Methylation of miR-155-3p in mantle cell lymphoma and other non-Hodgkin’s lymphomas
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Rita Lh Yim1, Kwan Yeung Wong1, Yok Lam Kwong1, Florence Loong2, Chung Ying Leung3, Raymond Chu4, William Wai Lung Lam5, Pak Kwan Hui6, Raymond Lai7, Chor Sang Chim1
1Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
2Department of Pathology, Queen Mary Hospital, Hong Kong
3Department of Pathology, United Christian Hospital, Hong Kong
4Department of Pathology, Pamela Youde Nethersole Eastern Hospital, Hong Kong
5Department of Pathology, Princess Margaret Hospital, Hong Kong
6Department of Pathology, Kwong Wah Hospital, Hong Kong
7Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
Chor-Sang Chim, e-mail: email@example.com
Key Words: tumor suppressive microRNA, hypermethylation, miR-155-3p, mantle cell lymphoma, non-Hodgkin’s lymphoma
Received: July 08, 2014 Accepted: August 23, 2014 Published: November 11, 2014
Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin’s lymphoma (NHL). In cancers, tumor suppressive microRNAs may be silenced by DNA hypermethylation. By microRNA profiling of representative EBV-negative MCL cell lines before and after demethylation treatment, miR-155-3p was found significantly restored. Methylation-specific PCR, verified by pyrosequencing, showed complete methylation of miR-155-3p in one MCL cell line (REC-1). 5-aza-2′-deoxycytidine treatment of REC-1 led to demethylation and re-expression of miR-155-3p. Over-expression of miR-155-3p led to increased sub-G1 apoptotic cells and reduced cellular viability, demonstrating its tumor suppressive properties. By luciferase assay, lymphotoxin-beta (LT-β) was validated as a miR-155-3p target. In 31 primary MCL, miR-155-3p was found hypermethylated in 6(19%) cases. To test if methylation of miR-155-3p was MCL-specific, miR-155-3p methylation was tested in an additional 191 B-cell, T-cell and NK-cell NHLs, yielding miR-155-3p methylation in 66(34.6%) including 36(27%) non-MCL B-cell, 24(53%) T-cell and 6(46%) of NK-cell lymphoma. Moreover, in 72 primary NHL samples with RNA, miR-155-3p methylation correlated with miR-155-3p downregulation (p=0.024), and LT-β upregulation (p=0.043). Collectively, miR-155-3p is a potential tumor suppressive microRNA hypermethylated in MCL and other NHL subtypes. As miR-155-3p targets LT-β, which is an upstream activator of the non-canonical NF-kB signaling, miR-155-3p methylation is potentially important in lymphomagenesis.
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