{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:35:58Z","timestamp":1788910558992,"version":"build-2803163510"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:00:00Z","timestamp":1668384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81760105, 82060108, 81970502"],"award-info":[{"award-number":["81760105, 82060108, 81970502"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Colon adenocarcinoma (COAD) is a common digestive system malignancy with high mortality and poor prognosis. Accumulating evidence indicates that choline metabolism is closely related to tumorigenesis and development. However, the efficacy of choline metabolism-related signature in predicting patient prognosis, immune microenvironment and chemotherapy response has not been fully clarified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Choline metabolism-related differentially expressed genes (DEGs) between normal and COAD tissues were screened using datasets from The Cancer Genome Atlas (TCGA), Kyoto Encyclopedia of Genes and Genomes (KEGG), AmiGO2 and Reactome Pathway databases. Two choline metabolism-related genes (CHKB and PEMT) were identified by univariate and multivariate Cox regression analyses. TCGA-COAD was the training cohort, and GSE17536 was the validation cohort. Patients in the high- and low-risk groups were distinguished according to the optimal cutoff value of the risk score. A nomogram was used to assess the prognostic accuracy of the choline metabolism-related signature. Calibration curves, decision curve analysis (DCA), and clinical impact curve (CIC) were used to improve the clinical applicability of the prognostic signature. Gene Ontology (GO) and KEGG pathway enrichment analyses of DEGs in the high- and low-risk groups were performed. KEGG cluster analysis was conducted by the KOBAS-i database. The distribution and expression of CHKB and PEMT in various types of immune cells were analyzed based on single-cell RNA sequencing (scRNA-seq). The CIBERSORT and ESTIMATE algorithms evaluated tumor immune cell infiltration in the high- and low-risk groups. Evaluation of the half maximal inhibitory concentration (IC<jats:sub>50<\/jats:sub>) of common chemotherapeutic drugs based on the choline metabolism-related signature was performed. Small molecule compounds were predicted using the Connectivity Map (CMap) database. Molecular docking is used to simulate the binding conformation of small molecule compounds and key targets. By immunohistochemistry (IHC), Western blot, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) experiments, the expression levels of CHKB and PEMT in human, mouse, and cell lines were detected.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We constructed and validated a choline metabolism-related signature containing two genes (CHKB and PEMT). The overall survival (OS) of patients in the high-risk group was significantly worse than that of patients in the low-risk group. The nomogram could effectively and accurately predict the OS of COAD patients at 1, 3, and 5 years. The DCA curve and CIC demonstrate the clinical utility of the nomogram. scRNA-seq showed that CHKB was mainly distributed in endothelial cells, while PEMT was mainly distributed in CD4<jats:sup>+<\/jats:sup> T cells and CD8<jats:sup>+<\/jats:sup> T cells. In addition, multiple types of immune cells expressing CHKB and PEMT differed significantly. There were significant differences in the immune microenvironment, immune checkpoint expression and chemotherapy response between the two risk groups. In addition, we screened five potential small molecule drugs that targeted treatment for COAD. Finally, the results of IHC, Western blot, and qRT-PCR consistently showed that the expression of CHKB in human, mouse, and cell lines was elevated in normal samples, while PMET showed the opposite trend.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In conclusion, we constructed a choline metabolism-related signature in COAD and revealed its potential application value in predicting the prognosis, immune microenvironment, and chemotherapy response of patients, which may lay an important theoretical basis for future personalized precision therapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1038927","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T04:40:39Z","timestamp":1668400839000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":30,"title":["Construction of a novel choline metabolism-related signature to predict prognosis, immune landscape, and chemotherapy response in colon adenocarcinoma"],"prefix":"10.3389","volume":"13","author":[{"given":"Cong","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingwei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangfei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinliang","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0189-8","article-title":"Global burden of colorectal cancer: Emerging trends, risk factors and prevention strategies","volume":"16","author":"Keum","year":"2019","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33203","article-title":"Survival impact of adjuvant chemotherapy in patients with stage iia colon cancer: Analysis of the national cancer database","volume":"148","author":"Achilli","year":"2021","journal-title":"Int J Cancer"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-022-03258-6","article-title":"Genetic variants in choline metabolism pathway are associated with the risk of