Data from The Noncoding RNA <i>MALAT1</i> Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells

Abstract

<div>Abstract<p>The long noncoding RNA <i>MALAT1</i> (metastasis-associated lung adenocarcinoma transcript 1), also known as <i>MALAT-1</i> or <i>NEAT2</i> (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 <i>MALAT1</i> knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements using zinc finger nucleases. The achieved 1,000-fold <i>MALAT1</i> silencing provides a unique loss-of-function model. Proposed mechanisms of action include regulation of splicing or gene expression. In lung cancer, <i>MALAT1</i> does not alter alternative splicing but actively regulates gene expression including a set of metastasis-associated genes. Consequently, <i>MALAT1</i>-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft. Antisense oligonucleotides (ASO) blocking <i>MALAT1</i> prevent metastasis formation after tumor implantation. Thus, targeting <i>MALAT1</i> 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 of <i>MALAT1</i> in lung cancer metastasis. In summary, 10 years after the discovery of the lncRNA <i>MALAT1</i> as a biomarker for lung cancer metastasis, our loss-of-function model unravels the active function of <i>MALAT1</i> as a regulator of gene expression governing hallmarks of lung cancer metastasis. <i>Cancer Res; 73(3); 1180–9. ©2012 AACR</i>.</p></div>