{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T10:54:36Z","timestamp":1762253676869,"version":"3.40.5"},"reference-count":67,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T00:00:00Z","timestamp":1611014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Evasion of apoptosis is associated with treatment resistance and metastasis in colorectal cancer (CRC). Various cellular processes are associated with evasion of apoptosis. These include overexpression of pro-apoptotic proteins (including p53 and PD-L1), anti-apoptotic proteins (BIRC7\/Livin and Bcl-2), chemokine receptors (including DARC), and dysregulation of DNA mismatch repair proteins (including MSH2 and PMS2). The aim of this study was to determine the effect of folinic acid, 5-FU and oxaliplatin (FOLFOX) as a single agent and aspirin plus FOLFOX in various combinations on the aforementioned proteins in human CRC, SW480 cell line and rat models of N-Methyl-N-Nitrosourea (NMU)-induced CRC. In addition, effects of the NMU-induced CRC and chemotherapeutic regimens on haematological and biochemical parameters in the rat models were studied. Immunohistochemistry, immunofluorescence and immunoblot techniques were used to study the expression pattern of the related proteins in the human CRC cells pre- and post-treatment. Double contrast barium enema, post-mortem examination and histological analyses were used to confirm tumour growth and the effect of the treatment<jats:italic>in vivo<\/jats:italic>in rat models. Notably, we found in human mucinous CRC, a significant increase in expression of the BIRC7\/Livin post-FOLFOX treatment compared with pre-treatment (<jats:italic>p<\/jats:italic>= 0.0001). This increase provides new insights into the prognostic role of BIRC7\/Livin in evasion of apoptosis and facilitation of treatment resistance, local recurrence and metastasis particularly among mucinous CRCs post-FOLFOX chemotherapy. These poor prognostic features in the CRC may be further compounded by the significant suppression of DARC, PD-L1, PMS2 and overexpression of MSH2 and anti-apoptotic Bcl-2 and p53 proteins observed in our study (p &lt; 0.05). Importantly, we found a significant reduction in expression of BIRC7\/Livin and reactivation of DARC and PD-L1 with a surge in Annexin V expression in rat models of CRC cells post-treatment with a sequential dose of aspirin plus FOLFOX compared with other treatments<jats:italic>in vivo<\/jats:italic>(<jats:italic>p<\/jats:italic>&lt;0.05). The mechanistic rational of these effects underscores the importance of expanded concept of possible aspirin combination therapy with FOLFOX sequentially in future CRC management. Validation of our findings through randomized clinical trials of aspirin plus FOLFOX sequentially in patients with CRC is therefore warranted.<\/jats:p>","DOI":"10.1371\/journal.pone.0245581","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T18:37:15Z","timestamp":1611081435000},"page":"e0245581","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Prognostic significance of BIRC7\/Livin, Bcl-2, p53, Annexin V, PD-L1, DARC, MSH2 and PMS2 in colorectal cancer treated with FOLFOX chemotherapy with or without aspirin"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2319-8948","authenticated-orcid":true,"given":"Mohammed","family":"Faruk","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sani","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surajo Mohammed","family":"Aminu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed","family":"Adamu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2223-3820","authenticated-orcid":true,"given":"Adamu","family":"Abdullahi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aishatu Maude","family":"Suleiman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdulmumini Hassan","family":"Rafindadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdullahi","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yawale","family":"Iliyasu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Idoko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rakiya","family":"Saidu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdullahi Jibril","family":"Randawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Halimatu Sadiya","family":"Musa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4830-8365","authenticated-orcid":true,"given":"Atara","family":"Ntekim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khalid Zahir","family":"Shah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sani","family":"Abubakar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kasimu Umar","family":"Adoke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Manko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheh