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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Targeted nanocomplex carrying siRNA against MALAT1 sensitizes glioblastoma to temozolomide
TL;DR: Results suggest that combining standard TMZ treatment with lncRNA-targeting therapies using the nanocomplex could substantially enhance the very poor prognosis for GBM patients.
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Preclinical Study using Malat1 Small Interfering RNA or Androgen Receptor Splicing Variant 7 Degradation Enhancer ASC-J9® to Suppress Enzalutamide-resistant Prostate Cancer Progression
Ronghao Wang,Yin Sun,Lei Li,Lei Li,Yuanjie Niu,WanYing Lin,Changyi Lin,Emmanuel S. Antonarakis,Jun Luo,Shuyuan Yeh,Chawnshang Chang,Chawnshang Chang,Chawnshang Chang +12 more
TL;DR: It is demonstrated that Malat 1 is indispensable for Enz-induced AR-v7 production in VCaP and EnzR-C4-2 cells and new therapies using Malat1-short interfering RNA or ASC-J9® may be developed in the future to better suppress enzalutamide-resistant prostate cancer.
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Long non-coding RNAs in cancer: implications for personalized therapy.
TL;DR: This concise review of three classes of long non-coding RNAs describes their appeal as targets and as drugs, while pointing out the limitations that still lie ahead of their definitive entry into clinical practice.
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Long noncoding RNA Malat1 regulates differential activation of macrophages and response to lung injury.
Huachun Cui,Sami Banerjee,Sijia Guo,Sijia Guo,Na Xie,Jing Ge,Jing Ge,Dingyuan Jiang,Dingyuan Jiang,Martin Zörnig,Victor J. Thannickal,Gang Liu +11 more
TL;DR: It is found that lncRNA Malat1 expression is distinctly regulated in differentially activated macrophages in that it is upregulated in LPS-treated and downregulated in IL-4-treated cells, and the role of Malat 1 in the regulation of macrophage polarization is identified.
Journal ArticleDOI
miR-489 inhibits silica-induced pulmonary fibrosis by targeting MyD88 and Smad3 and is negatively regulated by lncRNA CHRF.
Qiuyun Wu,Lei Han,Lei Han,Weiwen Yan,Xiaoming Ji,Ruhui Han,Jingjin Yang,Jiali Yuan,Chunhui Ni +8 more
TL;DR: The data indicate that the CHRF-miR-489-MyD88 Smad3 signaling axis exerts key functions in silica-induced pulmonary fibrosis and may represent a therapeutic target for silicosis.
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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.
Journal ArticleDOI
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Miao-Chih Tsai,Ohad Manor,Yue Wan,Nima Mosammaparast,Jordon K. Wang,Fei Lan,Yang Shi,Eran Segal,Howard Y. Chang +8 more
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RNA Maps Reveal New RNA Classes and a Possible Function for Pervasive Transcription
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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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