Methylation of miR-155-3p in mantle cell lymphoma and other non-Hodgkin's lymphomas

Abstract

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.

Downregulation of miR-129-2 by promoter hypermethylation regulates breast cancer cell proliferation and apoptosis

“…The hypermethylation of promoter CpG islands has been found to affect not only tumor-suppressor mRNAs, but also tumor-suppressor miRNAs. Several tumor-associated miRNAs have been reported to be silenced by the aberrant hypermethylation of their promoter regions in breast cancer, including miR-124, miR-34c, miR-148a, miR-155, miR-203 and miR-129 (3,(18)(19)(20)(21)(22).…”

Methylation status and AP1 elements are involved in EBV-mediated miR-155 expression in EBV positive lymphoma cells

“…We have reported that the DNA methyltransferase inhibitor, 5-aza-deoxycytidine (5-aza-C) induces expression of both the primary and mature forms of miR-155 in the EBV latency type I cells, Akata and MutuI (Yin et al, 2008a), but the detailed methylation status of the miR-155 promoter in EBV latency type I, II and III cells is not well documented. Albeit a report shows that hypermethylation of miR-155-3p correlates with miR-155-3p repression in Mantle cell lymphoma and other non-Hodgkin’s lymphomas (Yim et al, 2014). The mechanism regarding how EBV activates miR-155 expression is not fully understood; however, it is very clear that EBV latent infection activates AP1 protein expression, and that AP1 proteins mediate BCR-regulated miR-155 in EBV negative cells (Yin et al, 2008b).…”

DNA methylation at enhancer regions Novel avenues for epigenetic biomarker development

“…Another exciting development has been the recent discovery that a significant fraction of tumor-suppressive microRNAs (miRNAs) becomes epigenetically silenced in various neoplasms (119,120). Since enhancer methylation often dictates the transcriptional competency of target genes, hypomethylating agents may lead to the re-induction of these miRNAs, thereby hampering tumor growth (120,121).…”