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ATPase copper transporter A, negatively regulated by miR-148a-3p, contributes to cisplatin resistance in breast cancer cells.

ABSTRACT: BACKGROUND:Breast cancer is the leading cause of death among women. Cisplatin is an effective drug for breast cancer, but resistance often develops during long term chemotherapy. While the mechanism of chemotherapy resistance is still not fully understood. METHODS:Survival analyses of ATP7A and ATP7B were used to evaluate their effects on the development of Breast invasive carcinoma (BRCA). Immunostaining, flow cytometry, and IC50 assay were utilized to examine the effects of ATP7A-siRNA combined with cisplatin on apoptosis in breast cancer cells. Q-PCR, western blotting, and dual-luciferase assay were employed to confirm ATP7A is a novel target gene of miR-148a-3p. RESULTS:In this current study, we identified knocking-down ATP7A could enhance cytotoxicity treatment of cisplatin in breast cancer cells. We also demonstrated miR-148a-3p overexpression in BRCA cells increased the sensitivity to cisplatin, and subsequently enhanced DNA damage and apoptosis. Moreover, we found ATP7A is a novel target gene of miR-148a-3p. In brief, our results showed miR-148a could accelerate chemotherapy induced-apoptosis in breast cancer cells by inhibiting ATP7A expression. CONCLUSIONS:Our results highlight that inhibition of ATP7A is a potential strategy for targeting breast cancer resistant to cisplatin, and we provided an interesting method to compare the involvement of various genes in the assessment of cisplatin resistance.

SUBMITTER: Yu Z

PROVIDER: S-EPMC7240853 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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ATPase copper transporter A, negatively regulated by miR-148a-3p, contributes to cisplatin resistance in breast cancer cells.

Yu Ze Z Cao Weifan W Ren Yuan Y Zhang Qijia Q Liu Jia J

Clinical and translational medicine 20200101 1

<h4>Background</h4>Breast cancer is the leading cause of death among women. Cisplatin is an effective drug for breast cancer, but resistance often develops during long term chemotherapy. While the mechanism of chemotherapy resistance is still not fully understood.<h4>Methods</h4>Survival analyses of ATP7A and ATP7B were used to evaluate their effects on the development of Breast invasive carcinoma (BRCA). Immunostaining, flow cytometry, and IC50 assay were utilized to examine the effects of ATP7 ...[more]

PMID: 32508020

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Project description:Atherosclerosis (AS) seriously affects human health. The role of microRNAs (miRNAs) in the pathogenesis and progression of AS has become a focus of research. Our goal was to identify the biological effect of differentially expressed miRNAs (DE-miRNAs) in AS. To analyze differentially expressed genes (DEGs), including differentially expressed mRNAs (DE-mRNAs) and DE-miRNAs, in AS by using the Gene Expression Omnibus (GEO) database and limma package. DEGs protein-protein interaction (PPI) network and functional enrichment analysis were constructed by using the search tool for the retrieval of interacting genes/proteins (STRING) database, Cytoscape software and Cytoscape plugin "ClueGO2.5.6". We established a coexpression network of dysregulated miRNAs and mRNAs to predict the function of miRNAs by using miRWalk database and Pearson correlation coefficient (PCC) analysis. Cellular experiments were used to validate the results of bioinformatics. First, 69 common DEGs were obtained from datasets GSE43292 and GSE97210 using the limma package in R. Next, a DEG PPI network was constructed. Functional enrichment analysis of DEGs showed that 11 functional pathways were significantly enriched, such as positive regulation of monocyte chemotaxis. Seven common DE-miRNAs were obtained from the GSE99685 dataset and DE-mRNAs predicted miRNAs through the miRWalk database. The miRNA-mRNA network constructed using Cytoscape software suggested that miR-148a-3p targeted contactin 4 (CNTN4). Quantitative real-time polymerase chain reaction (qRT-PCR) assay results indicated that miR-148a-3p was downregulated and CNTN4 was upregulated in the THP-1 + phorbol 12-myristate 13-acetate (PMA) + oxidized low-density lipoprotein (oxLDL) group compared with the THP-1 + PMA group. qRT-PCR, flow cytometry, and enzyme-linked immunosorbent assay (ELISA) found that upregulated miR-148a-3p significantly inhibited the expression of CNTN4, cell apoptosis, and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) concentrations in oxLDL-induced THP-1 macrophages. In addition, a dual-luciferase reporter assay demonstrated that CNTN4 was a target gene of miR-148a-3p. Overall, these findings suggested that miR-148a-3p inhibited oxLDL-induced cell apoptosis and inflammation via targeting CNTN4 in THP-1 macrophages.

Dataset Information

ATPase copper transporter A, negatively regulated by miR-148a-3p, contributes to cisplatin resistance in breast cancer cells.

Publications

ATPase copper transporter A, negatively regulated by miR-148a-3p, contributes to cisplatin resistance in breast cancer cells.

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