating MicroRNA Networks

Abstract

Rhabdomyosarcoma (RMS) is a predominant soft tissue tumor in children and adolescents. For high-grade RMS with metastatic involvement, the 3-year overall survival rate is only 25 to 30%. Thus, understanding the regulatory mechanisms involved in promoting the metastasis of RMS is important. Here, we demonstrate for the first time that the SNAIL transcription factor regulates the metastatic behavior of RMS both in vitro and in vivo. SNAIL upregulates the protein expression of EZRIN and AKT, known to promote metastatic behavior, by direct interaction with their promoters. Our data suggest that SNAIL promotes RMS cell motility, invasion and chemotaxis towards the prometastatic factors: HGF and SDF-1 by regulating RHO, AKT and GSK3b activity. In addition, miRNA transcriptome analysis revealed that SNAIL-miRNA axis regulates processes associated with actin cytoskeleton reorganization. Our data show a novel role of SNAIL in regulating RMS cell metastasis that may also be important in other mesenchymal tumor types and clearly suggests SNAIL as a promising new target for future RMS therapies.

Exosomes-Mediated Transfer of Itga2 Promotes Migration and Invasion of Prostate Cancer Cells by Inducing Epithelial-Mesenchymal Transition

“…In addition, ITGA2-induced chemoresistance is reversed by upregulation of miR-135b-5p, which inhibits MAPK/ERK and EMT pathways in gastric cancer cells [27]. The expression of ITGA2 is inhibited by silencing SNAIL in rhabdomyosarcoma RH30 cells and the overall metastatic behavior is reduced [28]. However, the role of exosomes-mediated transfer of integrins from CRPC to AR-dependent cells has not been investigated.…”

Enhancement of myogenic differentiation and inhibition of rhabdomyosarcoma progression by miR-28-3p and miR-193a-5p regulated by SNAIL

“… 6 , 10 Furthermore, SNAIL regulates RMS metastasis by affecting the EZRIN cytoskeletal protein and AKT serine/threonine kinase levels. 11 In addition to the regulation of protein expression, SNAIL is also a crucial regulator of noncoding RNAs, including microRNAs (miRNAs). 7 , 11 SNAIL may affect miRNA expression either indirectly or directly by binding to their promoters or regulatory elements.…”

“… 11 In addition to the regulation of protein expression, SNAIL is also a crucial regulator of noncoding RNAs, including microRNAs (miRNAs). 7 , 11 SNAIL may affect miRNA expression either indirectly or directly by binding to their promoters or regulatory elements. 7 In our previous studies, we demonstrated that in RMS cells SNAIL is the regulator of the whole miRNA transcriptome, and gene ontology analysis revealed that the SNAIL-miRNA axis regulates processes associated with differentiation, migration, and reorganization of the actin cytoskeleton.…”

“… 7 In our previous studies, we demonstrated that in RMS cells SNAIL is the regulator of the whole miRNA transcriptome, and gene ontology analysis revealed that the SNAIL-miRNA axis regulates processes associated with differentiation, migration, and reorganization of the actin cytoskeleton. 11 Furthermore, we selected miRNAs that were the most potently regulated by SNAIL for further investigation of their effects on RMS migration. Two of the candidates, miR-28-3p and miR-193a-5p, regulated the motility of RMS cells after transient transfection with miRNA mimics, 11 but their precise modes of action have not been described.…”

“… 25 Furthermore, our previous studies suggested important roles of SNAIL-dependent miR-28-3p and miR-193a-5p in the regulation of RMS migration. 11 Therefore, in this study we evaluated the roles of miR-28-3p and miR-193a-5p in RMS growth, differentiation, vascularization, and metastasis. We found that miR-28-3p and miR-193a-5p are crucial mediators of SNAIL action and important targets for future therapies.…”