From the Biomedical Research Institute, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center, 518036 Shenzhen.
J Biol Chem. 2014 Jan 3;289(1):529-39. doi: 10.1074/jbc.M113.494716. Epub 2013 Nov 18.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma found in children and young adults. It is characterized by the expression of a number of skeletal muscle-specific proteins, including MyoD and muscle α-actin. However, unlike normal myoblasts, RMS cells differentiate poorly both in vivo and in culture. As microRNAs are known to regulate tumorigenesis, intensive efforts have been made to identify microRNAs that are involved in RMS development. In this work, we found that miR-203 was frequently down-regulated by promoter hypermethylation in both RMS cell lines and RMS biopsies and could be reactivated by DNA-demethylating agents. Re-expression of miR-203 in RMS cells inhibited their migration and proliferation and promoted terminal myogenic differentiation. Mechanistically, miR-203 exerts its tumor-suppressive effect by directly targeting p63 and leukemia inhibitory factor receptor in RMS cells, which promotes myogenic differentiation by inhibiting the Notch and the JAK1/STAT1/STAT3 pathways, respectively. Our work reveals that miR-203 functions as a tumor suppressor in RMS development.
横纹肌肉瘤 (RMS) 是儿童和青年中最常见的软组织肉瘤。它的特征是表达许多骨骼肌特异性蛋白，包括 MyoD 和肌肉α-肌动蛋白。然而，与正常成肌细胞不同，RMS 细胞在体内和体外分化能力都很差。由于 microRNA 已知可调节肿瘤发生，因此人们已经做出了巨大努力来鉴定参与 RMS 发育的 microRNA。在这项工作中，我们发现 miR-203 在 RMS 细胞系和 RMS 活检中经常因启动子过度甲基化而下调，并且可以被 DNA 去甲基化剂重新激活。在 RMS 细胞中重新表达 miR-203 可抑制其迁移和增殖，并促进终末成肌分化。从机制上讲，miR-203 通过直接靶向 RMS 细胞中的 p63 和白血病抑制因子受体发挥其肿瘤抑制作用，分别通过抑制 Notch 和 JAK1/STAT1/STAT3 通路来促进成肌分化。我们的工作表明，miR-203 在 RMS 发育中作为肿瘤抑制因子发挥作用。
