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      Identification of an Immune-Related Nine-lncRNA Signature Predictive of Overall Survival in Colon Cancer

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          Abstract

          Growing evidence suggests that immune-related genes (IRGs) and long non-coding RNAs (lncRNAs) can serve as prognostic markers of overall survival (OS) in patients with colon cancer. This study aimed to identify an immune-related lncRNA signature for the prospective assessment of prognosis in these patients. Gene expression and clinical data of colon cancer patients were downloaded from The Cancer Genome Atlas (TCGA). Immune-related lncRNAs were identified by a correlation analysis between IRGs and lncRNAs. In total, 447 samples were divided into a training cohort (224 samples) and a testing cohort (223 samples). Univariate, lasso and multivariate Cox regression analyses identified an immune-related nine-lncRNA signature closely related to OS in colon cancer patients in the training dataset. A risk score formula involving nine immune-related lncRNAs was developed to evaluate the prognostic value of the lncRNA signature in the training dataset. Colon cancer patients with a high risk score had poorer OS than those with a low risk score. A multivariate Cox regression analysis confirmed that the immune-related nine-lncRNA signature could be an independent prognostic factor in colon cancer patients. The results were further confirmed in the testing cohort and the entire TCGA cohort. Furthermore, a gene set enrichment analysis revealed several pathways with significant enrichment in the high- and low-risk groups that may be helpful in formulating clinical strategies and understanding the underlying mechanisms. Finally, a quantitative real-time polymerase chain reaction assay found that the nine lncRNAs were significantly differentially expressed in colon cancer cell lines. The results of this study indicate that this signature has important clinical implications for improving predictive outcomes and guiding individualized treatment in colon cancer patients. These lncRNAs could be potential biomarkers affecting the prognosis of colon cancer.

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          An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion

          John D Klement, Amy V Paschall, Priscilla Redd … (2018)
          Despite breakthroughs in immune checkpoint inhibitor (ICI) immunotherapy, not all human cancers respond to ICI immunotherapy and a large fraction of patients with the responsive types of cancers do not respond to current ICI immunotherapy. This clinical conundrum suggests that additional immune checkpoints exist. We report here that interferon regulatory factor 8 (IRF8) deficiency led to impairment of cytotoxic T lymphocyte (CTL) activation and allograft tumor tolerance. However, analysis of chimera mice with competitive reconstitution of WT and IRF8-KO bone marrow cells as well as mice with IRF8 deficiency only in T cells indicated that IRF8 plays no intrinsic role in CTL activation. Instead, IRF8 functioned as a repressor of osteopontin (OPN), the physiological ligand for CD44 on T cells, in CD11b + Ly6C lo Ly6G + myeloid cells and OPN acted as a potent T cell suppressor. IRF8 bound to the Spp1 promoter to repress OPN expression in colon epithelial cells, and colon carcinoma exhibited decreased IRF8 and increased OPN expression. The elevated expression of OPN in human colon carcinoma was correlated with decreased patient survival. Our data indicate that myeloid and tumor cell–expressed OPN acts as an immune checkpoint to suppress T cell activation and confer host tumor immune tolerance.
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            A Positive Feed-Forward Loop between LncRNA-CYTOR and Wnt/β-Catenin Signaling Promotes Metastasis of Colon Cancer

