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The Noncoding RNA MALAT1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells

Gutschner, Tony, Hämmerle, Monika, Eißmann, Moritz, Hsu, Jeff, Kim, Youngsoo, Hung, Gene, Revenko, Alexey, Arun, Gayatri, Stentrup, Marion, Groß, Matthias, Zörnig, Martin, MacLeod, A. Robert, Spector, David L., Diederichs, Sven·2013·Cancer Research
DOI 10.1158/0008-5472.can-12-2850PMC PMC3589741

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Abstract

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. Cancer Res; 73(3); 1180–9. ©2012 AACR.

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Metadata

Authors
Gutschner, T., Hämmerle, M., Eißmann, M., Hsu, J., Kim, Y., Hung, G., Revenko, A., Arun, G., Stentrup, M., Groß, M., Zörnig, M., MacLeod, A. R., Spector, D. L., & Diederichs, S.
Affiliations
Authors' Affiliations: 1Helmholtz-University-Group “Molecular RNA Biology & Cancer,” German Cancer Research Center DKFZ & Institute of Pathology; 2Institute of Pathology, University Hospital Heidelberg, Heidelberg; 3Georg-Speyer-Haus, Frankfurt am Main, Germany; 4ISIS Pharmaceuticals, Carlsbad, California; and 5Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2013-01-31
Volume
73
Issue
3
Pages
1180-1189
ISSN
  • 0008-5472
  • 1538-7445
DOI
10.1158/0008-5472.can-12-2850
PMC
PMC3589741
Cited by
1,415
References
3
Language
en

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