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Open AccessArticle

The Tumor Suppressive mir-148a Is Epigenetically Inactivated in Classical Hodgkin Lymphoma

1
Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland
2
Dr. Senckenberg Institute of Pathology, Goethe University Hospital, 60590 Frankfurt am Main, Germany
3
Reference and Consultant Center for Lymph Node and Lymphoma Pathology, Goethe University, 60590 Frankfurt am Main, Germany
4
Frankfurt Institute for Advanced Studies, 60438 Frankfurt am Main, Germany
*
Author to whom correspondence should be addressed.
Cells 2020, 9(10), 2292; https://doi.org/10.3390/cells9102292
Received: 24 September 2020 / Revised: 11 October 2020 / Accepted: 11 October 2020 / Published: 14 October 2020
(This article belongs to the Special Issue Regulation of Gene Expression in Cancer)
DNA methylation was shown previously to be a crucial mechanism responsible for transcriptional deregulation in the pathogenesis of classical Hodgkin lymphoma (cHL). To identify epigenetically inactivated miRNAs in cHL, we have analyzed the set of miRNAs downregulated in cHL cell lines using bisulfite pyrosequencing. We focused on miRNAs with promoter regions located within or <1000 bp from a CpG island. Most promising candidate miRNAs were further studied in primary Hodgkin and Reed-Sternberg (HRS) cells obtained by laser capture microdissection. Last, to evaluate the function of identified miRNAs, we performed a luciferase reporter assay to confirm miRNA: mRNA interactions and therefore established cHL cell lines with stable overexpression of selected miRNAs for proliferation tests. We found a significant reverse correlation between DNA methylation and expression levels of mir-339-3p, mir-148a-3p, mir-148a-5p and mir-193a-5 demonstrating epigenetic regulation of these miRNAs in cHL cell lines. Moreover, we demonstrated direct interaction between miR-148a-3p and IL15 and HOMER1 transcripts as well as between mir-148a-5p and SUB1 and SERPINH1 transcripts. Furthermore, mir-148a overexpression resulted in reduced cell proliferation in the KM-H2 cell line. In summary, we report that mir-148a is a novel tumor suppressor inactivated in cHL and that epigenetic silencing of miRNAs is a common phenomenon in cHL. View Full-Text
Keywords: cHL; epigenetic; microRNA; DNA methylation; mir-148a cHL; epigenetic; microRNA; DNA methylation; mir-148a
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Paczkowska, J.; Janiszewska, J.; Bein, J.; Schneider, M.; Bednarek, K.; Ustaszewski, A.; Hartmann, S.; Hansmann, M.-L.; Giefing, M. The Tumor Suppressive mir-148a Is Epigenetically Inactivated in Classical Hodgkin Lymphoma. Cells 2020, 9, 2292.

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