The Noncoding RNA MALAT1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells
Tony Gutschner,Monika Hämmerle,Moritz Eißmann,Jeff Hsu,Youngsoo Kim,Gene Hung,Alexey S. Revenko,Gayatri Arun,Marion Stentrup,Matthias Groß,Martin Zörnig,A. Robert MacLeod,David L. Spector,Sven Diederichs +13 more
TLDR
A loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis with this ncRNA serving as both predictive marker and therapeutic target.Abstract:
The long non-coding RNA MALAT1, also known as MALAT-1 or NEAT2, is a highly conserved nuclear 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 1000-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 blocking MALAT1 prevent metastasis formation after tumor implantation. Thus, targeting MALAT1 with antisense oligonucleotides provides a potential therapeutic approach to prevent lung cancer metastasis with MALAT1 serving as both, predictive marker and therapeutic target. Lastly, regulating gene expression, but not alternative splicing is the critical function of MALAT1 in lung cancer metastasis. In summary, ten 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.read more
Citations
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Malat1 regulates serum response factor through miR-133 as a competing endogenous RNA in myogenesis.
TL;DR: It is demonstrated that Malat1 modulates Srf through miR‐133 as a competing endogenous RNA in myogenesis and established a novel connection among Malat 1, miR-133, and Srf in myoblast differentiation.
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LncRNAtor: A comprehensive resource for functional investigation of long non-coding RNAs
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The role of long non-coding RNAs in genome formatting and expression.
TL;DR: The different types of lncRNAs, their mechanisms of action on genome formatting and expression are reviewed and emphasis is emphasized on the multifaceted action of the H19 lncRNA.
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MicroRNAs, Long Noncoding RNAs, and Their Functions in Human Disease.
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TL;DR: The complexity, flexibility, and versatility of the structures and functions of miRNAs and lncRNAs demand integration of experimental and bioinformatics tools to acquire sufficient knowledge for applications of these noncoding RNAs in clinical care.
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The Clinical Relevance of Long Non-Coding RNAs in Cancer
TL;DR: The value of lncRNAs in the clinical setting is considered, and in particular their potential roles as diagnostic and prognostic markers in cancer are considered.
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TL;DR: Detailed polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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TL;DR: Three potentially functional classes of RNAs have been identified, two of which are syntenically conserved and correlate with the expression state of protein-coding genes and support a highly interleaved organization of the human transcriptome.
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