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A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate
Published on: May 3, 2021
Doxorubicin inhibits osteosarcoma progression by regulating circ_0000006/miR-646/ BDNF axis
Abulimiti Amuti1, Dehu Liu2, Ayiguli Maimaiti1
1Department of Orthopaedics, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Background:
Osteosarcoma (OS) is the most common aggressive bone tumor in children and teenagers. Doxorubicin (DOX) is a chemotherapeutic drug for OS. This study aims to reveal the effects and underneath mechanism of DOX treatment in OS progression.
Methods:
The expression of circular_0000006 (circ_0000006), microRNA-646 (miR-646) and brain-derived neurotrophic factor (BDNF) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). BDNF protein expression was determined by western blot. Cell proliferation was illustrated by cell counting kit-8 (CCK-8) and cell colony formation assays. Cell migration and invasion were revealed by transwell migration and wound-healing assays and transwell invasion assay, respectively. Cell apoptosis was demonstrated by flow cytometry analysis. The binding relationship of miR-646 and circ_0000006 or BDNF was predicted by circRNA interactome and targetscan online database, respectively, and verified by dual-luciferase reporter assay. The effects of circ_0000006 knockdown on tumor growth in vivo were manifested by in vivo tumor formation assay.
Results:
Circ_0000006 expression and the mRNA and protein levels of BDNF were dramatically upregulated, and miR-646 expression was effectively downregulated in OS tissues or cells compared with control groups. Circ_0000006 expression and BDNF protein expression were lower, and miR-646 expression was higher in DOX treatment groups than in control groups in OS cells. Circ_0000006 knockdown repressed cell proliferation, migration and invasion, whereas promoted cell apoptosis under DOX treatment in OS cells; however, these effects were attenuated by miR-646 inhibitor. Additionally, circ_0000006 sponged miR-646 to bind to BDNF. Circ_0000006 silencing suppressed tumor growth in vivo.
Conclusion:
Circ_0000006 knockdown promoted DOX-mediated effects on OS development by miR-646/BDNF pathway, which provided a theoretical basis in treating OS with DOX.
Insights
This study reveals that targeting circular RNA (circ_0000006) enhances doxorubicin (DOX) chemotherapy effectiveness in osteosarcoma (OS). Knocking down circ_0000006 boosts DOX
Area of Science:
- Molecular oncology
- Cancer biology
- Biochemistry
Background:
- Osteosarcoma (OS) is a prevalent and aggressive bone tumor in pediatric and adolescent populations.
- Doxorubicin (DOX) is a cornerstone chemotherapeutic agent used in OS treatment.
- Understanding the molecular mechanisms underlying DOX efficacy is crucial for improving OS therapy.
Purpose of the Study:
- To investigate the role of circular RNA (circ_0000006) in osteosarcoma (OS) progression.
- To elucidate the underlying mechanism of doxorubicin (DOX) treatment in OS.
- To explore the potential of targeting circ_0000006 to enhance DOX chemotherapy in OS.
Main Methods:
- Quantitative real-time PCR (qRT-PCR) and Western blot were used to measure gene and protein expression.
- Cell proliferation, migration, invasion, and apoptosis assays were performed to assess cellular functions.
- Dual-luciferase reporter assays and bioinformatics tools were employed to determine molecular interactions.
Main Results:
- Circ_0000006 and brain-derived neurotrophic factor (BDNF) were upregulated, while microRNA-646 (miR-646) was downregulated in OS tissues.
- DOX treatment decreased circ_0000006 and BDNF expression but increased miR-646 expression in OS cells.
- Knockdown of circ_0000006 enhanced DOX effects by inhibiting proliferation, migration, and invasion, and promoting apoptosis, via the miR-646/BDNF pathway.
Conclusions:
- Circ_0000006 knockdown potentiates doxorubicin (DOX)-induced anti-tumor effects in osteosarcoma (OS) through the miR-646/BDNF axis.
- This study provides a theoretical foundation for utilizing circ_0000006 as a therapeutic target to improve DOX treatment outcomes in OS.
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