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Published on: August 2, 2024
MiR-27a modulates MDR1/P-glycoprotein expression by targeting HIPK2 in human ovarian cancer cells
1Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Objective:
MicroRNAs (miRNAs) are non-coding, single-stranded small RNAs that regulate gene expression negatively, which is involved in fundamental cellular processes and the initiation, development and progression of human cancer. In this study, we investigated the role of miR-27a in the development of drug resistance in ovarian cancer cells.
Methods:
Expression of miR-27a in ovarian cancer cell lines A2780 and A2780/Taxol were detected by stem-loop real-time PCR. A2780 and A2780/Taxol cells were transfected with the mimics or inhibitors of miR-27a or negative control RNA (NC) by Lipofectamine 2000. The expression levels of MDR1 mRNA, P-glycoprotein (P-gp) and Homeodomain-interacting protein kinase-2 (HIPK2) proteins were assessed by real-time PCR and western blot respectively. Drug sensitivity was analyzed by MTT assay while apoptosis and the fluorescence intensity of intracellular Rhodamine 123 (Rh-123) were measured by FACS.
Results:
The expression levels of miR-27a and P-gp were up-regulated in paclitaxel-resistant ovarian cancer cell line A2780/Taxol as compared with its parental line A2780. Transfection of A2780/Taxol cells with the inhibitors of miR-27a decreased the expression of MDR1 mRNA and P-gp protein, increased HIPK2 protein expression, enhanced the sensitivity of A2780/taxol cells to paclitaxel, increased paclitaxel-induced apoptosis and the fluorescence intensity of intracellular Rh-123. Expression of MDR1 mRNA was increased while the sensitivity to paclitaxel was decreased in A2780 cells management with the mimics of miR-27a.
Conclusions:
The deregulation of miR-27a may be involved in the development of drug resistance, regulating the expression of MDR1/P-gp, at least in part, by targeting HIPK2 in ovarian cancer cells.
Insights
MicroRNA 27a (miR-27a) plays a role in ovarian cancer drug resistance. Inhibiting miR-27a in paclitaxel-resistant cells restores sensitivity by targeting MDR1/P-gp and HIPK2.
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- MicroRNAs (miRNAs) are key regulators of gene expression implicated in cancer development.
- Drug resistance remains a significant challenge in ovarian cancer treatment.
Purpose of the Study:
- To investigate the role of miR-27a in the development of drug resistance in ovarian cancer cells.
- To elucidate the molecular mechanisms underlying miR-27a's function in chemoresistance.
Main Methods:
- Real-time PCR and Western blot to assess gene and protein expression.
- Cell viability (MTT assay), apoptosis, and drug uptake (FACS) assays were performed.
- Ovarian cancer cell lines (A2780 and A2780/Taxol) were transfected with miR-27a mimics or inhibitors.
Main Results:
- miR-27a and P-glycoprotein (P-gp) were upregulated in paclitaxel-resistant cells.
- Inhibiting miR-27a decreased MDR1 mRNA and P-gp, increased HIPK2, enhanced paclitaxel sensitivity, and promoted apoptosis.
- miR-27a mimics increased MDR1 mRNA and decreased paclitaxel sensitivity in parental cells.
Conclusions:
- miR-27a deregulation contributes to drug resistance in ovarian cancer.
- miR-27a regulates MDR1/P-gp expression, potentially by targeting HIPK2.
- Targeting miR-27a may offer a therapeutic strategy to overcome chemoresistance in ovarian cancer.
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