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

摘要

Rhabdomyosarcoma (RMS) is a soft tissue mesenchymal tumor that affects mostly children and adolescents. It originates from the impaired myogenic differentiation of stem cells or early progenitors. SNAIL, a transcription factor that regulates epithelial-to-mesenchymal transition in tumors of epithelial origin, is also a key regulator of RMS growth, progression, and myogenic differentiation. Here, we demonstrate that the SNAIL-dependent microRNAs (miRNAs) miR-28-3p and miR-193a-5p are crucial regulators of RMS growth, differentiation, and progression. miR-28-3p and miR-193a-5p diminished proliferation and arrested RMS cells in G0/G1 phase in vitro. They induced the myogenic differentiation of both RMS cells and human myoblasts by upregulating myogenic factors. Furthermore, miR-28-3p and miR-193a-5p inhibited migration in a scratch assay, adhesion to endothelial cells, chemotaxis, and invasion toward SDF-1 and HGF and regulated angiogenic capabilities of the cells. Overexpression of miR-28-3p and miR-193a-5p induced formation of fibrotic structures and abnormal blood vessels in RMS xenografts in immunodeficient mice in vivo. Simultaneous overexpression of both miRNAs diminished tumor growth after subcutaneous implantation and inhibited the engraftment of RMS cells into bone marrow after intravenous injection in vivo. To conclude, we discovered novel SNAIL-dependent miRNAs that may become new therapeutic targets in RMS in the future.