MicroRNA145 Targets BNIP3 and Suppresses Prostate Cancer Progression
MicroRNA145 Targets BNIP3 and Suppresses Prostate Cancer Progression
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MicroRNA145 靶向 BNIP3 并抑制前列腺癌进展
DOI：
10.1158/0008-5472.can-09-3718
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发表时间：
2010-04-01
期刊：
影响因子：
11.2
通讯作者：
Zhou, Qiao
中科院分区：
文献类型：
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作者：
Chen, Xueqin;Gong, Jing;Zhou, Qiao
假定的肿瘤抑制因子miR145受TP53转录调控，在许多肿瘤中表达下调；然而，其在前列腺癌中的作用尚不清楚。另一方面，BCL2/腺病毒E1B 19 - kDa相互作用蛋白3（BNIP3）在包括前列腺癌在内的多种肿瘤中过表达，并且可能转录抑制凋亡诱导因子（AIF）基因。尽管BNIP3的转录受缺氧诱导因子1α（在前列腺癌中也升高）控制，但我们通过生物信息学分析推测miR145对BNIP3存在转录后调控，并且在此我们通过实验表明miR145通过靶向BNIP3的3' - 非翻译区对其进行负调控。在前列腺癌PC - 3和DU145细胞中使用腺病毒载体人工过表达miR145可显著下调BNIP3，同时AIF上调，细胞生长受抑，细胞死亡增加。在PC - 3细胞（缺乏TP53蛋白）和DU145细胞（表达突变的无功能TP53）中人工过表达野生型TP53可显著上调miR145的表达，从而对BNIP3和细胞行为产生与miR145过表达相同的影响。对前列腺癌（n = 134）和良性前列腺（n = 83）组织样本的分析显示，前列腺癌中miR145显著降低，BNIP3表达增加（P < 0.001），特别是在肿瘤进展的病例中，并且这两种分子变化都与不良预后相关。作为TP53 - miR145 - BNIP3 - AIF网络一部分的miR145 - BNIP3对的异常可能在前列腺癌的发病机制和进展中起主要作用。《癌症研究》；70(7)；2728 - 38。（C）2010美国癌症研究协会。
The putative tumor suppressor miR145 is transcriptionally regulated by TP53 and is downregulated in many tumors; however, its role in prostate cancer is unknown. On the other hand, BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) is overexpressed in various tumors, including prostate cancer, and may transcriptionally repress the apoptosis-inducing factor (AIF) gene. Although BNIP3 transcription is controlled by hypoxia-inducible factor 1 alpha (also elevated in prostate cancer), we postulated the posttranscriptional regulation of BNIP3 by miR145 through bioinformatics analysis, and herein we experimentally showed that miR145 negatively regulated BNIP3 by targeting its 3'-untranslated region. Artificial overexpression of miR145 by using adenoviral vectors in prostate cancer PC-3 and DU145 cells significantly downregulated BNIP3, together with the upregulation of AIF, reduced cell growth, and increased cell death. Artificial overexpression of wild-type TP53 in PC-3 cells (which lack TP53 protein) and DU145 cells (in which mutated nonfunctioning TP53 is expressed) significantly upregulated miR145 expression with consequent effects on BNIP3 and cell behavior as with miR145 overexpression. Analysis of prostate cancer (n = 134) and benign prostate (n = 83) tissue sample showed significantly decreased miR145 and increased BNIP3 expression in prostate cancer (P < 0.001), particularly in those with tumor progression, and both molecular changes were associated with unfavorable outcome. Abnormalities of the miR145-BNIP3 pair as part of TP53-miR145-BNIP3-AIF network may play a major role in prostate cancer pathogenesis and progression. Cancer Res; 70(7); 2728-38. (C) 2010 AACR.