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Combinatorial targeting of microRNA-26b and microRNA-101 exerts a synergistic inhibition on cyclooxygenase-2 in brain metastatic triple-negative breast cancer cells

  • Preclinical study
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Abstract

Purpose

Extravasation of triple-negative (TN) metastatic breast cancer (BC) cells through the brain endothelium (BE) is a critical step in brain metastasis (BM). During extravasation, metastatic cells induce alteration in the inter-endothelial junctions and transmigrate through the endothelial barrier. Transmigration of metastatic cells is mediated by the upregulation of cyclooxygenase-2 (COX-2) that induces matrix metalloproteinase-1 (MMP-1) capable of degrading inter-endothelial junctional proteins. Despite their important role in BM, the molecular mechanisms upregulating COX-2 and MMP-1 in TNBC cells remain poorly understood. In this study, we unraveled a synergistic effect of a pair of micro-RNAs (miR-26b-5p and miR-101-3p) on COX-2 expression and the brain transmigration ability of BC cells.

Methods

Using a gain-and-loss of function approach, we modulated levels of miR-26b-5p and miR-101-3p in two TNBC cell lines (the parental MDA-MB-231 and its brain metastatic variant MDA-MB-231-BrM2), and examined the resultant effect on COX-2/MMP-1 expression and the transmigration of cancer cells through the BE.

Results

We observed that the dual inhibition of miR-26b-5p and miR-101-3p in BC cells results in higher increase of COX-2/MMP-1 expression and a higher trans-endothelial migration compared to either micro-RNA alone. The dual restoration of both micro-RNAs exerted a synergistic inhibition on COX-2/MMP-1 by targeting COX-2 and potentiated the suppression of trans-endothelial migration compared to single micro-RNA.

Conclusion

These findings provide new insights on a synergism between miR-26-5p and miR-101-3p in regulating COX-2 in metastatic TNBC cells and shed light on miR-26-5p and miR-101-3p as prognostic and therapeutic targets that can be exploited to predict or prevent BM.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and/or its supplementary material.

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Funding

This work was supported by the Terry Fox Foundation’s International Run Program (Grant ref. I1032). R Hamoudi is funded by Al-Jalila Foundation (Grant No: AJF201741). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, 27272, Sharjah, United Arab Emirates

    Rania Harati

  2. Sharjah Institute for Medical Research, University of Sharjah, 27272, Sharjah, United Arab Emirates

    Rania Harati, Ghalia Khoder & Rifat Hamoudi

  3. Department of Medicines and Healthcare Technologies, The French Alternative Energies and Atomic Energy Commission, Paris-Saclay University, 91191, Gif-sur-Yvette, France

    Aloïse Mabondzo

  4. Department of Applied Biology, College of Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates

    Abdelaziz Tlili & Mona Mahfood

  5. Department of Pharmaceutics and Pharmaceutical Technologies, College of Pharmacy, University of Sharjah, 27272, Sharjah, United Arab Emirates

    Ghalia Khoder

  6. Clinical Sciences Department, College of Medicine, University of Sharjah, 27272, Sharjah, United Arab Emirates

    Rifat Hamoudi

  7. Division of Surgery and Interventional Science, University College London, London, W1W 7EJ, UK

    Rifat Hamoudi

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Contributions

RH designed the study, performed research, analyzed, and interpreted the data and wrote the manuscript; AT, MM, and GK contributed to the luciferase reporter assay; AT, AM, GK, and RH provided support with analysis of data and interpretation of results. All authors read and approved the final manuscript.

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Correspondence to Rania Harati.

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All experiments were approved by the University of Sharjah animal care and use committee and conducted according to the UOS directives for animal care.

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Harati, R., Mabondzo, A., Tlili, A. et al. Combinatorial targeting of microRNA-26b and microRNA-101 exerts a synergistic inhibition on cyclooxygenase-2 in brain metastatic triple-negative breast cancer cells. Breast Cancer Res Treat 187, 695–713 (2021). https://doi.org/10.1007/s10549-021-06255-y

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