Agustin","family":"Awasum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,1,19]]},"reference":[{"key":"pone.0245581.ref001","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1136\/gutjnl-2015-310912","article-title":"Global patterns and trends in colorectal cancer incidence and mortality","volume":"66","author":"M Arnold","year":"2017","journal-title":"Gut"},{"key":"pone.0245581.ref002","doi-asserted-by":"crossref","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":"F Bray","year":"2018","journal-title":"Ca Cancer J Clin"},{"key":"pone.0245581.ref003","doi-asserted-by":"crossref","first-page":"e158","DOI":"10.1016\/S1470-2045(12)70472-2","article-title":"Treatment of cancer in sub-Saharan Africa","volume":"314","author":"TP Kingham","year":"2013","journal-title":"Lancet Oncol"},{"key":"pone.0245581.ref004","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1002\/jso.25768","article-title":"Treatment of colorectal cancer in Sub-Saharan Africa: Results from a prospective Nigerian hospital registry","volume":"121","author":"A Sharma","journal-title":"J Surg Oncol. 2020"},{"key":"pone.0245581.ref005","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nature11252","article-title":"Comprehensive molecular characterization of human colon and rectal cancer","volume":"487","author":"Network TCGA","year":"2012","journal-title":"Nature"},{"key":"pone.0245581.ref006","doi-asserted-by":"crossref","first-page":"3092","DOI":"10.1158\/0008-5472.CAN-16-2098","article-title":"The p53\/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins","volume":"77","author":"EM Kim","year":"2017","journal-title":"Cancer Res"},{"key":"pone.0245581.ref007","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nrclinonc.2015.140","article-title":"Advances in the care of patients with mucinous colorectal cancer","volume":"13","author":"N Hugen","year":"2016","journal-title":"Nat Rev Clin Oncol"},{"key":"pone.0245581.ref008","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/nm.3967","article-title":"The consensus molecular subtypes of colorectal cancer","volume":"21","author":"J Guinney","year":"2015","journal-title":"Nat. Med"},{"key":"pone.0245581.ref009","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","article-title":"The hallmarks of cancer","volume":"100","author":"D Hanahan","year":"2000","journal-title":"Cell"},{"key":"pone.0245581.ref010","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s12032-015-0512-3","article-title":"Preoperative chemoradiotherapy with 5-fluorouracil and oxaliplatin for locally advanced rectal cancer: long-term results of a phase II trial","volume":"32","author":"L Liu","year":"2015","journal-title":"Med Oncol"},{"key":"pone.0245581.ref011","doi-asserted-by":"crossref","first-page":"3238","DOI":"10.1074\/jbc.M003670200","article-title":"Livin, a novel inhibitor of apoptosis protein family member","volume":"276","author":"GM Kasof","year":"2001","journal-title":"J Biol Chem"},{"key":"pone.0245581.ref012","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1186\/1748-717X-8-281","article-title":"Livin expression is an independent factor in rectal cancer patients with or without preoperative radiotherapy","volume":"8","author":"ZY Ding","year":"2013","journal-title":"Radiat Oncol"},{"key":"pone.0245581.ref013","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1016\/S0960-9822(00)00781-8","article-title":"ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas","volume":"10","author":"D Vucic","year":"2000","journal-title":"Curr Biol"},{"key":"pone.0245581.ref014","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S0014-5793(01)02366-3","article-title":"Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern","volume":"495","author":"Y Ashhab","year":"2001","journal-title":"FEBS Lett"},{"key":"pone.0245581.ref015","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/10701","article-title":"Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat","volume":"6","author":"MG Hinds","year":"1999","journal-title":"Nat Struct Biol"},{"key":"pone.0245581.ref016","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1038\/sj.cdd.4401959","article-title":"Livin promotes Smac\/ DIABLO degradation by ubiquitin-proteasome pathway","volume":"13","author":"L Ma","year":"2006","journal-title":"Cell Death Differ"},{"key":"pone.0245581.ref017","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/j.1745-7270.2008.00407.x","article-title":"Inhibitor of apoptosis proteins and apoptosis","volume":"40","author":"Y Wei","year":"2008","journal-title":"Acta Biochim Biophys Sin"},{"key":"pone.0245581.ref018","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nrm2312","article-title":"Apoptosis: controlled demolition at the cellular