Long Non-coding RNA in Cancer

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October 25, 2013

Non-coding RNA profiles in cancer are largely unknown which greatly impedes the discovery of functionally important ncRNAs in tumorigenesis as well as the generation of genome-wide libraries. Here, we define the ncRNA expression landscape of lung, breast and liver cancer as well as normal tissue from the respective organs (N=150). In summary, we provide the first global comprehensive expression map of 17000 long ncRNA expression in a broad range of human tumor and normal tissue samples and discovered many new lncRNAs associated with cancer as well as tissue-, histology- and prognosis-specific ncRNA signatures. The long non-coding RNA MALAT1 was one of the first lncRNAs associated with cancer: it is a highly conserved nuclear ncRNA and a predictive marker for metastasis development in lung cancer. However, its high abundance and nuclear localization have greatly hampered its functional analysis since it is only inefficiently knocked down by RNA interference (RNAi). To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements site-specifically into the MALAT1 locus using Zinc Finger Nucleases (ZFN). This approach yielded a more than 1000-fold silencing of MALAT1 providing a unique loss-of-function model. Proposed mechanisms of action of MALAT1 include regulation of splicing or gene expression. In lung cancer, MALAT1 does not alter alternative splicing but actively regulates gene expression inducing a signature of metastasis-associated genes. Consequently, MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft model. Encouraged by this discovery of the essential function of MALAT1 in lung cancer metastasis, we wanted to analyze whether MALAT1 could also be therapeutically targeted: We developed Antisense oligonucleotides (ASOs) effectively blocking MALAT1 expression in the cell culture and in the animal. Notably, MALAT1-ASO treatment prevents 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. CV text: Since 2008, Sven Diederichs leads the research group “Molecular RNA Biology & Cancer” at the German Cancer Research Center DKFZ and the Institute of Pathology at the University of Heidelberg. His research is focused on the one hand side microRNA biogenesis and the improvement of RNA interference - on the other hand, he investigates the expression and function of long non-coding RNAs in cancer. Previously, he was a postdoctoral fellow with Daniel Haber at Harvard Medical School / MGH Cancer Center here in Boston. In 2004, he received his PhD in Biochemistry from the University of Muenster in Germany. His scientific work has been recogniozed by several awards including AACR Scholar-in-Training Awards, the Young Scientist Award of the German National Academy of Scientists Leopoldina and most recently the Innovation Award of the Society of Cell Biology and the Hella Bühler-Prize for Cancer Research endowed with 100.000 Euro.

Drug DiscoveryGenomicsInformatics

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