Abstract
Rhabdomyosarcoma is a highly aggressive malignant cancer that arises from skeletal muscle progenitor cells and is the third most common solid tumour in children. Despite significant advances, rhabdomyosarcoma still presents a therapeutic challenge, and while targeted therapy has shown promise, there are limited options because the molecular drivers of rhabdomyosarcoma are poorly understood. We previously reported that the T-box transcription factor 3 (TBX3), which has been identified as a druggable target in many cancers, is overexpressed in rhabdomyosarcoma patient samples and cell lines. To identify new molecular therapeutic targets to treat rhabdomyosarcoma, this study investigates the potential oncogenic role(s) for TBX3 and the factors responsible for upregulating it in this cancer. To this end, rhabdomyosarcoma cell culture models in which TBX3 was either stably knocked down or overexpressed were established and the impact on key hallmarks of cancer were examined using growth curves, soft agar and scratch motility assays, as well as tumour-forming ability in nude mice. Our data show that TBX3 promotes substrate-dependent and -independent proliferation, migration and tumour formation. We further reveal that TBX3 is upregulated by c-Myc transcriptionally and AKT1 post-translationally. This study identifies c-Myc/AKT1/TBX3 as an important axis that could be targeted for the treatment of rhabdomyosarcoma.
Highlights
Rhabdomyosarcoma (RMS), an aggressive and highly malignant cancer of the skeletal muscle, is the most common soft tissue sarcoma in children and adolescents and it is the third most prevalent extracranial solid childhood tumour after neuroblastoma and Wilms tumour [1,2,3]
To determine whether TBX3 overexpression is a common feature of RMS cells, the status of TBX3 was determined in Embryonal rhabdomyosarcoma (ERMS) (RD and FLOH-1) and ARMS (RH30 and AXOH-1) cell lines
ERMS cell culture models in which TBX3 was either stably overexpressed or knocked down in the RD cell line. mRNA and protein from (B) RD Flag-Empty, Flag-Tbx3 or Flag-Tbx3+2a cell lines and (C) RD shCTRL and sequence that targets TBX3 (shTBX3) clones were subjected to Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) with primers specific to TBX3 and GUSB and mRNA levels were normalised to GUSB and Western blotting with antibodies to (B) Flag-tag and (C) TBX3 and p38 was used as a loading control
Summary
Rhabdomyosarcoma (RMS), an aggressive and highly malignant cancer of the skeletal muscle, is the most common soft tissue sarcoma in children and adolescents and it is the third most prevalent extracranial solid childhood tumour after neuroblastoma and Wilms tumour [1,2,3]. ERMS is characterized by genetic aberrations, such as loss of heterozygosity at chromosome 11p15, a region that harbours insulin growth factor (IGF) 2, or gains at chromosomes 2, 8, 12 and 13 [4,5,6,7]. Both RMS subtypes express myogenic regulatory factors, such as MyoD and myogenin, and it has been postulated that RMS arises from a myogenic precursor cell that failed to correctly and completely differentiate into muscle cells. RMS tumours can originate in non-muscle sites, and their aetiology is under debate [8].
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