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      Long non-coding RNA Lnc-Tim3 exacerbates CD8 T cell exhaustion via binding to Tim-3 and inducing nuclear translocation of Bat3 in HCC

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          Abstract

          Although one of the first comprehensive examinations of long non-coding RNA (lncRNA) expression was performed in human CD8 T lymphocytes, little is known about their roles in CD8 T cells functions during the progression of hepatocellular carcinoma (HCC). Here, we show that Lnc-Tim3 is upregulated and negatively correlates with IFN-γ and IL-2 production in tumor-infiltrating CD8 T cells of HCC patients. Lnc-Tim3 plays a pivotal role in stimulating CD8 T exhaustion and the survival of the exhausted CD8 T cells. Mechanistically, Lnc-Tim3 specifically binds to Tim-3 and blocks its interaction with Bat3, thus suppressing downstream Lck/ NFAT1/AP-1 signaling, leading to nuclear localization of Bat3, and enhancing p300-dependent p53 and RelA transcriptional activation of anti-apoptosis genes including MDM2 and Bcl-2. In summary, Lnc-Tim3 promotes T cell exhaustion, a phenotype which is correlated with compromised anti-tumor immunity, suggesting that Lnc-Tim3 and its associated signaling pathways may influence the outcome of cancer therapies aimed at modulating the acquired immune system.

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          Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies.

          The 'hallmarks of cancer' are generally accepted as a set of genetic and epigenetic alterations that a normal cell must accrue to transform into a fully malignant cancer. It follows that therapies designed to counter these alterations might be effective as anti-cancer strategies. Over the past 30 years, research on the BCL-2-regulated apoptotic pathway has led to the development of small-molecule compounds, known as 'BH3-mimetics', that bind to pro-survival BCL-2 proteins to directly activate apoptosis of malignant cells. This Timeline article focuses on the discovery and study of BCL-2, the wider BCL-2 protein family and, specifically, its roles in cancer development and therapy.
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            Long non-coding RNAs in the regulation of the immune response

            Highlights • Widespread changes in lncRNA expresssion are associated with the immune response. • lncRNAs regulate the inflammatory response following activation of innate immunity. • lncRNAs regulate T cell differentiation and migration. • The action of long non-coding RNAs is mediated via diverse mechanisms.
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              The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion

              Long noncoding RNAs play a pivotal role in T-helper cell development but little is known about their roles in Treg differentiation and functions during the progression of hepatocellular carcinoma (HCC). Here, we show that lnc-epidermal growth factor receptor (EGFR) upregulation in Tregs correlates positively with the tumour size and expression of EGFR/Foxp3, but negatively with IFN-γ expression in patients and xenografted mouse models. Lnc-EGFR stimulates Treg differentiation, suppresses CTL activity and promotes HCC growth in an EGFR-dependent manner. Mechanistically, lnc-EGFR specifically binds to EGFR and blocks its interaction with and ubiquitination by c-CBL, stabilizing it and augmenting activation of itself and its downstream AP-1/NF-AT1 axis, which in turn elicits EGFR expression. Lnc-EGFR links an immunosuppressive state to cancer by promoting Treg cell differentiation, thus offering a potential therapeutic target for HCC.
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                Author and article information

                Contributors
                +86-25-68136746 , sunbc@njmu.edu.cn
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                30 April 2018
                30 April 2018
                May 2018
                : 9
                : 5
                : 478
                Affiliations
                [1 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, , Nanjing Medical University, ; Nanjing, Jiangsu Province China
                [2 ]ISNI 0000 0004 1799 0784, GRID grid.412676.0, Department of Laboratory Medicine, , the First Affiliated Hospital of Nanjing Medical University, ; Nanjing, Jiangsu Province China
                [3 ]GRID grid.452511.6, Department of Gastroenterology, The Second Affiliated Hospital of Nanjing Medical University, ; Nanjing, Jiangsu Province China
                [4 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Department of General Surgery, , The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, ; Nanjing, Jiangsu Province China
                Article
                528
                10.1038/s41419-018-0528-7
                5924754
                29706626
                ad9e295d-a72b-4620-8dbe-6310cee13d99
                © The Author(s) 2018

                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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 December 2017
                : 9 March 2018
                : 15 March 2018
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                © The Author(s) 2018

                Cell biology
                Cell biology

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