Downregulation of circulating miR 802-5p and miR 194-5p and upregulation of brain MEF2C along breast cancer brain metastasization

Sereno, Marta and Haskó, János and Molnár, Kinga and Medina, Sarah J. and Reisz, Zita and Wilhelm, Imola Mária and Krizbai, István Adorján (2020) Downregulation of circulating miR 802-5p and miR 194-5p and upregulation of brain MEF2C along breast cancer brain metastasization. MOLECULAR ONCOLOGY, 14 (3). pp. 520-538. ISSN 1574-7891


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Breast cancer brain metastases (BCBM) have been under-investigated despite their high incidence and poor outcome. Micro RNAs (miRNAs), and particularly circulating miRNAs, regulate multiple cellular functions and their deregulation has been reported in different types of cancer and metastasis. However, their signature in plasma along brain metastasis development and their relevant targets remain undetermined. Here, we used a mouse model of BCBM and Next-Generation Sequencing (NGS) to establish the alterations in circulating miRNAs during brain metastasis formation and development. We further performed bioinformatics analysis to identify their targets with relevance in the metastatic process. We additionally analyzed human resected brain metastasis samples of breast cancer patients for target expression validation. Breast cancer cells were injected in the carotid artery of mice to preferentially induce metastasis in the brain, and samples were collected at different time points (5 h, 3, 7 and 10 days) to follow metastasis development. Metastases were detected from 7 days onwards, mainly in the brain. NGS revealed a deregulation of circulating miRNA profile during BCBM progression, raising from 18% at 3 days to 30% at 10 days following malignant cells' injection. Work was focused on those altered prior to metastasis detection, among which were miR-802-5p and miR-194-5p, whose downregulation was validated by qPCR. Using TargetScan and DIANA Tools the transcription factor myocyte enhancer factor 2C (MEF2C) was identified as a target for both miRNAs, and its expression was increasingly observed in malignant cells along brain metastasis development. Its upregulation was also observed in peritumoral astrocytes pointing to a role of MEF2C in the crosstalk between tumor cells and astrocytes. MEF2C expression was also observed in human BCBM, validating the observation in mouse. Collectively, downregulation of circulating miR-802-5p and miR-194-5p appears as a precocious event in BCBM and MEF2C emerges as a new player in brain metastasis development.

Item Type: Article
Additional Information: Faculdade de Farmácia, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Portugal Institute of Biophysics, Biological Research Centre, Szeged, Hungary Prion Diseases Section, Public Health Agency of Canada, National Microbiology Laboratory, Winnipeg, MB, Canada Department of Pathology, University of Szeged, Hungary Faculdade de Ciências, BioISI, Instituto de Biossistemas e Ciências Integrativas, Universidade de Lisboa, Portugal Department of Galenic Pharmacy and Pharmaceutical Technology, Faculdade de Farmácia, Universidade de Lisboa, Portugal Department of Medical Microbiology and Infectious Diseases, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada Institute of Life Sciences, Vasile Goldiş Western University of Arad, Romania Department of Biochemistry and Human Biology, Faculdade de Farmmácia, Universidade de Lisboa, Portugal Export Date: 13 August 2020 Correspondence Address: Brito, M.A.; Faculdade de Farmácia, Research Institute for Medicines (iMed.ULisboa), Universidade de LisboaPortugal; email:
Uncontrolled Keywords: breast cancer; MICRORNAS; bioinformatics; brain metastasis; Next-generation sequencing; myocyte enhancer factor 2c;
Subjects: R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
Depositing User: MTMT SWORD
Date Deposited: 25 Jan 2021 16:25
Last Modified: 25 Jan 2021 16:25

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