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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
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
2015 Impact Factor: 3.694
2015 SCImago Journal Rankings: 1.766
PubMed Central 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.rightsCreative Commons: Attribution 3.0 Hong Kong License-
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.hkuros234371en_US
dc.identifier.hkuros231433-
dc.identifier.volume12en_US
dc.publisher.placeUnited Kingdom-

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