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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Treatment of Ewing's sarcoma using an antisense oligodeoxynucleotide to regulate the cell cycle
Satoru Asami1, Motoaki Chin, Hiroyuki Shichino
1Research Unit of Clinical Medicine, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
Abstract:
Ewing's sarcoma (ES) is one of the most malignant tumors of bone and soft tissue in children and young adults. ES belongs to a group of small round cell tumors (SRCTs) that also includes neuroblastoma, rhabdomyosarcoma, and malignant lymphoma. However, ES exhibits several specific chimeric genes (EWS-FLI1, EWS-ERG, EWS-ETV1, EWS-E1AF, and EWS-FEV) caused by chromosomal translocations that are not shared by other SRCTs. These chimeric genes regulate the expression of various other genes; that is, they activate inhibitors of DNA binding 2 (Id2) gene expression or they suppress transforming growth factor beta II (TbetaRII) receptor gene expression. The regulation of these chimeric genes may affect critical cell signal transductions, such as signals involved in cell cycle and apoptosis in ES tumor cells. Using an antisense oligodeoxynucleotide against a sequence containing the ATG initiation codon of the EWS-FLI1 chimeric gene that specifically reacts with the EWS-FLI1 and EWS-ERG chimeric genes, we were able to regulate the cell cycle through the down-regulation of Id2. Here, we report that treatment with an antisense oligodeoxynucleotide against this chimeric gene was very useful for inducing the regression of ES tumor growth; thus, this chimeric gene may be an important target for the treatment of ES patients.
Insights
Ewing sarcoma (ES) is a rare bone cancer. Targeting the EWS-FLI1 gene with antisense oligodeoxynucleotides effectively reduced tumor growth by regulating cell cycle and apoptosis, offering a potential new treatment strategy for ES.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ewing sarcoma (ES) is a highly malignant bone and soft tissue tumor affecting children and young adults.
- ES is a small round cell tumor (SRCT) characterized by specific chimeric genes, such as EWS-FLI1, resulting from chromosomal translocations.
- These chimeric genes influence critical cellular pathways, including cell cycle regulation and apoptosis.
Purpose of the Study:
- To investigate the therapeutic potential of targeting EWS-FLI1 chimeric genes in Ewing sarcoma.
- To explore the mechanism by which antisense oligodeoxynucleotides affect ES tumor growth.
Main Methods:
- Utilized an antisense oligodeoxynucleotide designed to target the ATG initiation codon of the EWS-FLI1 chimeric gene.
- Investigated the effect of the antisense oligodeoxynucleotide on Id2 gene expression and cell cycle regulation.
- Assessed the impact of the treatment on ES tumor growth in a relevant model.
Main Results:
- The antisense oligodeoxynucleotide specifically targeted EWS-FLI1 and EWS-ERG chimeric genes.
- Treatment led to the down-regulation of Id2 gene expression, influencing cell cycle regulation.
- Demonstrated significant regression of Ewing sarcoma tumor growth following treatment.
Conclusions:
- The EWS-FLI1 chimeric gene is a critical driver of Ewing sarcoma.
- Antisense oligodeoxynucleotide therapy targeting EWS-FLI1 shows promise for inducing tumor regression.
- This therapeutic strategy represents a potential new avenue for treating Ewing sarcoma patients.
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