Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma.
Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma.
复制标题
DOI：
10.1186/s13059-014-0575-z
复制
发表时间：
2015-01-13
期刊：
影响因子：
12.3
通讯作者：
Gallo A
中科院分区：
文献类型：
--
作者：
Tomaselli S;Galeano F;Alon S;Raho S;Galardi S;Polito VA;Presutti C;Vincenti S;Eisenberg E;Locatelli F;Gallo A
阿达尔酶将双链RNA（包括微小RNA（miRNA）前体）内的腺苷转化为肌苷，对miRNA重靶向和表达具有重要影响。ADAR 2活性在胶质母细胞瘤中受损，其拯救具有抗肿瘤作用。然而，ADAR 2活性如何影响miRNome和胶质母细胞瘤的进展尚不清楚。通过将深度测序和阵列方法与生物信息学分析和分子研究相结合，我们表明ADAR 2对于编辑少量成熟miRNA并显着调节胶质母细胞瘤细胞中约90种miRNA的表达至关重要。具体而言，癌细胞中ADAR 2活性的拯救恢复了胶质母细胞瘤细胞系和组织中丢失的编辑的miRNA群体，并将癌-miRNA和肿瘤抑制剂miRNA的表达重新平衡至正常人脑中观察到的水平。我们报道ADAR 2的主要作用是减少大量miRNA的表达，其中大部分作为致癌miRNA。ADAR 2在体内和体外均可编辑miR-222/221和miR-21前体，并降低相应成熟癌基因miRNA的表达，对细胞增殖和迁移具有重要影响。我们的研究结果揭示了miRNome调控的另一层复杂性，并提供了更好地了解ADAR 2编辑酶在胶质母细胞瘤中的影响的信息。我们认为ADAR 2是维持编辑的miRNA群体和平衡参与癌症的几种必需miRNA表达的关键因素。本文的在线版本（doi：10.1186/s13059-014-0575-z）包含补充材料，可供授权用户使用。
ADAR enzymes convert adenosines to inosines within double-stranded RNAs, including microRNA (miRNA) precursors, with important consequences on miRNA retargeting and expression. ADAR2 activity is impaired in glioblastoma and its rescue has anti-tumoral effects. However, how ADAR2 activity may impact the miRNome and the progression of glioblastoma is not known. By integrating deep-sequencing and array approaches with bioinformatics analyses and molecular studies, we show that ADAR2 is essential to edit a small number of mature miRNAs and to significantly modulate the expression of about 90 miRNAs in glioblastoma cells. Specifically, the rescue of ADAR2 activity in cancer cells recovers the edited miRNA population lost in glioblastoma cell lines and tissues, and rebalances expression of onco-miRNAs and tumor suppressor miRNAs to the levels observed in normal human brain. We report that the major effect of ADAR2 is to reduce the expression of a large number of miRNAs, most of which act as onco-miRNAs. ADAR2 can edit miR-222/221 and miR-21 precursors and decrease the expression of the corresponding mature onco-miRNAs in vivo and in vitro, with important effects on cell proliferation and migration. Our findings disclose an additional layer of complexity in miRNome regulation and provide information to better understand the impact of ADAR2 editing enzyme in glioblastoma. We propose that ADAR2 is a key factor for maintaining edited-miRNA population and balancing the expression of several essential miRNAs involved in cancer. The online version of this article (doi:10.1186/s13059-014-0575-z) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
11.4
作者：
Heale, Bret S. E.;Keegan, Liam P.;McGurk, Leeanne;Michlewski, Gracjan;Brindle, James;Stanton, Chloe M.;Caceres, Javier F.;O'Connell, Mary A.
通讯作者：
O'Connell, Mary A.
影响因子：
14.9
作者：
Kozomara A;Griffiths-Jones S
通讯作者：
Griffiths-Jones S
影响因子：
64.5
作者：
Han, Jinju;Lee, Yoontae;Kim, V. Narry
通讯作者：
Kim, V. Narry
影响因子：
--
作者：
Karsy, Michael;Arslan, Erol;Moy, Fred
通讯作者：
Moy, Fred
影响因子：
64.8
作者：
Denli, AM;Tops, BBJ;Hannon, GJ
通讯作者：
Hannon, GJ