{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T22:09:53Z","timestamp":1770329393221,"version":"3.49.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,24]],"date-time":"2021-09-24T00:00:00Z","timestamp":1632441600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012669","name":"Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012669","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Hepatocellular carcinoma (HCC) is one of the most common malignant tumors endangering human health and life in the 21st century. Chromatin licensing and DNA replication factor 1 (CDT1) is an important regulator of DNA replication licensing, which is essential for initiation of DNA replication. CDT1 overexpression in several human cancers reportedly leads to abnormal cell replication, activates DNA damage checkpoints, and predisposes malignant transformation. However, the abnormal expression of CDT1 in HCC and its diagnostic and prognostic value remains to be elucidated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>TCGA, ONCOMINE, UALCAN, HCCDB, HPA, Kaplan-Meier plotter, STRING, GEPIA, GeneMANIA, and TIMER were conducted for bioinformatics analysis. CDT1 protein expression was evaluated by immunohistochemistry in HCC tissues through a tissue microarray. qRT-PCR, western blot and a cohort of functional experiments were performed for <jats:italic>in vitro<\/jats:italic> validation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this study, we discovered remarkably upregulated transcription of CDT1 in HCC samples relative to normal liver samples through bioinformatic analysis, which was further verified in clinical tissue microarray samples and <jats:italic>in vitro<\/jats:italic> experiments. Moreover, the transcriptional level of CDT1 in HCC samples was positively associated with clinical parameters such as clinical tumor stage. Survival, logistic regression, and Cox regression analyses revealed the significant clinical prognostic value of CDT1 expression in HCC. The receiver operating characteristic curve and nomogram analysis results demonstrated the strong predictive ability of CDT1 in HCC. Kyoto Encyclopedia of Genes and Genomes and gene set enrichment analyses indicated that CDT1 was mainly associated with the cell cycle, DNA repair, and DNA replication. We further demonstrated the significant correlation between CDT1 and minichromosome maintenance (MCM) family genes, revealing abnormal expression and prognostic significance of MCMs in HCC. Immune infiltration analysis indicated that CDT1 was significantly associated with immune cell subsets and affected the survival of HCC patients. Finally, knockdown of CDT1 decreased, whereas overexpression of CDT1 promoted the proliferation, migration, invasion of HCC cells <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study findings demonstrate the potential diagnostic and prognostic significance of CDT1 expression in HCC, and elucidate the potential molecular mechanism underlying its role in promoting the occurrence and development of liver cancer. These results may provide new opportunities and research paths for targeted therapies in HCC.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2021.721644","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T10:59:37Z","timestamp":1636455577000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["CDT1 Is a Novel Prognostic and Predictive Biomarkers for Hepatocellular Carcinoma"],"prefix":"10.3389","volume":"11","author":[{"given":"Chenhui","family":"Cai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenhui","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sizhen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tongwei","family":"Chu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"879","DOI":"10.3390\/cancers11060879","article-title":"Prognostic Role of Albumin, Bilirubin, and ALBI Scores: Analysis of 1000 Patients With Hepatocellular Carcinoma Undergoing Radioembolization","volume":"11","author":"Antkowiak","year":"2019","journal-title":"Cancers"},{"key":"B2","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/s41419-020-03291-2","article-title":"ACOX2 is a Prognostic Marker and Impedes the Progression of Hepatocellular Carcinoma via Ppar\u03b1 Pathway","volume":"12","author":"Zhang","year":"2021","journal-title":"Cell Death Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2147\/ijn.S236927","article-title":"Nanocarrier-Based Therapeutics and Theranostics Drug Delivery Systems for Next Generation of Liver Cancer Nanodrug Modalities","volume":"15","author":"Ruman","year":"2020","journal-title":"Int J Nanomed"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-13-226","article-title":"Elevated Autocrine EDIL3 Protects Hepatocellular Carcinoma From Anoikis Through RGD-Mediated Integrin Activation","volume":"13","author":"Feng","year":"2014","journal-title":"Mol Cancer"},{"key":"B5","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1093\/nar\/gkz1101","article-title":"Multiple Roles of DNA2 Nuclease\/Helicase in DNA Metabolism, Genome Stability and Human Diseases","volume":"48","author":"Zheng","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1038\/s41598-017-00998-9","article-title":"The Prognostic Significance of Cdc6 and Cdt1 in Breast Cancer","volume":"7","author":"Mahadevappa","year":"2017","journal-title":"Sci Rep"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e50796","DOI":"10.7554\/eLife.50796","article-title":"Cdc7 Activates Replication Checkpoint by Phosphorylating the Chk1-Binding Domain of Claspin in Human Cells","volume":"8","author":"Yang","year":"2019","journal-title":"eLife"},{"key":"B8","doi-asserted-by":"publisher","first-page":"282","DOI":"10.3390\/cancers10090282","article-title":"DNA Replication Licensing Protein MCM10 Promotes Tumor Progression and Is a Novel Prognostic Biomarker and Potential Therapeutic Target in Breast Cancer","volume":"10","author":"Mahadevappa","year":"2018","journal-title":"Cancers"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.27.6.1511","article-title":"Expression of the Licensing Factors, Cdt1 and Geminin, in Human Colon Cancer","volume":"27","author":"Bravou","year":"2005","journal-title":"Int J Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-9440(10)63393-7","article-title":"Overexpression of the Replication Licensing Regulators Hcdt1 and Hcdc6 Characterizes a Subset of non-Small-Cell Lung Carcinomas: