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      LncRNA SATB2-AS1 inhibits tumor metastasis and affects the tumor immune cell microenvironment in colorectal cancer by regulating SATB2

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          Abstract

          Background

          Emerging studies suggest that long non-coding RNAs (lncRNAs) play crucial roles in colorectal cancer (CRC). Here, we report a lncRNA, SATB2-AS1, which is specifically expressed in colorectal tissue and is significantly reduced in CRC. We systematically elucidated its functions and possible molecular mechanisms in CRC.

          Methods

          LncRNA expression in CRC was analyzed by RNA-sequencing and RNA microarrays. The expression level of SATB2-AS1 in tissues was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH). The functional role of SATB2-AS1 in CRC was investigated by a series of in vivo and in vitro assays. RNA pull-down, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), chromatin isolation by RNA purification (ChIRP), Bisulfite Sequencing PCR (BSP) and bioinformatics analysis were utilized to explore the potential mechanisms of SATB2-AS1.

          Results

          SATB2-AS1 is specifically expressed in colorectal tissues and downregulated in CRC. Survival analysis indicates that decreased SATB2-AS1 expression is associated with poor survival. Functional experiments and bioinformatics analysis revealed that SATB2-AS1 inhibits CRC cell metastasis and regulates TH1-type chemokines expression and immune cell density in CRC. Mechanistically, SATB2-AS1 directly binds to WDR5 and GADD45A, cis-activating SATB2 (Special AT-rich binding protein 2) transcription via mediating histone H3 lysine 4 tri-methylation (H3K4me3) deposition and DNA demethylation of the promoter region of SATB2.

          Conclusions

          This study reveals the functions of SATB2-AS1 in CRC tumorigenesis and progression, suggesting new biomarkers and therapeutic targets in CRC.

          Electronic supplementary material

          The online version of this article (10.1186/s12943-019-1063-6) contains supplementary material, which is available to authorized users.

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          Most cited references26

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          Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

          J. Gao, B. A. Aksoy, U Dogrusoz … (2015)
          The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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            Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer.

            J Smith, Natasha Deane, Fei Wu … (2010)
            Staging inadequately predicts metastatic risk in patients with colon cancer. We used a gene expression profile derived from invasive, murine colon cancer cells that were highly metastatic in an immunocompetent mouse model to identify patients with colon cancer at risk of recurrence. This phase 1, exploratory biomarker study used 55 patients with colorectal cancer from Vanderbilt Medical Center (VMC) as the training dataset and 177 patients from the Moffitt Cancer Center as the independent dataset. The metastasis-associated gene expression profile developed from the mouse model was refined with comparative functional genomics in the VMC gene expression profiles to identify a 34-gene classifier associated with high risk of metastasis and death from colon cancer. A metastasis score derived from the biologically based classifier was tested in the Moffitt dataset. A high score was significantly associated with increased risk of metastasis and death from colon cancer across all pathologic stages and specifically in stage II and stage III patients. The metastasis score was shown to independently predict risk of cancer recurrence and death in univariate and multivariate models. For example, among stage III patients, a high score translated to increased relative risk of cancer recurrence (hazard ratio, 4.7; 95% confidence interval, 1.566-14.05). Furthermore, the metastasis score identified patients with stage III disease whose 5-year recurrence-free survival was >88% and for whom adjuvant chemotherapy did not increase survival time. A gene expression profile identified from an experimental model of colon cancer metastasis predicted cancer recurrence and death, independently of conventional measures, in patients with colon cancer. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
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              Transcriptome profile of human colorectal adenomas.

