Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and show characteristics of skeletal muscle differentiation. The two major RMS subtypes in children are alveolar (ARMS) and embryonal RMS (ERMS). We demonstrate that approximately 50% of ARMS and ERMS overexpress the LEF1/TCF transcription factor LEF1 when compared to normal skeletal muscle and that LEF1 can restrain aggressiveness especially of ARMS cells. LEF1 knockdown experiments in cell lines reveal that depending on the cellular context, LEF1 can induce pro-apoptotic signals. LEF1 can also suppress proliferation, migration and invasiveness of RMS cells both in vitro and in vivo. Furthermore, LEF1 can induce myodifferentiation of the tumor cells. This may involve regulation of other LEF1/TCF factors i.e. TCF1, whereas β-catenin activity plays a subordinate role. Together these data suggest that LEF1 rather has tumor suppressive functions and attenuates aggressiveness in a subset of RMS.
Highlights
Rhabdomyosarcoma is an aggressive form of sarcoma that in the vast majority of cases occur in children younger than 18 years
We demonstrate that approximately 50% of alveolar RMS (ARMS) and embryonal RMS (ERMS) overexpress the LEF1/TCF transcription factor LEF1 when compared to normal skeletal muscle and that LEF1 can restrain aggressiveness especially of ARMS cells
Consistent but variable overexpression of LEF1 was seen on mRNA level in all fresh-frozen biopsies of our collection of 10 human ERMS and 10 human fusion-positive ARMS when compared to normal muscle (Figure 1A, lower right panel)
Summary
Rhabdomyosarcoma is an aggressive form of sarcoma that in the vast majority of cases occur in children younger than 18 years. Despite being a rare cancer, it accounts for approximately 40% of all soft tissue sarcomas in children [1, 2]. The two major subtypes in children are alveolar RMS (ARMS) and embryonal RMS (ERMS) showing different histological, genetic and clinical features. ERMS account for approximately two thirds of all RMS and are associated with a more favorable prognosis with a 5-year overall survival of approximately 73% compared to 48% for ARMS [1, 2, 5]. The survival rate for metastatic disease is only 40% for ERMS [6] and 10–30% for ARMS [7]. A better understanding of the molecular basis of this disease is important to improve current treatment schemes
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