bladder cancer in the Chinese population","volume":"96","author":"Han","year":"2022","journal-title":"Arch Toxicol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1586\/14737159.6.6.821","article-title":"Choline metabolism in cancer: Implications for diagnosis and therapy","volume":"6","author":"Glunde","year":"2006","journal-title":"Expert Rev Mol Diagn"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00234-001-0760-0","article-title":"Clinical application of proton magnetic resonance spectroscopy in the diagnosis of intracranial mass lesions","volume":"44","author":"Moller-Hartmann","year":"2002","journal-title":"Neuroradiology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/jmri.20113","article-title":"Combined quantitative dynamic contrast-enhanced Mr imaging and (1)H Mr spectroscopic imaging of human prostate cancer","volume":"20","author":"van Dorsten","year":"2004","journal-title":"J Magn Reson Imaging"},{"key":"B7","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1002\/jmri.10427","article-title":"Proton magnetic resonance spectroscopic imaging of human breast cancer: A preliminary study","volume":"19","author":"Jacobs","year":"2004","journal-title":"J Magn Reson Imaging"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq537","article-title":"The genemania prediction server: Biological network integration for gene prioritization and predicting gene function","volume":"38","author":"Warde-Farley","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky311","article-title":"Genemania update 2018","volume":"46","author":"Franz","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty411","article-title":"Gscalite: A web server for gene set cancer analysis","volume":"34","author":"Liu","year":"2018","journal-title":"Bioinformatics"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab447","article-title":"Kobas-I: Intelligent prioritization and exploratory visualization of biological functions for gene enrichment analysis","volume":"49","author":"Bu","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1020","article-title":"Tisch: A comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment","volume":"49","author":"Sun","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-0689","article-title":"Tip: A web server for resolving tumor immunophenotype profiling","volume":"78","author":"Xu","year":"2018","journal-title":"Cancer Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1111","article-title":"Genomics of drug sensitivity in cancer (Gdsc): A resource for therapeutic biomarker discovery in cancer cells","volume":"41","author":"Yang","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1016\/j.cell.2017.10.049","article-title":"A next generation connectivity map: L1000 platform and the first 1,000,000 profiles","volume":"171","author":"Subramanian","year":"2017","journal-title":"Cell"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1126\/science.1132939","article-title":"The connectivity map: Using gene-expression signatures to connect small molecules, genes, and disease","volume":"313","author":"Lamb","year":"2006","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3908","article-title":"Inflammasome-independent role of Aim2 in suppressing colon tumorigenesis Via DNA-Pk and akt","volume":"21","author":"Wilson","year":"2015","journal-title":"Nat Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/nri.2017.76","article-title":"Single-cell rna sequencing to explore immune cell heterogeneity","volume":"18","author":"Papalexi","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01233-9","article-title":"Intratumoral heterogeneity in cancer progression and response to immunotherapy","volume":"27","author":"Vitale","year":"2021","journal-title":"Nat Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nrclinonc.2017.166","article-title":"Tumour heterogeneity and resistance to cancer therapies","volume":"15","author":"Dagogo-Jack","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1209","article-title":"Development of immunotherapy combination strategies in cancer","volume":"11","author":"Yap","year":"2021","journal-title":"Cancer Discovery"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20184331","article-title":"Molecular docking: Shifting paradigms in drug discovery","volume":"20","author":"Pinzi","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1124\/pharmrev.120.000246","article-title":"Structure-based virtual screening for ligands of G protein-coupled receptors: What can molecular docking do for you","volume":"73","author":"Ballante","year":"2021","journal-title":"Pharmacol Rev"},{"key":"B24","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2174\/0929867324666170111152436","article-title":"Colorectal cancer chemotherapy: The evolution of treatment and new approaches","volume":"24","author":"McQuade","year":"2017","journal-title":"Curr Med Chem"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.811734","article-title":"A prognostic pyroptosis-related lncrnas risk model correlates with the immune microenvironment in colon adenocarcinoma","volume":"9","author":"Xia","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.769685","article-title":"Identification of molecular subtypes and a prognostic signature based on inflammation-related genes in colon adenocarcinoma","volume":"12","author":"Qiu","year":"2021","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100604","article-title":"Choline transporter-like proteins 1 and 