level","volume":"9","author":"RC Taylor","year":"2008","journal-title":"Nat Rev Mol Cell Biol"},{"key":"pone.0245581.ref019","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nrc.2015.17","article-title":"Thirty Years of BCL-2: Translating cell death discoveries into novel cancer therapies","volume":"16","author":"AR Delbridge","year":"2016","journal-title":"Nat Rev Cancer"},{"key":"pone.0245581.ref020","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1126\/science.275.5303.1129","article-title":"Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked","volume":"275","author":"J Yang","year":"1997","journal-title":"Science"},{"key":"pone.0245581.ref021","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/cdd.2017.161","article-title":"Cory S The BCL-2 arbiters of apoptosis and their growing role as cancer targets","volume":"25","author":"JM Adams","year":"2018","journal-title":"Cell Death Differ"},{"key":"pone.0245581.ref022","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1038\/s41388-017-0060-8","article-title":"Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers","volume":"37","author":"H Solomon","year":"2018","journal-title":"Oncogene"},{"key":"pone.0245581.ref023","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1083\/jcb.201009059","article-title":"p53 and its mutants in tumor cell migration and invasion","volume":"192","author":"PA Muller","year":"2011","journal-title":"J Cell Biol"},{"key":"pone.0245581.ref024","first-page":"1","article-title":"The p53\/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins","volume":"77","author":"EM Kim","year":"2017","journal-title":"Cancer Res"},{"key":"pone.0245581.ref025","first-page":"4623","article-title":"The DNA of Annexin V-binding Apoptotic Cells Is Highly Fragmented","volume":"60","author":"Z Bacso","year":"2000","journal-title":"Cancer Res"},{"key":"pone.0245581.ref026","doi-asserted-by":"crossref","first-page":"42602","DOI":"10.18632\/oncotarget.16645","article-title":"Anti-cancer activity of Annexin V in murine melanoma model by suppressing tumor angiogenesis","volume":"8","author":"X Zhang","year":"2017","journal-title":"Oncotarget"},{"key":"pone.0245581.ref027","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1038\/ni.2703","article-title":"Innate and adaptive immune cells in the tumor microenvironment","volume":"14","author":"TF Gajewski","year":"2013","journal-title":"Nat Immunol"},{"key":"pone.0245581.ref028","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.cell.2010.01.025","article-title":"Immunity, inflammation, and cancer","volume":"140","author":"SI Grivennikov","year":"2010","journal-title":"Cell"},{"key":"pone.0245581.ref029","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1093\/annonc\/mds256","article-title":"Immuno-oncology: understanding the function and dysfunction of the immune system in cancer","volume":"23","author":"OJ Finn","year":"2012","journal-title":"Ann Oncol"},{"key":"pone.0245581.ref030","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev.immunol.20.091101.091806","article-title":"The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses","volume":"20","author":"BM Carreno","year":"2002","journal-title":"Annu Rev Immunol"},{"key":"pone.0245581.ref031","doi-asserted-by":"crossref","first-page":"30093","DOI":"10.1038\/srep30093","article-title":"Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in Osteosarcoma","volume":"6","author":"P Koirala","year":"2016","journal-title":"Sci. Rep"},{"key":"pone.0245581.ref032","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.cytogfr.2011.09.002","article-title":"The expression and role of CXC chemokines in colorectal cancer","volume":"22","author":"H Verbeke","year":"2011","journal-title":"Cytokine Growth F R"},{"key":"pone.0245581.ref033","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1158\/1055-9965.EPI-18-0955","article-title":"Atypical Chemokine Receptor 1 (DARC\/ACKR1) in Breast Tumors Is Associated with Survival, Circulating Chemokines, Tumor-Infiltrating Immune Cells, and African Ancestry","volume":"28","author":"BD Jenkins","year":"2019","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"pone.0245581.ref034","doi-asserted-by":"crossref","first-page":"50","DOI":"10.3390\/cancers9050050","article-title":"Immunotherapy for Colorectal Cancer","volume":"9","author":"PM Boland","year":"2017","journal-title":"Cancers (Basel)"},{"key":"pone.0245581.ref035","first-page":"557","article-title":"Activity of aspirin analogues and vanillin in a human colorectal cancer cell line","volume":"26","author":"J Deb","year":"2011","journal-title":"Oncol Rep"},{"key":"pone.0245581.ref036","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/j.cell.2015.08.015","article-title":"Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity","volume":"162","author":"S