miR-449a causes Rb-dependent cell cycle arrest and senescence in prostate cancer cells.
miR-449a causes Rb-dependent cell cycle arrest and senescence in prostate cancer cells.
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DOI：
10.18632/oncotarget.167
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Li LC
中科院分区：
文献类型：
--
作者：
Noonan EJ;Place RF;Basak S;Pookot D;Li LC
MicroRNA（miRNAs）是一类通过抑制翻译或触发互补mRNA序列降解来调节基因表达的小的非编码RNA（ncRNA）。某些miRNA已显示作为p53和/或视网膜母细胞瘤（Rb）调控网络的组成部分起作用。因此，miRNA失调可能对癌症发展产生深远影响。已有研究表明，miR-449 a在人前列腺癌组织中表达下调，具有潜在的肿瘤抑制功能。在本研究中，我们确定miR-449 a介导的前列腺癌细胞生长停滞依赖于Rb蛋白。我们发现突变型Rb前列腺癌细胞（DU-145）对miR-449 a诱导的细胞周期停滞和细胞衰老具有抗性，而野生型Rb在DU-145亚系（DU-1.1和B5）中的过表达恢复了miR-449 a的功能。3 'UTR区域的计算机分析揭示了细胞周期蛋白D1（CCND 1）转录物中的推定miR-449 a靶位点; CCND 1是一种直接参与调节Rb活性和细胞周期进程的癌基因。荧光素酶3 'UTR报告基因构建体和抑制性寡核苷酸证实了细胞周期蛋白D1是miR-449 a的直接下游靶标。我们还发现，miR-449 a通过敲低细胞周期蛋白D1和之前验证的靶点HDAC 1来抑制Rb磷酸化。通过靶向参与控制Rb活性的基因，miR-449 a以Rb依赖性方式调节生长和衰老。这些数据表明，miR-449 a是Rb通路的miRNA组分，其肿瘤抑制剂样作用部分取决于前列腺癌细胞中的Rb状态。
MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) that regulate gene expression by repressing translation or triggering the degradation of complementary mRNA sequences. Certain miRNAs have been shown to function as integral components of the p53 and/or retinoblastoma (Rb) regulatory networks. As such, miRNA dysregulation can have a profound effect on cancer development. Previous studies have shown that miR-449a is down-regulated in human prostate cancer tissue and possesses potential tumor suppressor function. In the present study, we identify miR-449a-mediated growth arrest in prostate cancer cells is dependent on the Rb protein. We show that mutant Rb prostate cancer cells (DU-145) are resistant to cell cycle arrest and cellular senescence induced by miR-449a, while overexpression of wild-type Rb in DU-145 sublines (DU-1.1 and B5) restores miR-449a function. In silico analysis of 3'UTR regions reveal a putative miR-449a target site in the transcript of Cyclin D1 (CCND1); an oncogene involved in directly regulating Rb activity and cell cycle progression. Luciferase 3'UTR reporter constructs and inhibitory oligonucleotides confirm that Cyclin D1 is a direct downstream target of miR-449a. We also reveal that miR-449a suppresses Rb phosphorylation through the knockdown of Cyclin D1 and previously validated target HDAC1. By targeting genes involved in controlling Rb activity, miR-449a regulates growth and senescence in an Rb-dependent manner. These data indicate that miR-449a is a miRNA component of the Rb pathway and its tumor suppressor-like effects, in part, depends on Rb status in prostate cancer cells.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
8
作者：
Noonan, E. J.;Place, R. F.;Dahiya, R.
通讯作者：
Dahiya, R.
影响因子：
64.8
作者：
He, Lin;He, Xingyue;Hannon, Gregory J.
通讯作者：
Hannon, Gregory J.
视网膜母细胞瘤易感基因（RB1）的丧失是前列腺肿瘤发生的常见和早期事件。
影响因子：
8.8
作者：
Phillips, S M;Barton, C M;Lee, S J;Morton, D G;Wallace, D M;Lemoine, N R;Neoptolemos, J P
通讯作者：
Neoptolemos, J P
影响因子：
--
作者：
Place, RF;Noonan, EJ;Giardina, C
通讯作者：
Giardina, C