            Ran Cui, Shenglong Qiu, Ming Zhong … (2018)
            We previously demonstrated that long non-coding RNA cytoskeleton regulator RNA (CYTOR), also known as Linc00152, was significantly overexpressed in colon cancer and conferred resistance to oxaliplatin-induced apoptosis. At the same time, elevated CYTOR expression was also reported in gastric cancer and exerted influences on epithelial-mesenchymal transition (EMT) markers. However, the precise mechanism by which CYTOR promotes the EMT phenotype and cancer metastasis remains poorly understood. Here, we showed that loss of epithelial characteristics and simultaneous gain of mesenchymal features correlated with CYTOR expression. Knockdown of CYTOR attenuated colon cancer cell migration and invasion. Conversely, ectopic expression of CYTOR induced an EMT program and enhanced metastatic properties of colon cancer cells. Mechanistically, the binding of CYTOR to cytoplasmic β-catenin impeded casein kinase 1 (CK1)-induced β-catenin phosphorylation that enabled it to accumulate and translocate to the nucleus. Reciprocally, β-catenin/TCF complex enhanced the transcription activity of CYTOR in nucleus, thus forming a positive feed-forward circuit. Moreover, elevated CYTOR, alone or combined with overexpression of nuclear β-catenin, was predictive of poor prognosis. Our findings suggest that CYTOR promotes colon cancer EMT and metastasis by interacting with β-catenin, and the positive feed-forward circuit of CYTOR-β-catenin might be a useful therapeutic target in antimetastatic strategy.
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              SNHG12: An LncRNA as a Potential Therapeutic Target and Biomarker for Human Cancer

              Suraksha Tamang, Varnali Acharya, Deepronil Roy … (2019)
              Limitations in current diagnostic procedures warrant identification of new methodologies to improve diagnoses of cancer patients. In this context, long non-coding RNAs (lncRNAs) have emerged as stable biomarkers which are expressed abundantly in tumors. Importantly, these can be detected at all stages of tumor development, and thus may provide potential biomarkers and/or therapeutic targets. Recently, we suggested that aberrant levels of lncRNAs can be used to determine the invasive and metastatic potential of tumor cells. Further, direct correlations of lncRNAs with cancer-derived inflammation, metastasis, epithelial-to-mesenchymal transition, and other hallmarks of cancer indicate their potential as biomarkers and targets for cancer. Thus, in this review we have discussed the importance of small nucleolar RNA host gene 12 (SNHG12), a lncRNA, as a potential biomarker for a variety of cancers. A meta-analysis of a large cohort of cancer patients revealed that SNHG12 may also serve as a potential target for cancer-directed interventions due to its involvement in unfolded protein responses, which many tumor cells exploit to both evade immune-mediated attack and enhance the polarization of effector immune cells (e.g., macrophages and T cells). Thus, we propose that SNHG12 may serve as both a biomarker and a druggable therapeutic target with promising clinical potential.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Genet
                Journal ID (iso-abbrev): Front Genet
                Journal ID (publisher-id): Front. Genet.
                Title: Frontiers in Genetics
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-8021
                Publication date (Electronic): 30 April 2020
                Publication date Collection: 2020
                Volume: 11
                Electronic Location Identifier: 318
                Affiliations
                [1] 1Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University , Fuzhou, China
                [2] 2Department of Radiotherapy, The First Affiliated Hospital of Fujian Medical University , Fuzhou, China
                Author notes

                Edited by: Juan Caballero, Universidad Autónoma de Querétaro, Mexico

                Reviewed by: Mohammad Taheri, Shahid Beheshti University of Medical Sciences, Iran; Meng Zhou, Wenzhou Medical University, China

                *Correspondence: Shaoqin Chen, chenshaoqln1613@ 123456163.com

                †These authors have contributed equally to this work

                This article was submitted to Bioinformatics and Computational Biology, a section of the journal Frontiers in Genetics

                Article
                DOI: 10.3389/fgene.2020.00318
                PMC ID: 7203495
                PubMed ID: 32425969
                SO-VID: f4ae9229-0d23-4dec-9632-a6f632214f34
                Copyright © Copyright © 2020 Lin, Pan, Chen, Lin and Chen.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 26 November 2019
                Date accepted : 17 March 2020
                Page count
                Figures: 9, Tables: 5, Equations: 0, References: 41, Pages: 16, Words: 0
                Categories
                Subject: Genetics
                Subject: Original Research

                ScienceOpen disciplines: Genetics
                Keywords: colon cancer,immune,lncrna,signature,prognosis
                Data availability:
                ScienceOpen disciplines: Genetics
                Keywords: colon cancer, immune, lncrna, signature, prognosis

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