Zelenay","year":"2015","journal-title":"Cell"},{"key":"pone.0245581.ref037","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1093\/carcin\/bgl220","article-title":"Aspirin activates the NF-kappaB signalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer","volume":"28","author":"LA Stark","year":"2007","journal-title":"Carcinogenesis"},{"key":"pone.0245581.ref038","doi-asserted-by":"crossref","first-page":"263","DOI":"10.3816\/CCC.2005.n.037","article-title":"FOLFOX alternated with FOLFIRI as first-line chemotherapy for metastatic colorectal cancer","volume":"5","author":"J Aparicio","year":"2005","journal-title":"Clin Colorectal Cancer"},{"key":"pone.0245581.ref039","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.neo.2017.05.002","article-title":"UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses","volume":"19","author":"DS Chandrashekar","year":"2017","journal-title":"Neoplasia"},{"key":"pone.0245581.ref040","doi-asserted-by":"crossref","first-page":"e73262","DOI":"10.1371\/journal.pone.0073262","article-title":"Expression of Livin in Colorectal Cancer and Its Relationship to Tumor Cell Behavior and Prognosis","volume":"8","author":"D Myung","year":"2013","journal-title":"Plos one"},{"key":"pone.0245581.ref041","first-page":"78","article-title":"BIRC7 promotes epithelial-mesenchymal transition and metastasis in papillary thyroid carcinoma through restraining autophagy","volume":"10","author":"K Liu","year":"2020","journal-title":"Am J Cancer Res"},{"key":"pone.0245581.ref042","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/s41379-019-0353-2","article-title":"Overexpression of TP53 protein is associated with the lack of adjuvant chemotherapy benefit in patients with stage III colorectal cancer","volume":"33","author":"DS Williams","year":"2020","journal-title":"Modern Pathol"},{"key":"pone.0245581.ref043","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s12943-016-0539-x","article-title":"Prognostic Impact of Programed Cell death-1 (PD-1) and PD-ligand 1 (PD-L1) Expression in Cancer Cells and Tumor Infiltrating Lymphocytes in Colorectal Cancer","volume":"15","author":"Y Li","year":"2016","journal-title":"Mol Cancer"},{"key":"pone.0245581.ref044","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1097\/PAP.0000000000000247","article-title":"Molecular Pathology of Colorectal Cancer","volume":"27","author":"H Shuko","year":"2020","journal-title":"Adv Anat Pathol."},{"key":"pone.0245581.ref045","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1007\/s00066-016-0988-6","article-title":"Neoadjuvant chemoradiotherapy of rectal carcinoma: Baseline hematologic parameters influencing outcomes","volume":"192","author":"M Hodek","year":"2016","journal-title":"Strahlenther Onkol"},{"issue":"30","key":"pone.0245581.ref046","doi-asserted-by":"crossref","first-page":"10316","DOI":"10.3748\/wjg.v20.i30.10316","article-title":"FOLFOX\/FOLFIRI pharmacogenetics: The call for a personalized approach in colorectal cancer therapy","volume":"20","author":"B Mohelnikova-Duchonova","year":"2014","journal-title":"World J Gastroenterol"},{"key":"pone.0245581.ref047","first-page":"297","article-title":"Clinical evidence for the use of aspirin in the treatment of cancer","volume":"7","author":"R.E Langley","year":"2013","journal-title":"Ecancermedicalscience"},{"key":"pone.0245581.ref048","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s11888-016-0306-9","article-title":"Aspirin and Colorectal Cancer Prevention and Treatment: Is It for Everyone?","volume":"12","author":"C Coyle","year":"2016","journal-title":"Curr Colorectal Cancer Rep"},{"key":"pone.0245581.ref049","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S1470-2045(11)70097-3","article-title":"Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial","volume":"12","author":"W van Gijn","year":"2011","journal-title":"Lancet Oncol"},{"key":"pone.0245581.ref050","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1200\/JCO.2011.40.1836","article-title":"Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO\/ARO\/AIO-94 randomized phase III trial after a median follow-up of 11 years","volume":"30","author":"R Sauer","year":"2012","journal-title":"J Clin Oncol"},{"key":"pone.0245581.ref051","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.ejca.2011.12.004","article-title":"Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer","volume":"48","author":"LJ Mekenkamp","year":"2012","journal-title":"Eur J Cancer"},{"key":"pone.0245581.ref052","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/cjp2.1","article-title":"The molecular background of mucinous carcinoma beyond MUC2","volume":"1","author":"N