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MicroRNA-340-5p modulates cisplatin resistance by targeting LPAATβ in osteosarcoma
1Department of Orthopedics, First Affiliated Hospital, Third Military Medical University, Chongqing, China.
Abstract:
MicroRNAs (miRNAs) play an important role in drug resistance and modulate the efficiency of chemotherapy. A recent study indicated that miR-340 functions as a tumor suppressor in various types of cancer. However, the role of miR-340 in chemotherapy has not been reported yet. In this study, we found that miR-340 enhanced cisplatin (CDDP)-induced cell death. Induction of miR-340-5p expression decreased the IC50 of CDDP and increased the apoptosis of CDDP-resistant MG-63 and Saos-2 cells. Moreover, miR-340-5p decreased the accumulation of MRP1 and MDR1. We further explored the mechanism underlying the promoting effects of miR-340-5p on CDDP-induced cell death. We identified a potential target of miR-340 in the 3' untranslated region of lysophosphatidic acid acyltransferase (LPAATβ) using the online program Targetscan (http://www.microrna.org). Luciferase reporter assays showed that miR-340 binds to the 3'UTR of LPAATβ. Enforced expression of miR-340-5p decreased the accumulation of LPAATβ in both MG-63 and Saos-2 cells. Silencing LPAATβ decreased the IC50 of CDDP and increased the apoptosis of CDDP-resistant MG-63 and Saos-2 cells, which is consistent with the effect of miR-340-5p on CDDP-induced cell death. Moreover, induced expression of LPAATβ compromised the effects of miR-340-5p on CDDP-induced cell death and accumulation of MRP1 and MDR1. Taken together, our data indicated that miR-340-5p enhanced the sensitivity to CDDP by targeting LPAATβ.
Insights
MicroRNA-340 enhances chemotherapy effectiveness by increasing cisplatin-induced cell death in drug-resistant cancer cells. It targets lysophosphatidic acid acyltransferase beta (LPAATβ), reducing chemoresistance markers and promoting apoptosis.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- MicroRNAs (miRNAs) are key regulators of gene expression impacting chemotherapy efficacy.
- miR-340 is recognized as a tumor suppressor, but its role in chemotherapy resistance is unexplored.
- Chemotherapy resistance, particularly to cisplatin (CDDP), remains a significant clinical challenge.
Purpose of the Study:
- To investigate the role of miR-340 in modulating chemoresistance to cisplatin.
- To elucidate the underlying molecular mechanisms of miR-340's action in CDDP-resistant cancer cells.
- To identify potential therapeutic targets for overcoming cisplatin resistance.
Main Methods:
- Assessing the impact of miR-340-5p induction on cisplatin sensitivity (IC50) and apoptosis in MG-63 and Saos-2 cells.
- Quantifying the expression levels of multidrug resistance proteins (MRP1 and MDR1) and lysophosphatidic acid acyltransferase beta (LPAATβ).
- Utilizing bioinformatics (Targetscan), luciferase reporter assays, and gene silencing/overexpression techniques to validate target interactions and functional effects.
Main Results:
- miR-340-5p induction significantly decreased cisplatin's IC50 and enhanced apoptosis in CDDP-resistant cells.
- miR-340-5p suppressed the accumulation of MRP1 and MDR1, key drug efflux pumps.
- LPAATβ was identified and validated as a direct target of miR-340-5p, with its downregulation mimicking miR-340-5p's chemosensitizing effects.
Conclusions:
- miR-340-5p functions as a potent sensitizer to cisplatin chemotherapy.
- The mechanism involves the downregulation of LPAATβ, leading to reduced expression of MRP1/MDR1 and increased apoptosis.
- Targeting the miR-340-5p/LPAATβ axis presents a promising strategy to overcome cisplatin resistance in cancer therapy.
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