02456nas a2200277   4500008004100000245010200041210006900143300001400212490000700226520156900233100002001802700002201822700002101844700001401865700001801879700001501897700002001912700001801932700002101950700002001971700002001991700002002011700002302031700002102054856010302075       2013                        eng d00aThe Noncoding RNA MALAT1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells0 aNoncoding RNA MALAT1 Is a Critical Regulator of the Metastasis P  a1180-11890 v733 a<p>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. Proposed mechanisms 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 of MALAT1 in lung cancer metastasis. In summary, 10 years after the discovery of the lncRNA MALAT1 as a biomarker for lung cancer metastasis, our loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis.</p>
1 aGutschner, Tony1 aHämmerle, Monika1 aEißmann, Moritz1 aHsu, Jeff1 aKim, Youngsoo1 aHung, Gene1 aRevenko, Alexey1 aArun, Gayatri1 aStentrup, Marion1 aGroß, Matthias1 aZörnig, Martin1 aMacLeod, Robert1 aSpector, David, L.1 aDiederichs, Sven  uhttps://dev7.lt.org/noncoding-rna-malat1-critical-regulator-metastasis-phenotype-lung-cancer-cells