Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation.
Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation.
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DOI：
10.1126/scisignal.2000594
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发表时间：
2010-04-13
影响因子：
7.3
通讯作者：
Pandolfi PP
中科院分区：
文献类型：
--
作者：
Poliseno L;Salmena L;Riccardi L;Fornari A;Song MS;Hobbs RM;Sportoletti P;Varmeh S;Egia A;Fedele G;Rameh L;Loda M;Pandolfi PP
PTEN（10号染色体上缺失的磷酸酶和紧张素同源物）是一种肿瘤抑制因子，通过磷脂酰肌醇-3-激酶- akt通路拮抗信号。我们已经证明，PTEN丰度的细微减少可能对肿瘤发生产生关键影响。在这里，我们使用计算方法鉴定miR-22， miR-25和miR-302是九个基因组位点中发现的三个靶向pten的microRNA （miRNA）家族。我们发现miR-22和miR-106b ~ 25簇在人类前列腺癌中异常过表达，与miRNA加工酶DICER的丰度相关，并在体外和体内增强细胞转化。我们证明了内含子miR-106b ~ 25簇在体外和体内的细胞转化中与其宿主基因MCM7合作，因此MCM7和miRNA簇的同时过表达引发转基因小鼠的前列腺上皮内瘤变。因此，当MCM7基因位点在人类癌症中扩增或过表达时，会同时产生两种致癌损伤。因此，我们发现了PTEN调控的原致癌mirna依赖网络，并将MCM7位点定义为启动前列腺肿瘤发生的关键因素。
PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor that antagonizes signaling through the phosphatidylinositol-3-kinase–Akt pathway. We have demonstrated that subtle decreases in PTEN abundance can have critical consequences for tumorigenesis. Here, we used a computational approach to identify miR-22, miR-25, and miR-302 as three PTEN-targeting microRNA (miRNA) families found within nine genomic loci. We showed that miR-22 and the miR-106b∼25 cluster are aberrantly overexpressed in human prostate cancer, correlate with abundance of the miRNA processing enzyme DICER, and potentiate cellular transformation both in vitro and in vivo. We demonstrated that the intronic miR-106b∼25 cluster cooperates with its host gene MCM7 in cellular transformation both in vitro and in vivo, so that the concomitant overexpression of MCM7 and the miRNA cluster triggers prostatic intraepithelial neoplasia in transgenic mice. Therefore, the MCM7 gene locus delivers two simultaneous oncogenic insults when amplified or overexpressed in human cancer. Thus, we have uncovered a proto-oncogenic miRNA-dependent network for PTEN regulation and defined the MCM7 locus as a critical factor in initiating prostate tumorigenesis.
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影响因子：
11.4
作者：
Drabkin, H;Parsy, C;Roche, J
通讯作者：
Roche, J
影响因子：
64.5
作者：
Lewis, BP;Shih, IH;Burge, CB
通讯作者：
Burge, CB
影响因子：
14.9
作者：
Griffiths-Jones S;Grocock RJ;van Dongen S;Bateman A;Enright AJ
通讯作者：
Enright AJ
DOI：
10.1073/pnas.0602266103
发表时间：
2006-05-02
影响因子：
11.1
作者：
Costinean, S;Zanesi, N;Croce, CM
通讯作者：
Croce, CM
影响因子：
9.8
作者：
John B;Enright AJ;Aravin A;Tuschl T;Sander C;Marks DS
通讯作者：
Marks DS