Skrzypek Klaudia, Nieszporek Artur, Badyra Bogna, Lasota Małgorzata, Majka Marcin
Jagiellonian University Medical College, Faculty of Medicine, Institute of Pediatrics, Department of Transplantation, Wielicka 265, 30-663 Krakow, Poland.
Mol Ther Nucleic Acids. 2021 Apr 20;24:888-904. doi: 10.1016/j.omtn.2021.04.013. eCollection 2021 Jun 4.
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 . 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 . Simultaneous overexpression of both miRNAs diminished tumor growth after subcutaneous implantation and inhibited the engraftment of RMS cells into bone marrow after intravenous injection . To conclude, we discovered novel SNAIL-dependent miRNAs that may become new therapeutic targets in RMS in the future.
横纹肌肉瘤（RMS）是一种软组织间充质肿瘤，主要影响儿童和青少年。它起源于干细胞或早期祖细胞的肌源性分化受损。SNAIL是一种转录因子，可调节上皮起源肿瘤中的上皮-间充质转化，也是RMS生长、进展和肌源性分化的关键调节因子。在此，我们证明了SNAIL依赖性微小RNA（miRNA）miR-28-3p和miR-193a-5p是RMS生长、分化和进展的关键调节因子。miR-28-3p和miR-193a-5p减少增殖并使RMS细胞停滞在G0/G1期。它们通过上调肌源性因子诱导RMS细胞和人成肌细胞的肌源性分化。此外，miR-28-3p和miR-193a-5p在划痕试验中抑制迁移、抑制与内皮细胞的粘附、趋化作用以及对SDF-1和HGF的侵袭，并调节细胞的血管生成能力。miR-28-3p和miR-193a-5p的过表达在免疫缺陷小鼠的RMS异种移植中诱导纤维化结构和异常血管的形成。两种miRNA的同时过表达在皮下植入后减少肿瘤生长，并在静脉注射后抑制RMS细胞植入骨髓。总之，我们发现了新的SNAIL依赖性miRNA，它们未来可能成为RMS的新治疗靶点。
