{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T02:09:52Z","timestamp":1789610992884,"version":"build-2803163510"},"reference-count":35,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,14]],"date-time":"2020-10-14T00:00:00Z","timestamp":1602633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Polish National Science Center","award":["2014\/14\/M\/NZ2\/00529"],"award-info":[{"award-number":["2014\/14\/M\/NZ2\/00529"]}]},{"name":"Polish National Science Center","award":["UMO-2019\/32\/T\/NZ5\/00441"],"award-info":[{"award-number":["UMO-2019\/32\/T\/NZ5\/00441"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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 &lt;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.<\/jats:p>","DOI":"10.3390\/cells9102292","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T21:42:21Z","timestamp":1602798141000},"page":"2292","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The Tumor Suppressive mir-148a Is Epigenetically Inactivated in Classical Hodgkin Lymphoma"],"prefix":"10.3390","volume":"9","author":[{"given":"Julia","family":"Paczkowska","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1765-0152","authenticated-orcid":false,"given":"Joanna","family":"Janiszewska","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Bein","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Pathology, Goethe University Hospital, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Schneider","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Pathology, Goethe University Hospital, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinga","family":"Bednarek","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9542-0029","authenticated-orcid":false,"given":"Adam","family":"Ustaszewski","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3424-1091","authenticated-orcid":false,"given":"Sylvia","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Pathology, Goethe University Hospital, 60590 Frankfurt am Main, Germany"},{"name":"Reference and Consultant Center for Lymph Node and Lymphoma Pathology, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin-Leo","family":"Hansmann","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Pathology, Goethe University Hospital, 60590 Frankfurt am Main, Germany"},{"name":"Reference and Consultant Center for Lymph Node and Lymphoma Pathology, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"Frankfurt Institute for Advanced Studies, 60438 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4760-8246","authenticated-orcid":false,"given":"Maciej","family":"Giefing","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pfeifer, G. (2018). Defining Driver DNA Methylation Changes in Human Cancer. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041166"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"933","DOI":"10.18632\/aging.100951","article-title":"MMP-9 overexpression is associated with intragenic hypermethylation of MMP9 gene in melanoma","volume":"8","author":"Falzone","year":"2016","journal-title":"Aging (Albany NY)"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1182\/blood-2005-09-3765","article-title":"Epigenetic processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma","volume":"107","author":"Ushmorov","year":"2006","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/leu.2011.194","article-title":"Array-based DNA methylation analysis in classical Hodgkin lymphoma reveals new insights into the mechanisms underlying silencing of B cell-specific genes","volume":"26","author":"Ammerpohl","year":"2012","journal-title":"Leukemia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1182\/blood-2002-03-0839","article-title":"Loss of the B-lineage-specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma","volume":"101","author":"Schwering","year":"2003","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1093\/hmg\/ddx138","article-title":"Clinical significance of miRNA host gene promoter methylation in prostate cancer","volume":"26","author":"Daniunaite","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45496","DOI":"10.18632\/oncotarget.17569","article-title":"DNA methylation mediated silencing of microRNA-874 is a promising diagnosis and prognostic marker in breast cancer","volume":"8","author":"Zhang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/leu.2012.242","article-title":"Suppression of the let-7b microRNA pathway by DNA hypermethylation in infant acute lymphoblastic leukemia with MLL gene rearrangements","volume":"27","author":"Nishi","year":"2013","journal-title":"Leukemia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9770","DOI":"10.18632\/oncotarget.2390","article-title":"Methylation of miR-155-3p in mantle cell lymphoma and other non-Hodgkin\u2019s lymphomas","volume":"5","author":"Yim","year":"2014","journal-title":"Oncotarget"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.3109\/10428194.2014.995650","article-title":"Epigenetic regulation of microRNA expression in Hodgkin lymphoma","volume":"56","author":"Navarro","year":"2015","journal-title":"Leuk. Lymphoma"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1002\/eji.201444637","article-title":"miR-148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2","volume":"45","author":"Porstner","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4340","DOI":"10.1182\/blood.V106.11.4340.4340","article-title":"Guide to leukemia-lymphoma cell lines on CD","volume":"106","author":"Drexler","year":"2005","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1159\/000112062","article-title":"U-HO1, a new cell line derived from a primary refractory classical Hodgkin lymphoma","volume":"119","author":"Mader","year":"2007","journal-title":"Cytogenet. Genome Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1084\/jem.20080809","article-title":"Origin and Pathogenesis of Nodular Lymphocyte Predominant Hodgkin Lymphoma as Revealed by Global Gene Expression Analysis","volume":"205","author":"Brune","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_15","first-page":"532","article-title":"A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples","volume":"15","author":"Chomczynski","year":"1993","journal-title":"Biotechniques"},{"key":"ref_16","first-page":"505","article-title":"Pyrosequencing-based DNA methylation profiling of Fanconi anemia\/BRCA pathway genes in laryngeal squamous cell carcinoma","volume":"39","author":"Szaumkessel","year":"2011","journal-title":"Int. J. