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      Establishment of a 5-gene risk model related to regulatory T cells for predicting gastric cancer prognosis

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          Abstract

          Background

          Gastric cancer (GC) is one of the high-risk cancers that lacks effective methods for prognosis prediction. Therefore, we searched for immune cells related to the prognosis of GC and studied the role of related genes in GC prognosis.

          Methods

          In this study, we collected the mRNA data of GC from The Cancer Genome Atlas (TCGA) database and studied the immune cells that were closely related to the prognosis of GC. Spearman correlation analysis was performed to show the association between immune cell-related genes and the differentially expressed genes (DEGs) of GC. Univariate and multivariate Cox regression analyses were conducted on the immune cell-related genes with a high correlation with GC. A prognostic risk score model was constructed and the most significant feature genes were identified. Kaplan–Meier method was then used to compare the overall survival (OS) of patients with high-risk and low-risk, and receiver operating characteristic (ROC) analysis was used to assess the accuracy of the risk model. In addition, GC patients were grouped according to the median expression of the features genes, and survival analysis was further carried out.

          Results

          It was noted that regulatory T cells (Tregs) were significantly correlated with the prognosis of GC, and 172 genes related to Tregs were found to be closely associated with GC. An optimal prognostic risk model was constructed, and a 5-gene (including LRFN4, ADAMTS12, MCEMP1, HP and MUC15) signature-based risk score was established. Survival analysis showed significant difference in OS between low-risk and high-risk samples. ROC analysis results indicated that the risk model had a high accuracy for the prognosis prediction of samples (AUC = 0.717). The results of survival analysis on each feature gene based on expression levels were consistent with the results of multivariate Cox analysis for predicting the risk rate of the 5 genes.

          Conclusion

          These results proved that the 5-gene signature-based risk score could be used to predict the survival of GC patients, and these 5 genes were closely related to Tregs. These findings are of great significance for studying the role of immune cells and related immune factors in regulating the prognosis of GC.

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          Most cited references11

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          Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation

          Background Circular RNAs (circRNAs) play important regulatory roles in the development of various cancers. However, biological functions and the underlying molecular mechanism of circRNAs in gastric cancer (GC) remain obscure. Methods Differentially expressed circRNAs were identified by RNA sequencing. The biological functions of circSHKBP1 in GC were investigated by a series of in vitro and in vivo experiments. The expression of circSHKBP1 was evaluated using quantitative real-time PCR and RNA in situ hybridization, and the molecular mechanism of circSHKBP1 was demonstrated by western blot, RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments. Lastly, mouse xenograft and bioluminescence imaging were used to exam the clinical relevance of circSHKBP1 in vivo. Results Increased expression of circSHKBP1(hsa_circ_0000936) was revealed in GC tissues and serum and was related to advanced TNM stage and poor survival. The level of exosomal circSHKBP1 significantly decreased after gastrectomy. Overexpression of circSHKBP1 promoted GC cell proliferation, migration, invasion and angiogenesis in vitro and in vivo, while suppression of circSHKBP1 plays the opposite role. Exosomes with upregulated circSHKBP1 promoted cocultured cells growth. Mechanistically, circSHKBP1 sponged miR-582-3p to increase HUR expression, enhancing VEGF mRNA stability. Moreover, circSHKBP1 directly bound to HSP90 and obstructed the interaction of STUB1 with HSP90, inhibiting the ubiquitination of HSP90, resulting in accelerated GC development in vitro and in vivo. Conclusion Our findings demonstrate that exosomal circSHKBP1 regulates the miR-582-3p/HUR/VEGF pathway, suppresses HSP90 degradation, and promotes GC progression. circSHKBP1 is a promising circulating biomarker for GC diagnosis and prognosis and an exceptional candidate for further therapeutic exploration.
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            Gastric cancer: epidemiology and risk factors.

            Gastric cancer is one of the major malignancies in the world. This article summarizes the current understanding of the worldwide burden of this disease, its geographic variation, and temporal trends. An overview is presented of known risk factors, including genetic, dietary, and behavioral, but focuses on Helicobacter pylori infection as the most important factor in noncardia gastric cancer. When the data and the literature allow, we distinguish between cardia and noncardia sub-sites, as it is now clear that these two anatomic locations present distinct and sometimes opposite epidemiological characteristics. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Programmed Death Ligand-1 Immunohistochemistry: Friend or Foe?

              The approval of anti-programmed death receptor (PD)-1 therapies for non-small cell lung cancer has directed the spotlight on programmed death ligand-1 (PD-L1) immunohistochemistry as the latest predictive biomarker potentially required in this disease. Several other drugs in this class will likely be approved in the future and each has been developed with a unique anti-PD-L1 immunohistochemistry test. The prospect of 5 drugs competing in the same treatment area, each possibly requiring PD-L1 immunohistochemistry testing, presents a challenge for pathologists unlike any previously faced. The key issue is whether laboratories will attempt to deliver the trial-validated assays for one or more of these treatments, or introduce instead one or more laboratory developed tests, or attempt to provide a single PD-L1 immunohistochemistry assay for all possible anti-PD-1 and anti-PD-L1 treatments that may be used. This paper discusses some of the issues, challenges, hazards, and possible solutions that have recently emerged in this most complex interface between cancer therapeutics and laboratory biomarker testing.
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                Author and article information

                Contributors
                hugang1121@163.com
                sunningjie2019@163.com
                Jiangjiansong2019@163.com
                chenxiansheng2020@163.com
                Journal
                Cancer Cell Int
                Cancer Cell Int
                Cancer Cell International
                BioMed Central (London )
                1475-2867
                3 September 2020
                3 September 2020
                2020
                : 20
                : 433
                Affiliations
                Department of Gastrointestinal Surgery, Yiwu Central Hospital, 699# Jiangdong Road, Jiangdong Street, 322000 Jinhua, China
                Author information
                http://orcid.org/0000-0002-6615-3371
                Article
                1502
                10.1186/s12935-020-01502-6
                7470613
                32908454
                b7c83c83-eaa9-41cb-8d41-74e199c3aa1b
                © The Author(s) 2020

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

                History
                : 10 November 2019
                : 18 August 2020
                Categories
                Primary Research
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy
                gastric cancer,regulatory t cells,mrna signature,tcga,prognosis prediction
                Oncology & Radiotherapy
                gastric cancer, regulatory t cells, mrna signature, tcga, prognosis prediction

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