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      Linc-ROR promotes esophageal squamous cell carcinoma progression through the derepression of SOX9

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          Abstract

          Background

          Novel therapies tailored to the molecular composition of esophageal squamous cell carcinoma (ESCC) are needed to improve patient survival. We investigated the regulatory network of long intergenic non-protein coding RNA, regulator of reprogramming (linc-ROR) and sex-determining region Y-box 9 (SOX9), and their therapeutic relevance in ESCC.

          Methods

          Linc-ROR and SOX9 expression were examined in ESCC specimens, cell lines, and cultured tumorspheres. We investigated the effects of linc-ROR on SOX9 expression and malignant phenotypes by CCK8, colony formation, Transwell, and sphere-forming assay. The linc-ROR/SOX9 interaction mediated by multiple microRNAs (miRNAs) was confirmed by bioinformatic analysis, luciferase assay, and RNA-binding protein immunoprecipitation, transient overexpression or antagonizing endogenous candidate miRNAs. The effect of linc-ROR depletion on tumor growth was assessed by xenograft assay.

          Results

          A positive correlation between linc-ROR and SOX9 expression was found in clinical ESCC specimens ( r = 0.562, P = 0.036), cell lines, and tumorspheres. Silencing of linc-ROR significantly inhibited cell proliferation, motility, chemoresistance, and self-renewal capacity. Mechanistically, linc-ROR modulating the derepression of SOX9 by directly sponging multiple miRNAs including miR-15b, miR-33a, miR-129, miR-145, and miR-206. Antagonizing these miRNAs counteracted with linc-ROR silencing, whereas the repression of SOX9 abrogated malignant phenotypes induced by the cocktail of miRNA inhibitors. Moreover, linc-ROR disruption was sufficient to attenuate tumor growth and cancer stem cell marker expression in vivo.

          Conclusions

          Our results demonstrate that the linc-ROR–miRNA–SOX9 regulatory network may represent a novel therapeutic target for ESCC.

          Electronic supplementary material

          The online version of this article (10.1186/s13046-017-0658-2) contains supplementary material, which is available to authorized users.

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          A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

          Laura Poliseno, Leonardo Salmena, JiangWen Zhang … (2010)
          The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs possess a biological role in cancer cells that relies upon their ability to compete for microRNA binding and is independent of their protein-coding function. As a paradigm for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene (PTENP1) and the critical consequences of this interaction. We find that PTENP1 is biologically active as determined by its ability to regulate cellular levels of PTEN, and that it can exert a growth-suppressive role. We also show that PTENP1 locus is selectively lost in human cancer. We extend our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. Further, we demonstrate that the transcripts of protein coding genes such as PTEN are also biologically active. Together, these findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.
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            Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells.

            Sabine Loewer, Moran Cabili, Mitchell Guttman … (2010)
            The conversion of lineage-committed cells to induced pluripotent stem cells (iPSCs) by reprogramming is accompanied by a global remodeling of the epigenome, resulting in altered patterns of gene expression. Here we characterize the transcriptional reorganization of large intergenic non-coding RNAs (lincRNAs) that occurs upon derivation of human iPSCs and identify numerous lincRNAs whose expression is linked to pluripotency. Among these, we defined ten lincRNAs whose expression was elevated in iPSCs compared with embryonic stem cells, suggesting that their activation may promote the emergence of iPSCs. Supporting this, our results indicate that these lincRNAs are direct targets of key pluripotency transcription factors. Using loss-of-function and gain-of-function approaches, we found that one such lincRNA (lincRNA-RoR) modulates reprogramming, thus providing a first demonstration for critical functions of lincRNAs in the derivation of pluripotent stem cells.
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              Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal.

              Yue Wang, Zhenyu Xu, Junfeng Jiang … (2013)
              The embryonic stem cell (ESC) transcriptional and epigenetic networks are controlled by a multilayer regulatory circuitry, including core transcription factors (TFs), posttranscriptional modifier microRNAs (miRNAs), and some other regulators. However, the role of large intergenic noncoding RNAs (lincRNAs) in this regulatory circuitry and their underlying mechanism remains undefined. Here, we demonstrate that a lincRNA, linc-RoR, may function as a key competing endogenous RNA to link the network of miRNAs and core TFs, e.g., Oct4, Sox2, and Nanog. We show that linc-RoR shares miRNA-response elements with these core TFs and that linc-RoR prevents these core TFs from miRNA-mediated suppression in self-renewing human ESC. We suggest that linc-RoR forms a feedback loop with core TFs and miRNAs to regulate ESC maintenance and differentiation. These results may provide insights into the functional interactions of the components of genetic networks during development and may lead to new therapies for many diseases. Copyright © 2013 Elsevier Inc. All rights reserved.
              Article 0 comments Cited 337 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jun Hou: houjun229@163.com
                Feng Li: lifeng7855@126.com
                Journal
                Journal ID (nlm-ta): J Exp Clin Cancer Res
                Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res
                Title: Journal of Experimental & Clinical Cancer Research : CR
                Publisher: BioMed Central (London )
                ISSN (Print): 0392-9078
                ISSN (Electronic): 1756-9966
                Publication date (Electronic): 13 December 2017
                Publication date PMC-release: 13 December 2017
                Publication date Collection: 2017
                Volume: 36
                Electronic Location Identifier: 182
                Affiliations
                [1 ]ISNI 0000 0001 0514 4044, GRID grid.411680.a, Department of Pathology and Key Laboratories for Xinjiang Endemic and Ethnic Diseases, , Shihezi University School of Medicine, ; Shihezi, Xinjiang China
                [2 ]ISNI 0000 0001 0514 4044, GRID grid.411680.a, Department of Immunology, , Shihezi University School of Medicine, ; Shihezi, Xinjiang China
                [3 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Department of Pathology, Beijing Chaoyang Hospital, , Capital Medical University, ; Beijing, China
                [4 ]ISNI 000000041936877X, GRID grid.5386.8, Department of Biomedical Sciences and Cornell Stem Cell Program, , Cornell University, ; Ithaca, NY USA
                [5 ]ISNI 0000 0001 0514 4044, GRID grid.411680.a, Department of Stomatology, , The First Affiliated Hospital of Shihezi University School of Medicine, ; Shihezi, Xinjiang China
                Article
                Publisher ID: 658
                DOI: 10.1186/s13046-017-0658-2
                PMC ID: 5727696
                PubMed ID: 29237490
                SO-VID: e7e4f583-14fd-4f81-99bc-3ed5843a6798
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 18 September 2017
                Date accepted : 1 December 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81460416
                Award ID: 81560399
                Award ID: 81602810
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002855, Ministry of Science and Technology of the People's Republic of China;
                Award ID: 2012AA02A503
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: linc-ror,sox9,stemness,therapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: linc-ror, sox9, stemness, therapy

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