Methylation of miR-155-3p in mantle cell lymphoma and other non-Hodgkin's lymphomas.
Methylation of miR-155-3p in mantle cell lymphoma and other non-Hodgkin's lymphomas.
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DOI：
10.18632/oncotarget.2390
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发表时间：
2014-10-30
期刊：
影响因子：
--
通讯作者：
Chim CS
中科院分区：
文献类型：
--
作者：
Yim RL;Wong KY;Kwong YL;Loong F;Leung CY;Chu R;Lam WW;Hui PK;Lai R;Chim CS
套细胞淋巴瘤（MCL）是一种侵袭性B细胞非霍奇金淋巴瘤（NHL）。在癌症中，肿瘤抑制性microRNA可以通过DNA超甲基化而沉默。通过对去甲基化处理前后的代表性EBV阴性MCL细胞系的microRNA分析，发现miR-155- 3 p显著恢复。通过焦磷酸测序验证的甲基化特异性PCR显示在一个MCL细胞系（REC-1）中miR-155- 3 p完全甲基化。5-aza-2′-deoxycytidine处理REC-1可导致miR-155- 3 p的去甲基化和重新表达。miR-155- 3 p的过表达导致亚G1期凋亡细胞增加和细胞活力降低，表明其肿瘤抑制特性。通过荧光素酶测定，验证了光敏素-β（LT-β）是miR-155- 3 p的靶标。在31例原发性MCL中，6例（19%）发现miR-155- 3 p高甲基化。为了测试miR-155- 3 p的甲基化是否是MCL特异性的，在另外191个B细胞、T细胞和NK细胞NHL中测试miR-155 - 3 p甲基化，在66个（34.6%）中产生miR-155 - 3 p甲基化，包括36个（27%）非MCL B细胞、24个（53%）T细胞和6个（46%）NK细胞淋巴瘤。此外，在72例有RNA的原发性NHL样本中，miR-155- 3 p甲基化与miR-155- 3 p下调（p = 0.024）和LT-β上调（p = 0.043）相关。总体而言，miR-155- 3 p是MCL和其他NHL亚型中高甲基化的潜在肿瘤抑制性microRNA。由于miR-155- 3 p靶向LT-β，LT-β是非经典NF-kB信号传导的上游激活剂，因此miR-155- 3 p甲基化在淋巴瘤发生中可能很重要。
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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