Uncovering growth-suppressive MicroRNAs in lung cancer.
Uncovering growth-suppressive MicroRNAs in lung cancer.
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DOI：
10.1158/1078-0432.ccr-08-1355
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发表时间：
2009-02-15
期刊：
影响因子：
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通讯作者：
Dmitrovsky E
中科院分区：
文献类型：
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作者：
Liu X;Sempere LF;Galimberti F;Freemantle SJ;Black C;Dragnev KH;Ma Y;Fiering S;Memoli V;Li H;DiRenzo J;Korc M;Cole CN;Bak M;Kauppinen S;Dmitrovsky E
MicroRNA(MiRNA)表达谱改善了包括肺癌在内的恶性肿瘤的分类、诊断和预后信息。这项研究发现了肺癌中独特的生长抑制miRNAs。在正常肺组织和来自野生型和蛋白酶体降解抗性Cyclin E转基因小鼠的腺癌上进行miRNA阵列，以揭示肺癌中抑制的miRNAs。实时和半定量逆转录-聚合酶链式反应以及原位杂交分析证实了这些发现。从每个转基因株系(分别命名为ED-1和ED-2细胞)中获得肺癌细胞系。每个突出显示的miRNA都被独立地导入这些细胞。探讨了抑制生长的机制。我们检测了一个通过计算预测的miRNA靶标的表达，并在一组正常和恶性的人类肺组织库中研究了这些miRNA。在转基因肺癌中，miR-34c、miR-145和miR-142-5p均被抑制。实时和半定量逆转录-聚合酶链式反应以及原位杂交分析证实了这一结果。类似的miRNA图谱也出现在人类正常肺组织和恶性肺组织中。单独过表达miR-34c、miR-145和miR-142-5p可显著抑制ED-1和ED-2细胞的生长。抗miR共转染可拮抗这种抑制作用。MiR-34c靶点细胞周期蛋白E被miR-34c基因所抑制，为观察到的生长抑制作用提供了机制。MiR-34c、miR-145和miR-142-5p在小鼠和人肺癌中均有表达。每个miRNA的转染组均显著抑制肺癌细胞生长。因此，这些miRNAs具有生长抑制作用，并被认为在肺中发挥抗肿瘤作用。
MicroRNA (miRNA) expression profiles improve classification, diagnosis, and prognostic information of malignancies, including lung cancer. This study uncovered unique growthsuppressive miRNAs in lung cancer. miRNA arrays were done on normal lung tissues and adenocarcinomas from wild-type and proteasome degradation-resistant cyclin E transgenic mice to reveal repressed miRNAs in lung cancer. Real-time and semiquantitative reverse transcription-PCR as well as in situ hybridization assays validated these findings. Lung cancer cell lines were derived from each transgenic line (designated as ED-1 and ED-2 cells, respectively). Each highlighted miRNA was independently transfected into these cells. Growth-suppressive mechanisms were explored. Expression of a computationally predictedmiRNA target was examined.ThesemiRNAs were studied in a paired normal-malignant human lung tissue bank. miR-34c, miR-145, and miR-142-5p were repressed in transgenic lung cancers. Findings were confirmed by real-time and semiquantitative reverse transcription-PCR as well as in situ hybridization assays. Similar miRNA profiles occurred in human normal versus malignant lung tissues. Individual overexpression of miR-34c, miR-145, and miR-142-5p in ED-1and ED-2 cells markedly repressed cell growth. Anti-miR cotransfections antagonized this inhibition. The miR-34c target, cyclin E, was repressed by miR-34c transfection and provided amechanism for observed growth suppression. miR-34c, miR-145, and miR-142-5p were repressed in murine and human lung cancers. Transfection of each miRNA significantly repressed lung cancer cell growth. Thus, these miRNAs were growth suppressive and are proposed to exert antineoplastic effects in the lung.