Abstract
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.
Highlights
Rhabdomyosarcoma (RMS) is a pediatric tumor that expresses several muscle-specific proteins with poor terminal differentiation
We showed that miR-203 exerts its tumor-suppressor functions in RMS cells by directly targeting p63 and the leukemia inhibitory factor receptor gene (LIFR), which promotes myogenic differentiation of RMS cells by inhibiting the Notch pathway and the JAK1/STAT1 pathway, respectively
Cells derived from hepatocarcinoma (i.e. HepG2 and SMMC-7721) and prostate cancers (i.e. PC3 and DU145) expressed a very low level of miR-203, cells derived from lung cancer (i.e. A549 and H1299) and colon cancer (i.e. SW480, Lovo, and HCT116) expressed miR-203 at a higher level compared with normal human muscle tissues (Fig. 1A), which was consistent with published reports (36 – 40)
Summary
Rhabdomyosarcoma (RMS) is a pediatric tumor that expresses several muscle-specific proteins with poor terminal differentiation. Results: miR-203 was frequently down-regulated in RMS, and its re-expression in RMS cells inhibited their growth and migration and promoted terminal differentiation. 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 ␣-actin. Re-expression of miR-203 in RMS cells inhibited their migration and proliferation and promoted terminal myogenic differentiation. 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. We showed that miR-203 exerts its tumor-suppressor functions in RMS cells by directly targeting p63 and the leukemia inhibitory factor receptor gene (LIFR), which promotes myogenic differentiation of RMS cells by inhibiting the Notch pathway and the JAK1/STAT1 pathway, respectively
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