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      Subtype specific expression and survival prediction of pivotal lncRNAs in muscle invasive bladder cancer

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          Abstract

          Comprehensive transcriptome expression analyses of bladder cancer revealed distinct lncRNA clusters with differential molecular and clinical characteristics. In this study, pivotal lncRNAs were assessed for their impact on survival and their differential expression between the molecular bladder cancer subtypes. FFPE samples from chemotherapy-naïve patients with muscle invasive bladder cancer (MIBC) were analyzed on the Nanostring nCounter platform for absolute quantification. An established 36-gene panel was used for molecular subtype classification into basal, luminal and infiltrated MIBC. In a second step, 14 pivotal lncRNAs were assessed for their molecular subtype attribution, and their predictive value in disease-specific survival. In silico validation was performed on a total of 487 MIBC patients (MDA, TGCA and Chungbuk cohort). Several pivotal lncRNAs showed a distinct molecular subtype attribution: e.g. MALAT1 showed a downregulation in the basal subtype ( p = 0.009), TUG1 and CBR3AS1 showed an upregulation in the luminal subtype ( p ≤ 0.001). High transcript levels of SNHG16, CBR3AS1 and H19 appeared to be predictive for a shorter disease-specific survival. Patients overexpressing putative oncogenes MALAT1 and TUG1 in MIBC tissue presented prolonged survival, suggesting tumor suppressive effects of both lncRNAs. The Nanostring nCounter proved to be a valid platform for the quantification of low-abundance transcripts including lncRNAs.

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          Most cited references 35

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          Direct multiplexed measurement of gene expression with color-coded probe pairs.

          We describe a technology, the NanoString nCounter gene expression system, which captures and counts individual mRNA transcripts. Advantages over existing platforms include direct measurement of mRNA expression levels without enzymatic reactions or bias, sensitivity coupled with high multiplex capability, and digital readout. Experiments performed on 509 human genes yielded a replicate correlation coefficient of 0.999, a detection limit between 0.1 fM and 0.5 fM, and a linear dynamic range of over 500-fold. Comparison of the NanoString nCounter gene expression system with microarrays and TaqMan PCR demonstrated that the nCounter system is more sensitive than microarrays and similar in sensitivity to real-time PCR. Finally, a comparison of transcript levels for 21 genes across seven samples measured by the nCounter system and SYBR Green real-time PCR demonstrated similar patterns of gene expression at all transcript levels.
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            Upregulated MALAT-1 contributes to bladder cancer cell migration by inducing epithelial-to-mesenchymal transition.

            Recent studies reveal that long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in cancer biology, and lncRNA MALAT-1 expression is upregulated in some tumors. However, the contributions of MALAT-1 to bladder cancer metastasis remain largely unknown. In the present study we evaluated MALAT-1 expression in bladder cancer tissues by real-time PCR, and defined its biological functions. We verified that MALAT-1 levels were upregulated in bladder cancer tissues compared with adjacent normal tissues, and MALAT-1 expression was remarkably increased in primary tumors that subsequently metastasized, when compared to those primary tumors that did not metastasize. SiRNA-mediated MALAT-1 silencing impaired in vitro bladder cancer cell migration. Downregulation of MALAT-1 resulted in a decrease of the epithelial-mesenchymal transition (EMT)-associated ZEB1, ZEB2 and Slug levels, and an increase of E-cadherin levels. We further demonstrated that MALAT-1 promoted EMT by activating Wnt signaling in vitro. These data suggest an important role for MALAT-1 in regulating metastasis of bladder cancer and the potential application of MALAT-1 in bladder cancer therapy.
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              Downregulated MEG3 activates autophagy and increases cell proliferation in bladder cancer.

              Maternally Expressed Gene 3 (MEG3) is an imprinted gene that encodes a long non-coding RNA (lncRNA) associated with tumorigenesis. Autophagy is activated in cancer cells and contributes to tumor cell survival. However, little is known about whether MEG3 regulates bladder cancer development by controlling autophagy. In the study, we found that MEG3 levels were significantly reduced in bladder cancer tissues compared with normal controls, and autophagy activity was increased in bladder cancer tissues. A significant negative correlation was observed between MEG3 levels and LC3-II (autophagy marker) levels in vivo. We further demonstrated that MEG3 markedly suppressed autophagy activation, whereas MEG3 knockdown activated autophagy in human bladder cancer cell lines. Downregulated expression of MEG3 inhibited cell apoptosis, whereas autophagy inhibition increased MEG3-knockdown cell apoptosis. MEG3 knockdown also increased cell proliferation. More importantly, autophagy inhibition abrogated MEG3 knockdown-induced cell proliferation. These data demonstrated that downregulated MEG3 activates autophagy and increases cell proliferation in bladder cancer.
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                Author and article information

                Contributors
                philipp.erben@medma.uni-heidelberg.de
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                24 November 2020
                24 November 2020
                2020
                : 10
                Affiliations
                [1 ]GRID grid.411778.c, ISNI 0000 0001 2162 1728, Department of Hematology and Oncology, , University Medical Centre Mannheim, ; Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
                [2 ]GRID grid.418041.8, ISNI 0000 0004 0578 0421, Department of Hematology and Oncology, , Centre Hospitalier de Luxembourg, ; Luxembourg, Luxembourg
                [3 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Division of Signalling and Functional Genomics, , German Cancer Research Center (DKFZ), ; Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
                [4 ]GRID grid.7700.0, ISNI 0000 0001 2190 4373, Department of Urology and Urosurgery, Medical Faculty Mannheim, , University of Heidelberg, ; Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
                [5 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Institute of Pathology, , Heidelberg University Hospital, ; Im Neuenheimer Feld 230, 69120 Heidelberg, Germany
                [6 ]GRID grid.5330.5, ISNI 0000 0001 2107 3311, Institute of Pathology, , University of Erlangen-Nuremberg, ; Krankenhausstraße 8-10, 91054 Erlangen, Germany
                [7 ]GRID grid.410607.4, Institute of Pathology, , University Medical Center Mainz, ; Langenbeckstraße 1, 55131 Mainz, Germany
                [8 ]GRID grid.6582.9, ISNI 0000 0004 1936 9748, Department of Urology, , University of Ulm, ; Prittwitzstraße 43, 89075 Ulm, Germany
                Article
                77252
                10.1038/s41598-020-77252-2
                7687888
                33235218
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: Eisenberger grant
                Award ID: WoT1/FE-14
                Award Recipient :
                Funded by: Projekt DEAL
                Categories
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                © The Author(s) 2020

                Uncategorized

                urological cancer, cancer

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