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LncRNA MCM3AP-AS1 promotes chemoresistance in triple-negative breast cancer through the miR-524-5p/RBM39 axis

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Abstract

Triple-negative breast cancer (TNBC) is the most lethal subtype of BC, with unfavorable treatment outcomes. Evidence suggests the engagement of lncRNA MCM3AP-AS1 in BC development. This study investigated the action of MCM3AP-AS1 in chemoresistance of TNBC cells. Drug-resistant TNBC cell lines SUM159PTR and MDA-MB-231R were constructed by exposure to increasing concentrations of doxorubicin/docetaxel (DOX/DXL). MCM3AP-AS1 and miR-524-5p expression levels were determined by RT-qPCR. RNA binding motif 39 (RBM39) level was measured using Western blot. Cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry. The targeted binding of miR-524-5p with MCM3AP-AS1 or RBM39 was predicted by ECORI database and validated by dual-luciferase assays. The gain-and-loss of function assays were conducted in cells to investigate the interactions among MCM3AP-AS1, miR-524-5p, and RBM39. TNBC xenograft mouse models were established through subcutaneous injection of MCM3AP-AS1-silencing MDA-MB-231R cells and intraperitoneally administrated with DOX/DXL to verify the role of MCM3AP-AS1 in vivo. MCM3AP-AS1 was upregulated in drug-resistant TNBC cells, and MCM3AP-AS1 silencing could sensitize drug-resistant TNBC cells to chemotherapeutic drugs by promoting apoptosis. MCM3AP-AS1 targeted miR-524-5p. After DOX/DXL treatment, miR-524-5p inhibition partially reversed the effect of MCM3AP-AS1 silencing on inhibiting chemoresistance and promoting apoptosis of drug-resistant TNBC cells. miR-524-5p targeted RBM39. Silencing MCM3AP-AS1 promoted apoptosis via the miR-524-5p/RBM39 axis, thereby enhancing chemosensitivity of drug-resistant TNBC cells. MCM3AP-AS1 knockdown upregulated miR-524-5p, downregulated RBM39, and restrained tumor development in vivo. MCM3AP-AS1 silencing potentiates apoptosis of drug-resistant TNBC cells by upregulating miR-524-5p and downregulating RBM39, thereby suppressing chemoresistance in TNBC.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

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Funding

This study was partially supported by grants from the Major Project in Natural Science Research in Higher Education Institutions of Anhui Province, Grant/Award Number: 2023AH040393.

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Authors and Affiliations

  1. Department of Medical Laboratory Science, Anhui No. 2 Provincial People’s Hospital, 1868 #Dangshan Road, North 2nd Ring, Hefei, 230041, Anhui, China

    Yueping Wang, Xuedong Wang, Ziyun Zhang & Juan Gu

  2. Department of Molecular and Cellular Biology, University of Connecticut, Storrs, CT, 06269, USA

    Yueping Wang

  3. School of Clinical Medicine, Anhui Medical University, Hefei, 230032, Anhui, China

    Haiyi Sun

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  1. Yueping Wang
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Contributions

YPW is the guarantor of integrity of the entire study and contributed to the statistical analysis; YPW, HYS contributed to the study concepts, manuscript editing; XDW contributed to the study design, literature research, manuscript review; ZYZ, HYS contributed to the definition of intellectual content; ZYZ, JG contributed to the experimental studies, manuscript preparation; JG, XDW contributed to the data acquisition; YPW, ZYZ contributed to the data analysis; All authors read and approved the final manuscript.

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Correspondence to Xuedong Wang.

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All animal experimental procedures were ratified by the Research Ethics Committee of Anhui Medical University and conducted in strict accordance with the National Guide for Laboratory Animals(Approval number: LLSC20220982). Considerable efforts were made to minimize the animal amount and their suffering.

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11010_2023_4908_MOESM1_ESM.tiff

Figure S1 Knockdown of miR-524-5p increased the drug resistance of SUM159PT and MDA-MB-231. RT-qPCR to determine miR-524-5p expression in A SUM159PT and B MDA-MB-231 cells; Flow cytometry to assess apoptosis in C SUM159PT and D MDA-MB-231 cells with or without DOX/DXL treatment; CCK-8 to evaluate E SUM159PT and F MDA-MB-231 cell viability. The cellular experiments were repeated three times. Data were expressed as mean ± SD, and one-way ANOVA was utilized for comparisons among multiple groups, followed by Tukey’s test. *p < 0.05, **p < 0.01

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Wang, Y., Wang, X., Sun, H. et al. LncRNA MCM3AP-AS1 promotes chemoresistance in triple-negative breast cancer through the miR-524-5p/RBM39 axis. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-023-04908-8

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