MicroRNA-17-92 down-regulates expression of distinct targets in different B-cell lymphoma subtypes
MicroRNA-17-92 down-regulates expression of distinct targets in different B-cell lymphoma subtypes
复制标题
DOI：
10.1182/blood-2008-07-163907
复制
发表时间：
2009-01-08
期刊：
影响因子：
20.3
通讯作者：
Sawada, Kenichi
中科院分区：
文献类型：
--
作者：
Inomata, Mika;Tagawa, Hiroyuki;Sawada, Kenichi
miR-17-92多顺反子的异常过表达与B细胞淋巴瘤发生密切相关。最近的研究表明，miR-17-92下调促凋亡蛋白Bim，导致Bcl 2过表达，这可能在淋巴瘤发生中起关键作用。然而，来自套细胞淋巴瘤的Jeko-1细胞表现出BIM的纯合缺失和miR-17-92的过表达的事实表明其他靶点也参与B细胞淋巴瘤发生。为了鉴定miR-17-92在淋巴瘤发生中的基本靶标，我们首先将miR-17 -92转染到2种遗传上不同的B细胞淋巴瘤细胞系中：Raji，其过表达c-Myc，和SUDHL 4，其过表达Bcl 2。转染miR-17- 19 b-1的Raji细胞Bim表达下调，Bcl 2表达轻微上调。另一方面，SUDHL 4转染子表现出积极的细胞生长，反映了在G（1）到S转变时促进的细胞周期进程，以及与p53表达无关的CDKN 1AmRNA和p21蛋白（CDKN 1A/p21）表达的降低。相反，将针对miR-17和miR-20 a的反义寡核苷酸转染到Jeko-1中导致CDKN 1A/p21上调，导致细胞生长减少，G1至S停滞。因此，CDKN 1A/p21似乎是B细胞淋巴瘤发生过程中miR-17-92的重要靶标，这表明miR-17-92多顺反子在不同的B细胞淋巴瘤亚型中具有不同的靶标。（血。2009;113：396-402）
Aberrant overexpression of the miR-17-92 polycistron is strongly associated with B-cell lymphomagenesis. Recent studies have shown that miR-17-92 down-regulates the proapoptotic protein Bim, leading to overexpression of Bcl2, which likely plays a key role in lymphomagenesis. However, the fact that Jeko-1 cells derived from mantle cell lymphoma exhibit both homozygous deletion of BIM and overexpression of miR-17-92 suggests other targets are also involved in B-cell lymphomagenesis. To identify essential target(s) of miR-17-92 in lymphomagenesis, we first transfected miR17-92 into 2 genetically distinct B-cell lymphoma cell lines: Raji, which overexpress c-Myc, and SUDHL4, which overexpress Bcl2. Raji transfected with miR-17-19b-1 exhibited down-regulated expression of Bim and a slight up-regulation in Bcl2 expression. On the other hand, SUDHL4 transfectants showed aggressive cell growth reflecting facilitated cell cycle progression at the G(1) to S transition and decreased expression of CDKN1AmRNA and p21 protein (CDKN1A/p21) that was independent of p53 expression. Conversely, transfection of antisense oligonucleotides against miR-17 and miR-20a into Jeko-1 led to up-regulation of CDKN1A/p21, resulting in decreased cell growth with G1 to S arrest. Thus, CDKN1A/p21 appears to be an essential target of miR-17-92 during B-cell lymphomagenesis, which suggests the miR-17-92 polycistron has distinct targets in different B-cell lymphoma subtypes. (Blood. 2009;113:396-402)