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MiR-18a upregulation decreases Dicer expression and confers paclitaxel resistance in triple negative breast cancer
1Department of Pharmacy, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. Huizhange@outlook.com.
Objective:
MiR-18a is a miRNA that is aberrantly overexpressed in triple-negative breast cancer (TNBC). However, its biophysical function in TNBC is still not clear. In this study, we investigated the association among miR-18a dysregulation, Dicer dysregulation and paclitaxel (PTX) resistance in TNBC cells.
Patients And Methods:
20 TNBC patients who received neoadjuvant chemotherapy before surgery were recruited. MiR-18a expression was quantified using QRT-PCR. The effects of miR-18a overexpression or knockdown on cell viability and apoptosis of PTX sensitive MDA-MB-231 cells and PTX resistant MDA-MB-231 cells after PTX treatment were studied. The influence of miR-18a overexpression on Dicer expression was measured by qRT-PCR and Western blot analysis.
Results:
Tissues from patients with stable disease (SD, n = 5) and progressive disease (PD, n = 2) to paclitaxel (PTX) containing neoadjuvant chemotherapy had significantly higher miR-18a expression than that from patients with partial response (PR, n = 13). MDA-MB-231/PTX cells had higher miR-18a expression than MDA-MB-231 cells. MiR-18a overexpression directly led to Dicer repression at mRNA and protein level. MiR-18a overexpression significantly increased PTX IC50 and reduced PTX induced cell apoptosis, while miR-18a suppression substantially decreased PTX IC50 and increased PTX induced cell apoptosis.
Conclusions:
This study found that miR-18a is an important miRNA that suppresses Dicer expression and increases PTX resistance in TNBC cells.
Insights
MicroRNA-18a (miR-18a) overexpression in triple-negative breast cancer (TNBC) suppresses Dicer and increases paclitaxel resistance. Suppressing miR-18a enhances chemotherapy sensitivity in TNBC cells.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Triple-negative breast cancer (TNBC) exhibits aberrant microRNA (miRNA) expression.
- The specific role of miR-18a in TNBC biophysical function and its association with chemotherapy resistance remain unclear.
Purpose of the Study:
- To investigate the relationship between miR-18a dysregulation, Dicer expression, and paclitaxel (PTX) resistance in TNBC cells.
- To elucidate the functional impact of miR-18a on chemotherapy response in TNBC.
Main Methods:
- Quantitative real-time PCR (QRT-PCR) and Western blot analysis were used to quantify miR-18a and Dicer expression.
- miR-18a overexpression and knockdown experiments were performed in PTX-sensitive and PTX-resistant MDA-MB-231 TNBC cell lines.
- Cell viability, apoptosis, and PTX IC50 were assessed following PTX treatment.
Main Results:
- Higher miR-18a expression was observed in TNBC patient tissues with progressive disease compared to partial response.
- MDA-MB-231/PTX cells showed elevated miR-18a levels compared to sensitive cells.
- miR-18a overexpression led to Dicer repression and significantly increased PTX resistance (higher IC50, reduced apoptosis).
- Conversely, miR-18a suppression decreased PTX resistance and enhanced apoptosis.
Conclusions:
- miR-18a plays a crucial role in promoting paclitaxel resistance in TNBC by suppressing Dicer expression.
- Targeting miR-18a may represent a therapeutic strategy to overcome chemotherapy resistance in TNBC.
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