2 are newly identified plasma membrane and mitochondrial ethanolamine transporters","volume":"296","author":"Taylor","year":"2021","journal-title":"J Biol Chem"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.REV120.013529","article-title":"Genetic diseases of the Kennedy pathways for membrane synthesis","volume":"295","author":"Tavasoli","year":"2020","journal-title":"J Biol Chem"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2015.20","article-title":"New splicing mutation in the choline kinase beta (Chkb) gene causing a muscular dystrophy detected by whole-exome sequencing","volume":"60","author":"Oliveira","year":"2015","journal-title":"J Hum Genet"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1186\/s40170-021-00245-w","article-title":"The pd-L1 metabolic interactome intersects with choline metabolism and inflammation","volume":"9","author":"Pacheco-Torres","year":"2021","journal-title":"Cancer Metab"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.7b01257","article-title":"Identification of a unique inhibitor-binding site on choline kinase alpha","volume":"57","author":"Kall","year":"2018","journal-title":"Biochemistry"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2018.10.021","article-title":"Importance of polymorphic variants of phosphatidylethanolamine n-methyltransferase (Pemt) gene in the etiology of intrauterine fetal death in the polish population","volume":"231","author":"Seremak-Mrozikiewicz","year":"2018","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1097-0215(20000501)86:3<362::aid-ijc10>3.0.co;2-a","article-title":"Inactivation of phosphatidylethanolamine n-Methyltransferase-2 in aflatoxin-induced liver cancer and partial reversion of the neoplastic phenotype by pemt transfection of hepatoma cells","volume":"86","author":"Tessitore","year":"2000","journal-title":"Int J Cancer"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00959","article-title":"Dysregulation of lipid metabolism in macrophages is responsible for severe endotoxin tolerance in fcgriib-deficient lupus mice","volume":"11","author":"Jaroonwitchawan","year":"2020","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.02.022","article-title":"Accessories to the crime: Functions of cells recruited to the tumor microenvironment","volume":"21","author":"Hanahan","year":"2012","journal-title":"Cancer Cell"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3394","article-title":"Microenvironmental regulation of tumor progression and metastasis","volume":"19","author":"Quail","year":"2013","journal-title":"Nat Med"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-017-2058-z","article-title":"Transcriptomic analysis of the tumor microenvironment to guide prognosis and immunotherapies","volume":"67","author":"Petitprez","year":"2018","journal-title":"Cancer Immunol Immunother"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.02.008","article-title":"Obstacles posed by the tumor microenvironment to T cell activity: A case for synergistic therapies","volume":"31","author":"Anderson","year":"2017","journal-title":"Cancer Cell"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.0c07680","article-title":"A potent cancer vaccine adjuvant system for particleization of short, synthetic Cd8(+) T cell epitopes","volume":"15","author":"He","year":"2021","journal-title":"ACS Nano"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2016.151","article-title":"Regulatory T cells in cancer immunotherapy","volume":"27","author":"Tanaka","year":"2017","journal-title":"Cell Res"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.971045","article-title":"Neglected, yet significant role of Foxp1 in T-cell quiescence, differentiation and exhaustion","volume":"13","author":"Kaminskiy","year":"2022","journal-title":"Front Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/srep15179","article-title":"Prognostic value of tumor-infiltrating Foxp3+ regulatory T cells in cancers: A systematic review and meta-analysis","volume":"5","author":"Shang","year":"2015","journal-title":"Sci Rep"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.11.003","article-title":"Durable response in patients with thymic carcinoma treated with pembrolizumab after prolonged follow-up","volume":"16","author":"Giaccone","year":"2021","journal-title":"J Thorac Oncol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2021.01.003","article-title":"Lung and thymic carcinoids: Esmo clinical practice guidelines for diagnosis, treatment and follow-up()","volume":"32","author":"Baudin","year":"2021","journal-title":"Ann Oncol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.7150\/thno.57828","article-title":"Recent progress in nanomedicine for enhanced cancer chemotherapy","volume":"11","author":"Wei","year":"2021","journal-title":"Theranostics"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.07.018","article-title":"Overcoming chemotherapy resistance in sclc","volume":"16","author":"Herzog","year":"2021","journal-title":"J Thorac Oncol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1038\/s41416-020-0949-9","article-title":"Axitinib plus immune checkpoint inhibitor: Evidence- and expert-based consensus recommendation for treatment optimisation and management of related adverse events","volume":"123","author":"Grunwald","year":"2020","journal-title":"Br J Cancer"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-1061","article-title":"Randomized phase ii study of axitinib versus observation in