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Article: Epigenetic inactivation of mir-34b/c in addition to mir-34a and DAPK1 in chronic lymphocytic leukemia

TitleEpigenetic inactivation of mir-34b/c in addition to mir-34a and DAPK1 in chronic lymphocytic leukemia
Authors
KeywordsChronic lymphocytic leukemia
DNA methylation
MicroRNA
TP53 network
Tumor suppressor
Issue Date2014
PublisherBioMed Central Ltd. The Journal's web site is located at http://www.translational-medicine.com/home/
Citation
Journal of Translational Medicine, 2014, v. 12, article no. 52 How to Cite?
AbstractBACKGROUND: TP53 mutation/deletion is uncommon in chronic lymphocytic leukemia (CLL). We postulated that components of TP53-centered tumor suppressor network, miR-34b/c, in addition to DAPK1 and miR-34a might be inactivated by DNA hypermethylation. Moreover, we tested if miR-34b/c methylation might correlate with miR-203 or miR-124-1 methylation in CLL. METHODS: miR-34b/c, miR-34a and DAPK1 methylation was studied in 11 normal controls, 7 CLL cell lines, and 78 diagnostic CLL samples by methylation-specific polymerase chain reaction. MEC-1 cells were treated with 5-Aza-2'-deoxycytidine for reversal of methylation-associated miRNA silencing. Tumor suppressor properties of miR-34b were demonstrated by over-expression of precursor miR-34b in MEC-1 cells. RESULTS: miR-34b/c promoter was unmethylated in normal controls, but completely methylated in 4 CLL cell lines. miR-34b/c expression was inversely correlated with miR-34b/c methylation. Different MSP statuses of miR-34b/c, including complete methylation and complete unmethylation, were verified by quantitative bisulfite pyrosequencing. 5-Aza-2'-deoxycytidine treatment resulted in promoter demethylation and miR-34b re-expression in MEC1 cells. Moreover, over-expression of miR-34b resulted in inhibition of cellular proliferation and increased cell death. In primary CLL samples, miR-34a, miR-34b/c and DAPK1 methylation was detected in 2.6%, 17.9% and 34.6% of patients at diagnosis respectively. Furthermore, 39.7%, 3.8% and 2.6% patients had methylation of one, two or all three genes respectively. Overall, 46.2% patients had methylation of at least one of these three genes. Besides, miR-34b/c methylation was associated with methylation of miR-34a (P = 0.03) and miR-203 (P = 0.012) in CLL. CONCLUSIONS: Taken together, miR-34b/c is a tumor suppressor miRNA frequently methylated, and hence silenced in CLL. Together with DAPK1 methylation, miR-34b/c methylation is implicated in the disruption of the TP53-centered tumor suppressor network. Moreover, the association of miRNA methylation warrants further study.
Persistent Identifierhttp://hdl.handle.net/10722/200462
ISSN
2018 Impact Factor: 4.098
2020 SCImago Journal Rankings: 1.576
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWang, LQen_US
dc.contributor.authorKwong, YLen_US
dc.contributor.authorWong, KFen_US
dc.contributor.authorKho, CSBen_US
dc.contributor.authorJin, Den_US
dc.contributor.authorTse, EWCen_US
dc.contributor.authorRosen, Aen_US
dc.contributor.authorChim, JCSen_US
dc.date.accessioned2014-08-21T06:47:27Z-
dc.date.available2014-08-21T06:47:27Z-
dc.date.issued2014en_US
dc.identifier.citationJournal of Translational Medicine, 2014, v. 12, article no. 52en_US
dc.identifier.issn1479-5876-
dc.identifier.urihttp://hdl.handle.net/10722/200462-
dc.description.abstractBACKGROUND: TP53 mutation/deletion is uncommon in chronic lymphocytic leukemia (CLL). We postulated that components of TP53-centered tumor suppressor network, miR-34b/c, in addition to DAPK1 and miR-34a might be inactivated by DNA hypermethylation. Moreover, we tested if miR-34b/c methylation might correlate with miR-203 or miR-124-1 methylation in CLL. METHODS: miR-34b/c, miR-34a and DAPK1 methylation was studied in 11 normal controls, 7 CLL cell lines, and 78 diagnostic CLL samples by methylation-specific polymerase chain reaction. MEC-1 cells were treated with 5-Aza-2'-deoxycytidine for reversal of methylation-associated miRNA silencing. Tumor suppressor properties of miR-34b were demonstrated by over-expression of precursor miR-34b in MEC-1 cells. RESULTS: miR-34b/c promoter was unmethylated in normal controls, but completely methylated in 4 CLL cell lines. miR-34b/c expression was inversely correlated with miR-34b/c methylation. Different MSP statuses of miR-34b/c, including complete methylation and complete unmethylation, were verified by quantitative bisulfite pyrosequencing. 5-Aza-2'-deoxycytidine treatment resulted in promoter demethylation and miR-34b re-expression in MEC1 cells. Moreover, over-expression of miR-34b resulted in inhibition of cellular proliferation and increased cell death. In primary CLL samples, miR-34a, miR-34b/c and DAPK1 methylation was detected in 2.6%, 17.9% and 34.6% of patients at diagnosis respectively. Furthermore, 39.7%, 3.8% and 2.6% patients had methylation of one, two or all three genes respectively. Overall, 46.2% patients had methylation of at least one of these three genes. Besides, miR-34b/c methylation was associated with methylation of miR-34a (P = 0.03) and miR-203 (P = 0.012) in CLL. CONCLUSIONS: Taken together, miR-34b/c is a tumor suppressor miRNA frequently methylated, and hence silenced in CLL. Together with DAPK1 methylation, miR-34b/c methylation is implicated in the disruption of the TP53-centered tumor suppressor network. Moreover, the association of miRNA methylation warrants further study.-
dc.languageengen_US
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.translational-medicine.com/home/-
dc.relation.ispartofJournal of Translational Medicineen_US
dc.rightsJournal of Translational Medicine. Copyright © BioMed Central Ltd.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectChronic lymphocytic leukemia-
dc.subjectDNA methylation-
dc.subjectMicroRNA-
dc.subjectTP53 network-
dc.subjectTumor suppressor-
dc.subject.meshBone Marrow Cells - drug effects - metabolism-
dc.subject.meshDeath-Associated Protein Kinases - genetics - metabolism-
dc.subject.meshEpigenesis, Genetic - drug effects-
dc.subject.meshLeukemia, Lymphocytic, Chronic, B-Cell - diagnosis - genetics-
dc.subject.meshMicroRNAs - genetics - metabolism-
dc.titleEpigenetic inactivation of mir-34b/c in addition to mir-34a and DAPK1 in chronic lymphocytic leukemiaen_US
dc.typeArticleen_US
dc.identifier.emailKwong, YL: ylkwong@hku.hken_US
dc.identifier.emailJin, D: dyjin@hku.hken_US
dc.identifier.emailTse, EWC: ewctse@hku.hken_US
dc.identifier.emailChim, JCS: jcschim@hku.hken_US
dc.identifier.authorityKwong, YL=rp00358en_US
dc.identifier.authorityJin, D=rp00452en_US
dc.identifier.authorityTse, EWC=rp00471en_US
dc.identifier.authorityChim, JCS=rp00408en_US
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/1479-5876-12-52-
dc.identifier.pmid24559316-
dc.identifier.pmcidPMC3941938-
dc.identifier.scopuseid_2-s2.0-84895430477-
dc.identifier.hkuros234371en_US
dc.identifier.hkuros231433-
dc.identifier.volume12en_US
dc.identifier.isiWOS:000335533000002-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl1479-5876-

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