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      Long noncoding RNA FER1L4 suppresses cancer cell growth by acting as a competing endogenous RNA and regulating PTEN expression

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          Abstract

          Aberrantly expressed long noncoding RNAs (lncRNAs) are associated with various cancers. However, the roles of lncRNAs in the pathogenesis of most cancers are unclear. Here, we report that the lncRNA FER1L4 (fer-1-like family member 4, pseudogene) acts as a competing endogenous RNA (ceRNA) to regulate the expression of PTEN (a well-known tumor suppressor gene) by taking up miR-106a-5p in gastric cancer. We observed that FER1L4 was downregulated in gastric cancer and that its level corresponded with that of PTEN mRNA. Both FER1L4 and PTEN mRNA were targets of miR-106a-5p. Further experiments demonstrated that FER1L4 downregulation liberates miR-106a-5p and decreases the abundances of PTEN mRNA and protein. More importantly, FER1L4 downregulation accelerated cell proliferation by promoting the G 0/G 1 to S phase transition. We conclude that one mechanism by which lncRNAs function in in tumorigenesis is as ceRNAs for tumor suppressor mRNAs.

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          Most cited references 65

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          Circular RNAs are a large class of animal RNAs with regulatory potency.

          Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.
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            Natural RNA circles function as efficient microRNA sponges.

            MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.
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              A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?

              Here, we present a unifying hypothesis about how messenger RNAs, transcribed pseudogenes, and long noncoding RNAs "talk" to each other using microRNA response elements (MREs) as letters of a new language. We propose that this "competing endogenous RNA" (ceRNA) activity forms a large-scale regulatory network across the transcriptome, greatly expanding the functional genetic information in the human genome and playing important roles in pathological conditions, such as cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                26 August 2015
                2015
                : 5
                Affiliations
                [1 ]Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Ningbo University School of Medicine , Ningbo, Zhejiang, 315211, China
                Author notes
                [*]

                Current address: Department of Biochemistry, School of Preclinical Medicine, North Sichuan Medical College, Nanchong, Sichuan, 637000, China.

                Article
                srep13445
                10.1038/srep13445
                4549704
                26306906
                Copyright © 2015, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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