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3672","DOI":"10.1182\/blood-2014-02-553263","article-title":"The PRDX2 gene is transcriptionally silenced and de novo methylated in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma","volume":"123","author":"Schneider","year":"2014","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.3324\/haematol.2013.099515","article-title":"MicroRNA-128-3p is a novel oncomiR targeting PHF6 in T-cell acute lymphoblastic leukemia","volume":"99","author":"Mets","year":"2014","journal-title":"Haematologica"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/978-1-62703-269-8_15","article-title":"Studying microRNAs in lymphoma","volume":"971","author":"Kluiver","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1002\/gcc.20789","article-title":"Rare occurrence of biallelic CYLD gene mutations in classical Hodgkin lymphoma","volume":"49","author":"Schmidt","year":"2010","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1111\/j.1365-2141.2012.09113.x","article-title":"Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma","volume":"157","author":"Otto","year":"2012","journal-title":"Br. J. Haematol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1172\/JCI200316624","article-title":"Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling","volume":"111","author":"Klein","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e05005","DOI":"10.7554\/eLife.05005","article-title":"Predicting effective microRNA target sites in mammalian mRNAs","volume":"4","author":"Agarwal","year":"2015","journal-title":"Elife"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"87","DOI":"10.2174\/2211536605666160825150830","article-title":"Aberrant expression of MicroRNAs in B-cell lymphomas","volume":"5","author":"Sole","year":"2016","journal-title":"Microrna"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.canlet.2017.07.020","article-title":"miRNAs in B-cell lymphoma: Molecular mechanisms and biomarker potential","volume":"405","author":"Larrea","year":"2017","journal-title":"Cancer Lett"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cordeiro, A., Monz\u00f3, M., and Navarro, A. (2017). Non-Coding RNAs in Hodgkin Lymphoma. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18061154"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1016\/j.ajpath.2017.02.016","article-title":"miR-24-3p Is Overexpressed in Hodgkin Lymphoma and Protects Hodgkin and Reed-Sternberg Cells from Apoptosis","volume":"187","author":"Yuan","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.7150\/jca.14616","article-title":"The Role of Mir-148a in Cancer","volume":"7","author":"Li","year":"2016","journal-title":"J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5482","DOI":"10.1038\/onc.2015.6","article-title":"Regulatory circuit of PKM2\/NF-\u03baB\/miR-148a\/152-modulated tumor angiogenesis and cancer progression","volume":"34","author":"Xu","year":"2015","journal-title":"Oncogene"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"267","DOI":"10.3109\/07357907.2015.1025794","article-title":"The Interplay Between miR-148a and DNMT1 Might be Exploited for Pancreatic Cancer Therapy","volume":"33","author":"Zhan","year":"2015","journal-title":"Cancer Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1261\/rna.972008","article-title":"miR-148 targets human DNMT3b protein coding region","volume":"14","author":"Duursma","year":"2008","journal-title":"RNA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1038\/leu.2014.345","article-title":"The IL-15 cytokine system provides growth and survival signals in Hodgkin lymphoma and enhances the inflammatory phenotype of HRS cells","volume":"29","author":"Ullrich","year":"2015","journal-title":"Leukemia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1007\/s10495-012-0736-z","article-title":"Protective effect of Homer 1a on tumor necrosis factor-\u03b1 with cycloheximide-induced apoptosis is mediated by mitogen-activated protein kinase pathways","volume":"17","author":"Luo","year":"2012","journal-title":"Apoptosis"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6330","DOI":"10.1038\/onc.2016.164","article-title":"MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer","volume":"35","author":"Chakravarthi","year":"2016","journal-title":"Oncogene"},{"key":"ref_35","first-page":"82","article-title":"PC4 is a novel oncogenic gene for mesenchymal stem cell transformation and mediates the reciprocal actions between mesenchymal stem cells and prostate cancer cells","volume":"36","author":"Shi","year":"2008","journal-title":"Exp. Hematol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/10\/2292\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:21:00Z","timestamp":1760178060000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/10\/2292"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,14]]},"references-count":35,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["cells9102292"],"URL":"https:\/\/doi.org\/10.3390\/cells9102292","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,14]]}}}