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Induction of Mesenchymal-Epithelial Transitions in Sarcoma Cells
Published on: April 7, 2017
MiR-193b, downregulated in Ewing Sarcoma, targets the ErbB4 oncogene to inhibit anchorage-independent growth
Colin Moore1, Janet K Parrish2, Paul Jedlicka2
1Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado, United States of America.
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.
Insights
Researchers identified microRNA-193b (miR-193b) as a growth-suppressive factor in Ewing sarcoma. This microRNA targets the ErbB4 oncogene, offering a potential new therapeutic strategy for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ewing sarcoma is an aggressive cancer driven by oncofusions, primarily affecting young individuals.
- Previous research identified microRNAs regulated by the EWS/Fli1 oncofusion with growth-modulatory roles.
- Novel therapeutic targets are needed for Ewing sarcoma treatment.
Purpose of the Study:
- To identify microRNAs repressed by EWS/Fli1 that suppress Ewing sarcoma cell growth.
- To evaluate the therapeutic potential of replacing these microRNAs in cancer cells.
Main Methods:
- Eight candidate microRNAs, including miR-193b, were selected based on EWS/Fli1 repression and growth-suppressive roles in other cancers.
- MicroRNAs were introduced into Ewing sarcoma cell lines (A673, SK-ES-1) to assess growth inhibition.
- Gene expression analysis was performed to identify miR-193b targets, focusing on ErbB4.
Main Results:
- miR-193b significantly inhibited proliferation in both high and low-density growth assays across two Ewing sarcoma cell lines.
- Overexpression of miR-193b suppressed anchorage-independent growth.
- miR-193b was found to negatively regulate ErbB4 oncogene expression, and ErbB4 depletion also inhibited anchorage-independent growth.
Conclusions:
- The EWS/Fli1-repressed miR-193b acts as a tumor suppressor in Ewing sarcoma.
- ErbB4 is identified as a direct target of miR-193b and a potential mediator of its growth-suppressive effects.
- miR-193b represents a promising candidate for novel therapeutic strategies against Ewing sarcoma.
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