              Jacob Sabates-Bellver, Laurens van der Flier, Mariagrazia de Palo … (2007)
              Colorectal cancers are believed to arise predominantly from adenomas. Although these precancerous lesions have been subjected to extensive clinical, pathologic, and molecular analyses, little is currently known about the global gene expression changes accompanying their formation. To characterize the molecular processes underlying the transformation of normal colonic epithelium, we compared the transcriptomes of 32 prospectively collected adenomas with those of normal mucosa from the same individuals. Important differences emerged not only between the expression profiles of normal and adenomatous tissues but also between those of small and large adenomas. A key feature of the transformation process was the remodeling of the Wnt pathway reflected in patent overexpression and underexpression of 78 known components of this signaling cascade. The expression of 19 Wnt targets was closely correlated with clear up-regulation of KIAA1199, whose function is currently unknown. In normal mucosa, KIAA1199 expression was confined to cells in the lower portion of intestinal crypts, where Wnt signaling is physiologically active, but it was markedly increased in all adenomas, where it was expressed in most of the epithelial cells, and in colon cancer cell lines, it was markedly reduced by inactivation of the beta-catenin/T-cell factor(s) transcription complex, the pivotal mediator of Wnt signaling. Our transcriptomic profiles of normal colonic mucosa and colorectal adenomas shed new light on the early stages of colorectal tumorigenesis and identified KIAA1199 as a novel target of the Wnt signaling pathway and a putative marker of colorectal adenomatous transformation.
              Article 0 comments Cited 226 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Mu Xu: xumu123456@126.com
                Xueni Xu: 18795867526@163.com
                Bei Pan: panbei9656@163.com
                Xiaoxiang Chen: chenxiaoxiang1987@126.com
                Kang Lin: linkang345@126.com
                Kaixuan Zeng: kaixuanzeng@163.com
                Xiangxiang Liu: 15720802961@163.com
                Tao Xu: 18360861755@163.com
                Li Sun: 540585362@qq.com
                Jian Qin: qinjiankey@163.com
                Bangshun He: hebangshun@163.com
                Yuqin Pan: panyuqin01@163.com
                Huiling Sun: sunhuiling1988@yeah.net
                Shukui Wang:
                ORCID: http://orcid.org/0000-0001-6972-2587
                +86 025 52271000 , sk_wang@njmu.edu.cn
                Journal
                Journal ID (nlm-ta): Mol Cancer
                Journal ID (iso-abbrev): Mol. Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1476-4598
                Publication date (Electronic): 6 September 2019
                Publication date PMC-release: 6 September 2019
                Publication date Collection: 2019
                Volume: 18
                Electronic Location Identifier: 135
                Affiliations
                [1 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, General Clinical Research Center, Nanjing First Hospital, , Nanjing Medical University, ; No. 68, Changle Road, Nanjing, 210006 China
                [2 ]ISNI 0000 0004 1761 0489, GRID grid.263826.b, School of Medicine, , Southeast University, ; Nanjing, 210009 China
                [3 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Department of Laboratory Medicine, Nanjing First Hospital, , Nanjing Medical University, ; Nanjing, 210006 China
                [4 ]GRID grid.452511.6, Department of Laboratory Medicine, , The Second Affiliated Hospital of Nanjing Medical University, ; Nanjing, 210011 China
                Author information
                http://orcid.org/0000-0001-6972-2587
                Article
                Publisher ID: 1063
                DOI: 10.1186/s12943-019-1063-6
                PMC ID: 6729021
                PubMed ID: 31492160
                SO-VID: a68fc092-c6b1-44c5-80af-a04cd4a3dedc
                Copyright © © The Author(s). 2019
                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 : 8 May 2019
                Date accepted : 28 August 2019
                Funding
                Funded by: Key Project of Science and Technology Development of Nanjing Medicine
                Award ID: ZDX16001
                Award Recipient :
                Funded by: National Nature Science Foundation of China
                Award ID: 81802093
                Award Recipient :
                Funded by: Innovation team of Jiangsu provincial health-strengthening engineering by science and education
                Award ID: CXTDB2017008
                Award Recipient :
                Funded by: Jiangsu Youth Medical Talents Training Project
                Award ID: QNRC2016066
                Award ID: QNRC2016074
                Award Recipient :
                Funded by: Jiangsu 333 High-level Talents Cultivating Project
                Award ID: BRA201702
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: satb2-as1,colorectal cancer,satb2,metastasis,immune response,wdr5,gadd45a
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: satb2-as1, colorectal cancer, satb2, metastasis, immune response, wdr5, gadd45a

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