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miR-1293 suppresses osteosarcoma progression by modulating drug sensitivity in response to cisplatin treatment
Tingxuan Wang1, Jincheng Huang2, Gang Chen3
1Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510005, China.
Abstract:
Chemotherapy is considered the primary treatment for osteosarcoma. however, its effectiveness is limited due to drug resistance and toxicity. Thus, identifying novel therapeutic targets to enhance the efficacy of chemotherapy is urgently needed. Here, we identified a novel cisplatin-sensitivity enhancing mechanism via up-regulation of the tumour suppressor gene, miR-1293. Meanwhile, higher levels of miR-1293 observed in prechemotherapy patients were associated with a more favorable prognosis. The mechanism underlying cisplatin upregulated miR-1293 expression involves hypomethylation of the miR-1293 promoter, which blocks the binding of the transcription repressor TFAP2A to the promoter. Furthermore, miR-1293 inhibits osteosarcoma progression by targeting TIMP1 to inactivate the Notch1/Hes1 and TGFBR1/Smad2/3 pathways, thereby promoting tumour cell death. The findings presented herein unveil a novel mechanism for enhancing cisplatin sensitivity and proposed a potential therapeutic strategy for osteosarcoma through pre-chemotherapy supplementation of miR-1293.
Insights
This study reveals that increasing miR-1293 levels enhances chemotherapy effectiveness in osteosarcoma. Higher miR-1293 in patients predicts better outcomes, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chemotherapy is the primary osteosarcoma treatment, but drug resistance and toxicity limit its efficacy.
- Novel therapeutic targets are crucial to improve chemotherapy outcomes in osteosarcoma patients.
Purpose of the Study:
- To identify novel mechanisms that enhance cisplatin sensitivity in osteosarcoma.
- To investigate the role of miR-1293 as a potential therapeutic target for osteosarcoma.
Main Methods:
- Analysis of miR-1293 expression levels in osteosarcoma patients.
- Investigation of the molecular mechanisms underlying miR-1293 regulation by cisplatin.
- Validation of miR-1293's function in inhibiting osteosarcoma progression in vitro and in vivo.
Main Results:
- Upregulation of the tumor suppressor miR-1293 enhances cisplatin sensitivity in osteosarcoma.
- Higher pre-chemotherapy miR-1293 levels correlate with favorable patient prognosis.
- miR-1293 targets TIMP1, inactivating Notch1/Hes1 and TGFBR1/Smad2/3 pathways to promote tumor cell death.
Conclusions:
- miR-1293 represents a novel mechanism for enhancing cisplatin sensitivity in osteosarcoma.
- Pre-chemotherapy miR-1293 supplementation is a potential therapeutic strategy for osteosarcoma.
- miR-1293 serves as a promising biomarker for predicting osteosarcoma treatment response.
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