The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities
The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities
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DOI：
10.1038/nm.1880
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发表时间：
2008-11-01
期刊：
影响因子：
82.9
通讯作者：
De Maria, Ruggero
中科院分区：
文献类型：
--
作者：
Bonci, Desiree;Coppola, Valeria;De Maria, Ruggero
MicroRNAs(MiRNAs)是一种非编码的小RNA，通过靶向特定的信使RNA来抑制蛋白质翻译。MiR-15a和miR-16-1通过靶向癌基因bcl2发挥潜在的肿瘤抑制作用。这些miRNAs在染色体13q14区域形成一个簇，该区域在癌症中经常缺失。在这里，我们报告了miR-15a和miR-16-1簇针对CCND1(编码细胞周期蛋白D1)和WNT3a，它促进了一些肿瘤发生的特征，如生存，增殖和侵袭。在晚期前列腺癌的癌细胞中，miR-15a和miR-16的表达水平显著降低，而bcl2、CCND1和WNT3a的表达则相反上调。将miR-15a和miR-16特异性的抗癌基因导入正常小鼠的前列腺可导致显著的增生，而敲除miR-15a和miR-16可促进未转化的前列腺细胞的存活、增殖和侵袭性，这些细胞在免疫缺陷的NOD-SCID小鼠中成为肿瘤细胞。相反，miR-15a和miR-16-1表达的重建会导致前列腺癌移植瘤生长停滞、细胞凋亡和显著消退。综上所述，我们认为miR-15a和miR-16通过调控细胞的存活、增殖和侵袭，在前列腺癌中发挥抑癌基因的作用。这些发现具有治疗意义，并可能被用于未来前列腺癌的治疗。
MicroRNAs (miRNAs) are noncoding small RNAs that repress protein translation by targeting specific messenger RNAs. miR-15a and miR-16-1 act as putative tumor suppressors by targeting the oncogene BCL2. These miRNAs form a cluster at the chromosomal region 13q14, which is frequently deleted in cancer. Here, we report that the miR-15a and miR-16-1 cluster targets CCND1 (encoding cyclin D1) and WNT3A, which promotes several tumorigenic features such as survival, proliferation and invasion. In cancer cells of advanced prostate tumors, the miR-15a and miR-16 level is significantly decreased, whereas the expression of BCL2, CCND1 and WNT3A is inversely upregulated. Delivery of antagomirs specific for miR-15a and miR-16 to normal mouse prostate results in marked hyperplasia, and knockdown of miR-15a and miR-16 promotes survival, proliferation and invasiveness of untransformed prostate cells, which become tumorigenic in immunodeficient NOD-SCID mice. Conversely, reconstitution of miR-15a and miR-16-1 expression results in growth arrest, apoptosis and marked regression of prostate tumor xenografts. Altogether, we propose that miR-15a and miR-16 act as tumor suppressor genes in prostate cancer through the control of cell survival, proliferation and invasion. These findings have therapeutic implications and may be exploited for future treatment of prostate cancer.