Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia
Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia
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DOI：
10.1182/blood-2009-06-222794
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发表时间：
2009-10-08
期刊：
影响因子：
20.3
通讯作者：
Sawada, Ken-ichi
中科院分区：
文献类型：
--
作者：
Yamanaka, Yasuo;Tagawa, Hiroyuki;Sawada, Ken-ichi
自然杀伤(NK)细胞淋巴瘤/白血病的致病基因(S)尚未确定。在本研究中，我们发现在NK细胞淋巴瘤细胞系(n=10)和原发淋巴瘤(n=10)标本中miR-21和miR-155的表达水平呈负相关，且显著高于正常自然杀伤细胞(CD3(-)CD56(+))(n=8)。为了确定这些microRNAs在淋巴癌发生中的作用，我们检测了针对miR-21(ASO-21)和/或miR-155(ASO-155)的反义寡核苷酸(ASO)在过量表达其中一个或两个miRNAs的NK细胞淋巴瘤株中的作用。相反，利用慢病毒载体转导miR-21或miR-155内源性表达很少的细胞，导致其过表达。MiR-21或miR-155的表达减少导致磷酸酶和紧张素同源蛋白(PTEN)、程序性细胞死亡4(PDCD4)或含Src同源2结构域的肌醇5-磷酸酶1(SHIP1)表达上调。ASO-21和ASO-155处理的细胞株均显示磷酸化AKT(Ser473)表达下调。此外，miR-21或miR-155转导导致PTEN和PDCD4或SHIP1表达下调，而磷酸化AKT(Ser473)表达上调。总之，这些结果为NK细胞淋巴瘤/白血病的发病机制提供了重要的新见解，并提示靶向miR-21和/或miR-155可能是治疗NK细胞淋巴瘤/白血病的有用方法。(血。2009；114：3265-3275)
The gene(s) responsible for natural killer (NK)-cell lymphoma/leukemia have not been identified. In the present study, we found that in NK-cell lymphoma lines (n = 10) and specimens of primary lymphoma (n = 10), levels of miR-21 and miR-155 expression were inversely related and were significantly greater than those found in normal natural killer (CD3(-)CD56(+)) cells (n = 8). To determine the functions of these microRNAs in lymphomagenesis, we examined the effects of antisense oligonucleotides (ASOs) targeting miR-21 (ASO-21) and/or miR-155 (ASO-155) in NK-cell lymphoma lines over-expressing one or both of these miRNAs. Conversely, cells showing little endogenous expression of miR-21 or miR-155 were transduced by the use of lentiviral vectors, leading to their overexpression. Reducing expression of miR-21 or miR-155 led to up-regulation of phosphatase and tensin homologue (PTEN), programmed cell death 4 (PDCD4), or Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1). ASO-21- and ASO-155-treated cell lines all showed down-regulation of phosphorylated AKT(ser473). Moreover, transduction with either miR-21 or miR-155 led to down-regulation of PTEN and PDCD4 or SHIP1 with up-regulation of phosphorylated AKT(ser473). Collectively, these results provide important new insight into the pathogenesis of NK-cell lymphoma/leukemia and suggest targeting miR-21 and/or miR-155 may represent a useful approach to treating NK-cell lymphoma/leukemia. (Blood. 2009; 114: 3265-3275)