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      Characterization of the alternative splicing landscape in lung adenocarcinoma reveals novel prognosis signature associated with B cells

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          Abstract

          Background

          Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer-related death. Malignant pleural effusion (MPE) is a special microenvironment for lung cancer metastasis. Alternative splicing, which is regulated by splicing factors, affects the expression of most genes and influences carcinogenesis and metastasis.

          Methods

          mRNA-seq data and alternative splicing events in lung adenocarcinoma (LUAD) were obtained from The Cancer Genome Atlas (TCGA). A risk model was generated by Cox regression analyses and LASSO regression. Cell isolation and flow cytometry were used to identify B cells.

          Results

          We systematically analyzed the splicing factors, alternative splicing events, clinical characteristics, and immunologic features of LUAD in the TCGA cohort. A risk signature based on 23 alternative splicing events was established and identified as an independent prognosis factor in LUAD. Among all patients, the risk signature showed a better prognostic value in metastatic patients. By single-sample gene set enrichment analysis, we found that among tumor-infiltrating lymphocytes, B cells were most significantly correlated to the risk score. Furthermore, we investigated the classification and function of B cells in MPE, a metastatic microenvironment of LUAD, and found that regulatory B cells might participate in the regulation of the immune microenvironment of MPE through antigen presentation and promotion of regulatory T cell differentiation.

          Conclusions

          We evaluated the prognostic value of alternative splicing events in LUAD and metastatic LUAD. We found that regulatory B cells had the function of antigen presentation, inhibited naïve T cells from differentiating into Th1 cells, and promoted Treg differentiation in LUAD patients with MPE.

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          Most cited references48

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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            Hallmarks of Cancer: The Next Generation

            The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries

              In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Writing – original draft
                Role: Writing – original draft
                Role: Methodology
                Role: Methodology
                Role: Formal analysis
                Role: Methodology
                Role: Supervision
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLOS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                11 July 2023
                2023
                : 18
                : 7
                : e0279018
                Affiliations
                [001] Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
                University of Crete & IMBB-FORTH, GREECE
                Author notes

                Competing Interests: The authors have declared that no conflict of interest exists.

                Author information
                https://orcid.org/0000-0002-1154-7920
                Article
                PONE-D-22-01983
                10.1371/journal.pone.0279018
                10335703
                37432957
                8b2b22b2-9bd6-4e93-acfa-8c6bbfd9086f
                © 2023 Shao et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 26 February 2022
                : 7 November 2022
                Page count
                Figures: 6, Tables: 1, Pages: 17
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81730046
                Award Recipient :
                Funded by: Beijing Scholars Program
                Award ID: No. 048
                This work was supported by grants from National Natural Science Foundation of China (81730046) and Beijing Scholars Program (No. 048). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                Antibody-Producing Cells
                B Cells
                Biology and Life Sciences
                Immunology
                Immune Cells
                Antibody-Producing Cells
                B Cells
                Medicine and Health Sciences
                Immunology
                Immune Cells
                Antibody-Producing Cells
                B Cells
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                B Cells
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                B Cells
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                B Cells
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                B Cells
                Medicine and Health Sciences
                Epidemiology
                Medical Risk Factors
                Cancer Risk Factors
                Medicine and Health Sciences
                Oncology
                Cancer Risk Factors
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Lung and Intrathoracic Tumors
                Biology and life sciences
                Genetics
                Gene expression
                RNA processing
                Alternative Splicing
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                RNA processing
                Alternative Splicing
                Medicine and Health Sciences
                Oncology
                Metastasis
                Medicine and Health Sciences
                Oncology
                Basic Cancer Research
                Metastasis
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and Life Sciences
                Developmental Biology
                Cell Differentiation
                Biology and Life Sciences
                Cell Biology
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                White Blood Cells
                T Helper Cells
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                T Helper Cells
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                T Helper Cells
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                T Helper Cells
                Custom metadata
                The raw sequence data reported in this paper are available at the GEO (accession number: GSE220822, https://www.ncbi.nlm.nih.gov/geo/).

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