patients with recurred or metastatic adenoid cystic carcinoma","volume":"27","author":"Kang","year":"2021","journal-title":"Clin Cancer Res"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28389","article-title":"Long-term safety and clinical effects of nilotinib in parkinson's disease","volume":"36","author":"Pagan","year":"2021","journal-title":"Mov Disord"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.2217\/fon-2018-0468","article-title":"Nilotinib in the treatment of chronic myeloid leukemia","volume":"15","author":"Sacha","year":"2019","journal-title":"Future Oncol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s11658-019-0164-y","article-title":"Progress in research on paclitaxel and tumor immunotherapy","volume":"24","author":"Zhu","year":"2019","journal-title":"Cell Mol Biol Lett"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/biom9120789","article-title":"Paclitaxel's mechanistic and clinical effects on breast cancer","volume":"9","author":"Abu Samaan","year":"2019","journal-title":"Biomolecules"},{"key":"B55","article-title":"Nab-paclitaxel promotes the cancer-immunity cycle as a potential immunomodulator","volume":"11","author":"Chen","year":"2021","journal-title":"Am J Cancer Res"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.01.001","article-title":"Rapamycin: One drug, many effects","volume":"19","author":"Li","year":"2014","journal-title":"Cell Metab"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.54318","article-title":"Rapamycin rejuvenates oral health in aging mice","volume":"9","author":"An","year":"2020","journal-title":"Elife"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa065044","article-title":"Sunitinib versus interferon Alfa in metastatic renal-cell carcinoma","volume":"356","author":"Motzer","year":"2007","journal-title":"N Engl J Med"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.2174\/0929867324666171006165942","article-title":"Sunitinib in the treatment of thyroid cancer","volume":"26","author":"Ferrari","year":"2019","journal-title":"Curr Med Chem"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(73)90269-3","article-title":"Potentiation of vinblastine crystal formation in vivo by puromycin and colcemid","volume":"80","author":"Strahs","year":"1973","journal-title":"Exp Cell Res"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(84)90248-1","article-title":"Arrangement of protofilaments in two forms of tubulin crystal induced by vinblastine","volume":"178","author":"Amos","year":"1984","journal-title":"J Mol Biol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14626","article-title":"Desmoid with biweekly methotrexate and vinblastine shows similar effects to weekly administration: A phase ii clinical trial","volume":"111","author":"Nishida","year":"2020","journal-title":"Cancer Sci"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2014.10.016","article-title":"Cpne7, a preameloblast-derived factor, regulates odontoblastic differentiation of mesenchymal stem cells","volume":"37","author":"Oh","year":"2015","journal-title":"Biomaterials"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1111\/jcpe.13621","article-title":"Cpne7 regenerates periodontal ligament Via tau-mediated alignment and cementum attachment protein-mediated attachment","volume":"49","author":"Bai","year":"2022","journal-title":"J Clin Periodontol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.478","article-title":"Hsf4 regulates lens fiber cell differentiation by activating P53 and its downstream regulators","volume":"8","author":"Gao","year":"2017","journal-title":"Cell Death Dis"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1111\/liv.14410","article-title":"Hsp4 triggers epithelial-mesenchymal transition and promotes motility capacities of hepatocellular carcinoma cells Via activating akt","volume":"40","author":"Ma","year":"2020","journal-title":"Liver Int"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1172\/JCI68453","article-title":"Olfm4 deletion enhances defense against staphylococcus aureus in chronic granulomatous disease","volume":"123","author":"Liu","year":"2013","journal-title":"J Clin Invest"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofac061","article-title":"Olfactomedin 4 is a biomarker for the severity of infectious diseases","volume":"9","author":"Liu","year":"2022","journal-title":"Open Forum Infect Dis"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1007\/s00384-018-3097-4","article-title":"Association of ulcerative colitis with solute-linked carrier family 26 member A3 gene polymorphisms and its expression in colonic tissues in Chinese patients","volume":"33","author":"Shao","year":"2018","journal-title":"Int J Colorectal Dis"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.121370","article-title":"Slc26a3 inhibitor identified in small molecule screen blocks colonic fluid absorption and reduces constipation","volume":"3","author":"Haggie","year":"2018","journal-title":"JCI Insight"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1038927\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T04:40:54Z","timestamp":1668400854000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1038927\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,14]]},"references-count":70,"alternative-id":["10.3389\/fimmu.2022.1038927"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1038927","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,14]]},"article-number":"1038927"}}