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Epigenetic Modification of MicroRNA-219-1 and Its Association with Glioblastoma Multiforme

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Abstract

MicroRNA-219-1 (miR-219-1) acts as a tumor suppressor in a variety of cancers but, the regulatory epigenetic mechanism involved in its gene expression level has not been studied. Using real-time polymerase chain reaction (real-time PCR) and bisulfite genomic sequencing technology, promoter methylation level of miR-219-1 and gene expression levels of miR-219-5p and miR-219-1-3p were determined respectively, in glioblastoma multiforme (GBM) (n = 31), their adjacent normal tissues (n = 31), and GBM U87 cell line. Following treatment of GBM U87 cells with 5-aza-2′-deoxycitidine (5-aza-dC), miR-219-1 promoter methylation, their target mRNA, and protein levels were determined by genomic bisulfite modification, real-time-PCR, and ELISA techniques, respectively. Our results showed that gene expression levels of miR-219-5p and miR-219-1-3p were significantly lower in GBM patients relative to their adjacent normal tissues (p < 0.01). MiR-219-1 promoter had a high level of methylation in GBM tissues (p < 0.01) and a negative correlation was observed between the miRNAs gene expression and methylation levels in GBM tissues (p < 0.01). Treatment of GBM U87 cells by 5-aza-dC decreased the level of miR-219-1 methylation, amount of target mRNA, and levels of cyclin A2 and mucin 4 (MUC4) proteins, and increased the expression levels of miR-219-5p and miR-219-1-3p (p < 0.01). Using external miR-219-5p and miR-219-1-3p, the expression of cyclin A2 and MUC4 were suppressed and proliferative activity of the U87MG cell line was reduced (p < 0.01). These findings suggested that DNA methylation has a crucial role in the regulation of miR-219-1 gene expression and that hypermethylated miR-219-1 may be involved in GBM pathogenesis.

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Abbreviations

5-aza-dC:

5-aza-2′-deoxycitidine

DMED:

Dulbecco’s Modified Eagle’s Medium

ELISA:

enzyme-linked immunosorbent assay

GBM:

glioblastoma multiforme

miRNA:

microRNA

MUC4:

mucin 4

real-time PCR:

real time polymerase chain reaction

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Funding

This work was supported by the IRNA University of Medical Sciences (IUMS) [project no. 24756].

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Authors and Affiliations

  1. Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences (TUMS), 1417613151, Tehran, Iran

    Asghar Ghasemi

  2. Department of Clinical Biochemistry, School of Medicine, Iran University of Medical Sciences (IUMS), 1449614535, Tehran, Iran

    Asghar Mohammadi & Soudabeh Fallah

Authors
  1. Asghar Ghasemi
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  2. Asghar Mohammadi
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  3. Soudabeh Fallah
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Correspondence to Soudabeh Fallah.

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The authors declare no conflicts of interest in financial or any other sphere. All procedures performed in present study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Published in Russian in Biokhimiya, 2021, Vol. 86, No. 4, pp. 496-510, https://doi.org/10.31857/S0320972521040047.

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Ghasemi, A., Mohammadi, A. & Fallah, S. Epigenetic Modification of MicroRNA-219-1 and Its Association with Glioblastoma Multiforme. Biochemistry Moscow 86, 420–432 (2021). https://doi.org/10.1134/S0006297921040040

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  • DOI: https://doi.org/10.1134/S0006297921040040

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