Hugen","year":"2014","journal-title":"J Pathol Clin Res"},{"key":"pone.0245581.ref053","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/s41588-019-0423-x","article-title":"Quantitative evidence for early metastatic seeding in colorectal cancer","volume":"51","author":"Z Hu","year":"2019","journal-title":"Nat Genet"},{"key":"pone.0245581.ref054","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1038\/nrc2761","article-title":"Mucins in cancer: function, prognosis and therapy","volume":"9","author":"DW Kufe","year":"2009","journal-title":"Nat Rev Cancer"},{"key":"pone.0245581.ref055","doi-asserted-by":"crossref","first-page":"2819","DOI":"10.1093\/annonc\/mdt378","article-title":"Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma","volume":"24","author":"N Hugen","year":"2013","journal-title":"Ann Oncol"},{"key":"pone.0245581.ref056","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1056\/NEJMoa022289","article-title":"Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer","volume":"349","author":"CM Ribic","year":"2003","journal-title":"N Engl J Med"},{"key":"pone.0245581.ref057","first-page":"4611","article-title":"Thymidylate synthase, topoisomerase\u2011 1 and microsatellite instability: relationship with outcome in mucinous colorectal cancer treated with fluorouracil","volume":"33","author":"FV Negri","year":"2013","journal-title":"Anticancer Res"},{"key":"pone.0245581.ref058","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/nm.3175","article-title":"A colorectal cancer classification system that associates cellular phenotype and responses to therapy","volume":"19","author":"A Sadanandam","year":"2013","journal-title":"Nat Med"},{"key":"pone.0245581.ref059","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1093\/carcin\/bgh118","article-title":"DNA array analysis of the effects of aspirin on colon cancer cells: involvement of Rac1","volume":"25","author":"JC Hardwick","year":"2004","journal-title":"Carcinogenesis"},{"key":"pone.0245581.ref060","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.3748\/wjg.v17.i20.2563","article-title":"siRNA targeting Livin decreases tumor in a xenograft model for colon cancer","volume":"17","author":"B Oh","year":"2011","journal-title":"World J Gastroenterol"},{"key":"pone.0245581.ref061","first-page":"743","article-title":"ID Nicholl. Non-steroidal anti-Inflammatory drugs, DNA repair and Cancer","volume":"30","author":"HK Dibra","year":"2011","journal-title":"Intech"},{"key":"pone.0245581.ref062","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nrc.2016.4","article-title":"Aspirin and colorectal cancer: the promise of precision chemoprevention","volume":"16","author":"DA Drew","year":"2016","journal-title":"Nat Rev Cancer"},{"key":"pone.0245581.ref063","first-page":"1256","article-title":"A novel mechanism for the anticancer activity of aspirin and salicylates","volume":"54","author":"AIJ Bashir","year":"2019","journal-title":"Int J Oncol"},{"key":"pone.0245581.ref064","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1200\/JCO.2015.65.0994","article-title":"Racial\/Ethnic Disparities in Survival among Patients with Young-Onset Colorectal Cancer","volume":"34","author":"AN Holowatyj","year":"2016","journal-title":"J Clin Oncol"},{"key":"pone.0245581.ref065","doi-asserted-by":"crossref","first-page":"e00155","DOI":"10.14309\/ctg.0000000000000155","article-title":"Trends in Sociodemographic Disparities in Colorectal Cancer Staging and Survival: A SEER-Medicare Analysis","volume":"11","author":"PS Liang","year":"2020","journal-title":"Clin Transl Gastroenterol"},{"key":"pone.0245581.ref066","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s12943-016-0539-x","article-title":"Prognostic Impact of Programed Cell death-1 (PD-1) and PD-ligand 1 (PD-L1) Expression in Cancer Cells and Tumor Infiltrating Lymphocytes in Colorectal Cancer","volume":"15","author":"Y Li","year":"2016","journal-title":"Mol Cancer"},{"key":"pone.0245581.ref067","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.1158\/0008-5472.CAN-10-3055","article-title":"COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells","volume":"71","author":"M Fujita","year":"2011","journal-title":"Cancer Res"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0245581","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T06:46:16Z","timestamp":1670827576000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0245581"}},"subtitle":[],"editor":[{"given":"Irina V.","family":"Lebedeva","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,1,19]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1,19]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0245581","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2021,1,19]]}}}