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MicroRNA-765 sensitizes osteosarcoma cells to cisplatin via downregulating APE1 expression
Wei Liang1,2, Chongyi Li1, Mengxia Li1
1Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, People's Republic of China.
Objectives:
Osteosarcoma (OS) is the most common bone cancer diagnosed in children and adolescents. Expression of APE1 is commonly increased in OS, and this is negatively correlated with a sensitivity to platinum and a favorable prognosis. However, the mechanism underlying high APE1 expression in OS is not fully understood.
Methods:
A bioinformatics analysis of the APE1 3'-UTR combined with previous microarray data was used to identify miRNAs that regulate APE1 expression. The effects of miR-765 on cisplatin (cDDP) sensitivity were estimated in OS cell lines (9901 and HOS) and BALB/c mice (n=4 per group). The relative expression and association between miR-765 and APE1 were assessed in a cohort of OS patients (n=43 in total) with Kaplan-Meier and Cox proportional hazards regression. All statistical tests were two-sided and p<0.05 was considered significant.
Results:
Bioinformatics analysis implied that miR-765 may target APE1. Luciferase assay and WB showed that miR-765 bound directly to the 3'-UTR of APE1 and downregulated APE1 expression in OS cells. Further experiments revealed that miR-765 sensitized OS cells to cisplatin and was associated with decreased DNA repair activity. In vivo analyses suggested the sensitivity of cisplatin in xenograft OS tissues was increased after injection with miR-765 agomir. The clinical data showed a negative correlation between miR-765 and APE1 expression (r=0.307, p=0.045). Log-rank test revealed that OS patients with positive expression of miR-765 obtained a significantly longer survival than those with negative expression (22.0 vs. 9.0 months, p=0.001), which is just the opposite with respect to APE1 expression (12.00 vs. 22.00 months, p=0.039). The Cox regression analysis found miR-765 may be an independent prognostic factor for OS survival (p=0.007, HR=0.389, 95% CI: 0.196-0.772).
Conclusion:
miR-765 sensitizes OS cells to cisplatin and impedes DNA damage repair through the downregulation of APE1. High expression of miR-765 may benefit OS patient survival, making it a viable target for reversing cisplatin-induced resistance in OS patients.
Insights
MicroRNA-765 (miR-765) can increase osteosarcoma (OS) cells' sensitivity to cisplatin by downregulating APE1 expression and inhibiting DNA repair. Higher miR-765 levels correlate with better survival in OS patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Osteosarcoma (OS) is a prevalent bone cancer in children and adolescents.
- Elevated APE1 expression in OS correlates with reduced platinum sensitivity and poorer prognosis.
- The mechanisms driving high APE1 expression in OS remain unclear.
Purpose of the Study:
- To investigate the regulatory role of microRNAs (miRNAs) in APE1 expression within OS.
- To determine the impact of miR-765 on cisplatin sensitivity and DNA repair in OS.
- To assess the clinical significance of miR-765 and APE1 as prognostic markers in OS patients.
Main Methods:
- Bioinformatics analysis of APE1 3'-UTR to identify potential miRNA targets.
- Luciferase assays and Western blot to confirm miR-765 binding and APE1 downregulation.
- In vitro studies in OS cell lines and in vivo xenograft models to evaluate cisplatin sensitivity.
- Clinical data analysis of miR-765 and APE1 expression in OS patients (n=43) using Kaplan-Meier and Cox regression.
Main Results:
- miR-765 was identified as a direct regulator of APE1, downregulating its expression in OS cells.
- miR-765 enhanced OS cell sensitivity to cisplatin and reduced DNA repair activity.
- In vivo studies showed increased cisplatin sensitivity in OS xenografts treated with miR-765 agomir.
- Clinical data revealed a negative correlation between miR-765 and APE1 expression (p=0.045).
- High miR-765 expression was associated with significantly longer patient survival (22.0 vs. 9.0 months, p=0.001) and identified as an independent prognostic factor (p=0.007).
Conclusions:
- miR-765 sensitizes osteosarcoma cells to cisplatin by downregulating APE1 and impairing DNA damage repair.
- Elevated miR-765 expression is linked to improved survival in osteosarcoma patients.
- miR-765 represents a potential therapeutic target for overcoming cisplatin resistance in OS.
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