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

Klaudia Skrzypek,Marta Kot,Małgorzata Lasota,Paweł Konieczny,Wojciech Bobela,Urszula Jankowska,Marcin Majka,Anna Kusienicka,Sylwia Kędracka-Krok,Artur Nieszporek

doi:10.3390/cancers12071870

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 GSK3β 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.

Highlights

Rhabdomyosarcoma (RMS) is a mesenchymal soft tissue tumor that causes death and morbidity predominantly in children and adolescents
We sought to identify different noncanonical action mechanisms of Previously, we showed that SNAIL is a key regulator of ARMS tumor growth and differentiation through functional repression of MYF5 and MYOD [9]
Our studies demonstrated that stromal-derived factor-1 (SDF-1) and hepatocyte growth factor (HGF), which may stimulate tumor cells to form metastases, increase the SNAIL level by inducing GSK3 phosphorylation via the PI3K-AKT pathway

Summary

Introduction

Rhabdomyosarcoma (RMS) is a mesenchymal soft tissue tumor that causes death and morbidity predominantly in children and adolescents. Despite general improvement in the 5-year overall survival of pediatric RMS patients, for high grade tumors with metastatic involvement, the overall survival rate at 3 years is only 25–30% [1]. Metastasis, what significantly diminishes survival of the patients and makes them more prone to disease relapse and progression [2]. Cancers 2020, 12, 1870 metastatic behavior of different tumor types, including RMS, are hepatocyte growth factor (HGF). Histological analysis of tumors distinguishes two main subtypes of RMS, embryonal (ERMS). Among the critical regulators of RMS metastasis is the EZRIN protein, which acts as the actin filament-plasma membrane linker [8]

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Results

Conclusion