Molecular and Cellular Pathobiology The Noncoding RNA MALAT 1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells
Molecular and Cellular Pathobiology The Noncoding RNA MALAT 1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells
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发表时间：
2013
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通讯作者：
Tony Gutschner;Harant Monika;ammerle;M. Eissmann;J. Hsu;Youngsoo Kim;G. Hung;A. Revenko;G. Aru
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作者：
Tony Gutschner;Harant Monika;ammerle;M. Eissmann;J. Hsu;Youngsoo Kim;G. Hung;A. Revenko;G. Aru
长链非编码RNA MALAT1（转移相关肺腺癌转录本1），也被称为MALAT-1或NEAT2（核富集丰富转录本2），是一种高度保守的核非编码RNA (ncRNA)，是肺癌转移发展的预测标志物。为了揭示其功能重要性，我们利用锌指核酸酶对RNA不稳定元件进行基因组整合，在人肺肿瘤细胞中建立了MALAT1基因敲除模型。实现的1000倍MALAT1沉默提供了一个独特的功能损失模型。提出的作用机制包括剪接或基因表达的调节。在肺癌中，MALAT1不改变选择性剪接，但积极调节包括一组转移相关基因在内的基因表达。因此，在小鼠异种移植物中，缺乏malat1的细胞在迁移过程中受损，形成较少的肿瘤结节。阻断MALAT1的反义寡核苷酸（ASO）可防止肿瘤植入后的转移形成。因此，利用ASOs靶向MALAT1为预防肺癌转移提供了一种潜在的治疗方法，这种ncRNA既可以作为预测标志物，也可以作为治疗靶点。最后，调节基因表达，而不是选择性剪接，是malat1在肺癌转移中的关键功能。综上所述，在lncRNAMALAT1作为肺癌转移的生物标志物被发现10年后，我们的功能缺失模型揭示了malat1作为肺癌转移标志的基因表达调节因子的活性功能。癌症Res;73 (3);1 - 10。2012 AACR。
The long noncoding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), also known as MALAT-1 or NEAT2 (nuclear-enriched abundant transcript 2), is a highly conserved nuclear noncoding RNA (ncRNA) and a predictive marker for metastasis development in lung cancer. To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements using zinc finger nucleases. The achieved 1,000-fold MALAT1 silencing provides a unique loss-of-function model. Proposedmechanisms of action include regulation of splicing or gene expression. In lung cancer,MALAT1 does not alter alternative splicing but actively regulates gene expression including a set of metastasis-associated genes. Consequently, MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft. Antisense oligonucleotides (ASO) blocking MALAT1 prevent metastasis formation after tumor implantation. Thus, targeting MALAT1 with ASOs provides a potential therapeutic approach to prevent lung cancer metastasis with this ncRNA serving as both predictive marker and therapeutic target. Finally, regulating gene expression, but not alternative splicing, is the critical function ofMALAT1 in lung cancermetastasis. In summary, 10 years after the discovery of the lncRNAMALAT1 as a biomarker for lung cancer metastasis, our loss-of-function model unravels the active function ofMALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis. Cancer Res; 73(3); 1–10. 2012 AACR.