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- Wang, LQUniversity of Hong Kong, China (author)
Epigenetic inactivation of mir-34b/c in addition to mir-34a and DAPK1 in chronic lymphocytic leukemia
- Article/chapterEnglish2014
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- 2014-02-22
- BioMed Central,2014
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- LIBRIS-ID:oai:DiVA.org:liu-104694
- https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-104694URI
- https://doi.org/10.1186/1479-5876-12-52DOI
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- Language:English
- Summary in:English
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- BACKGROUND: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 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.
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- Kwong, YLUniversity of Hong Kong, China (author)
- Wong, KFQueen Elizabeth Hospital, Hong Kong, China (author)
- Kho, CSPamela Youde Nethersole Hospital, Hong Kong, China (author)
- Jin, DYUniversity of Hong Kong, China (author)
- Tse, EUniversity of Hong Kong, China (author)
- Rosén, AndersLinköpings universitet,Avdelningen för cellbiologi,Hälsouniversitetet(Swepub:liu)andro72 (author)
- Chim, CSUniversity of Hong Kong, China (author)
- University of Hong Kong, ChinaQueen Elizabeth Hospital, Hong Kong, China (creator_code:org_t)
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- In:Journal of Translational Medicine: BioMed Central12:521479-5876
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