Abstract
Ewing Sarcoma is an aggressive, oncofusion-driven, malignant neoplasm of bone and soft tissue affecting predominantly children and young adults. Seeking to identify potential novel therapeutic targets/agents for this disease, our previous studies uncovered microRNAs regulated by EWS/Fli1, the most common oncofusion, with growth modulatory properties. In the present study, we sought to identify EWS/Fli1-repressed, growth suppressive, microRNAs potentially amenable to replacement in Ewing Sarcoma cells. Eight microRNAs (143, 153, 184, 193b, 195, 203, 206 and 223) were selected for evaluation as EWS/Fli1-repressed and underexpressed in Ewing Sarcoma cells, and reported to be growth suppressive in other pediatric or/and adult cancers. The selected miRs, and appropriate non-targeting controls, were introduced into two different Ewing Sarcoma cell lines (A673 and SK-ES-1), and effects on growth were examined using a high and low-density growth assay. MiR-193b was growth inhibitory in both assays and cell lines. In subsequent analyses, we found that stable overexpression of miR-193b also inhibits anchorage-independent growth in both A673 and SK-ES-1 cells. We further show that miR-193b negatively regulates expression of the ErbB4 oncogene in A673 and SK-ES-1 cells, and that depletion of ErbB4 is itself inhibitory to anchorage-independent growth in the same cell lines. Together, our studies show that the EWS/Fli1-repressed miR-193b is growth suppressive in Ewing Sarcoma, and identify ErbB4 as a target gene and candidate mediator of this growth suppression.
Highlights
Ewing Sarcoma is a cancer of bone and soft tissue predominantly affecting the pediatric age group [1]
We were intrigued by EWS/Fli1-repressed, anti-oncogenic miRs, as such miRs could conceivably be introduced into Ewing Sarcoma cells to inhibit cancer phenotypes
We selected miRs that met two or more of the following three criteria: 1) miRs shown to have predominantly or exclusively anti-oncogenic effects in other cancers; 2) miRs with target profiles relevant to Ewing Sarcoma oncogenesis; and 3) miRs expressed at relatively low levels in Ewing Sarcoma cells
Summary
Ewing Sarcoma is a cancer of bone and soft tissue predominantly affecting the pediatric age group [1]. It is an aggressive malignancy with frequently poor outcomes, especially in patients presenting with metastatic disease or relapse [1]. The pathogenesis of Ewing Sarcoma is driven by EWS/Ets fusion oncoproteins, which arise as a consequence of recurrent chromosomal translocations [2]. MicroRNAs in Ewing Sarcoma (PJ), and the University of Colorado Cancer Center and School of Medicine (PJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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