Synergistic Effect With Mutant P53 on Tumor Growth and Chromosomal Instability\u2013Evidence of E2F-1 Transcriptional Control Over Hcdt1","volume":"165","author":"Karakaidos","year":"2004","journal-title":"Am J Pathol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208881","article-title":"Cdt1 Transgenic Mice Develop Lymphoblastic Lymphoma in the Absence of P53","volume":"24","author":"Seo","year":"2005","journal-title":"Oncogene"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s1476-5586(04)80047-2","article-title":"ONCOMINE: A Cancer Microarray Database and Integrated Data-Mining Platform","volume":"6","author":"Rhodes","year":"2004","journal-title":"Neoplasia (New York NY)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1186-3","article-title":"3rd","volume":"569","author":"Ghandi","year":"2019","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2018.07.003","article-title":"HCCDB: A Database of Hepatocellular Carcinoma Expression Atlas","volume":"16","author":"Lian","year":"2018","journal-title":"Genomics Proteomics Bioinf"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201100504","article-title":"Antibodies for Profiling the Human Proteome-The Human Protein Atlas as a Resource for Cancer Research","volume":"12","author":"Asplund","year":"2012","journal-title":"Proteomics"},{"key":"B16","doi-asserted-by":"publisher","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":"Chandrashekar","year":"2017","journal-title":"Neoplasia (New York NY)"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-009-0674-9","article-title":"An Online Survival Analysis Tool to Rapidly Assess the Effect of 22,277 Genes on Breast Cancer Prognosis Using Microarray Data of 1,809 Patients","volume":"123","author":"Gy\u00f6rffy","year":"2010","journal-title":"Breast Cancer Res Treat"},{"key":"B18","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1530\/erc-11-0329","article-title":"Implementing an Online Tool for Genome-Wide Validation of Survival-Associated Biomarkers in Ovarian-Cancer Using Microarray Data From 1287 Patients","volume":"19","author":"Gyorffy","year":"2012","journal-title":"Endocr-Related Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data With Deseq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"Clusterprofiler: An R Package for Comparing Biological Themes Among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics J Integr Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102","article-title":"Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"B22","doi-asserted-by":"publisher","first-page":"W98","DOI":"10.1093\/nar\/gkx247","article-title":"GEPIA: A Web Server for Cancer and Normal Gene Expression Profiling and Interactive Analyses","volume":"45","author":"Tang","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1131","article-title":"STRING V11: Protein-Protein Association Networks With Increased Coverage, Supporting Functional Discovery in Genome-Wide Experimental Datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B24","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":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.10.003","article-title":"Spatiotemporal Dynamics of Intratumoral Immune Cells Reveal the Immune Landscape in Human Cancer","volume":"39","author":"Bindea","year":"2013","journal-title":"Immunity"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-17-0307","article-title":"TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells","volume":"77","author":"Li","year":"2017","journal-title":"Cancer Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-77","article-title":"pROC: An Open-Source Package for R and S+ to Analyze and Compare ROC Curves","volume":"12","author":"Robin","year":"2011","journal-title":"BMC Bioinf"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-07-2837","article-title":"Deregulated Overexpression of Hcdt1 and Hcdc6 Promotes Malignant Behavior","volume":"67","author":"Liontos","year":"2007","journal-title":"Cancer Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.2741\/3018","article-title":"Cdt1 and Geminin in Cancer: Markers or Triggers of Malignant Transformation","volume":"13","author":"Petropoulou","year":"2008","journal-title":"Front Biosci J Virtual Library"},{"key":"B30","doi-asserted-by":"publisher","first-page":"a026252","DOI":"10.1101\/cshperspect.a026252","article-title":"TP53 Mutations in Breast and Ovarian Cancer","volume":"7","author":"Silwal-Pandit","year":"2017","journal-title":"Cold Spring Harbor Perspect Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2006231117","article-title":"Structural Mechanism of Helicase Loading Onto Replication Origin DNA by ORC-Cdc6","volume":"117","author":"Yuan","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/3750294","article-title":"MCMs in Cancer: Prognostic Potential and Mechanisms","volume":"2020","author":"Yu","year":"2020","journal-title":"Analytical Cell Pathol (Amsterdam)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.1745","article-title":"Profiles of Immune Infiltration in Colorectal Cancer and Their Clinical Significant: A Gene Expression-Based Study","volume":"7","author":"Xiong","year":"2018","journal-title":"Cancer Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1039\/c6sc04671a","article-title":"Enrichment and Single-Cell Analysis of Circulating Tumor Cells","volume":"8","author":"Song","year":"2017","journal-title":"Chem Sci"},{"key":"B35","doi-asserted-by":"publisher","first-page":"726","DOI":"10.3390\/cancers12030726","article-title":"Sea Hare Hydrolysate-Induced Reduction of Human Non-Small Cell Lung Cancer Cell Growth Through Regulation of Macrophage Polarization and Non-Apoptotic Regulated Cell Death Pathways","volume":"12","author":"Nyiramana","year":"2020","journal-title":"Cancers"},{"key":"B36","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s13059-016-1028-7","article-title":"Comprehensive Analyses of Tumor Immunity: Implications for Cancer Immunotherapy","volume":"17","author":"Li","year":"2016","journal-title":"Genome Biol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-11-253336","article-title":"Chemotherapy Rescues Tumor-Driven Aberrant CD4+ T-Cell Differentiation and Restores an Activated Polyfunctional Helper Phenotype","volume":"115","author":"Ding","year":"2010","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-103019-085803","article-title":"In Vivo CD4(+) T Cell Differentiation and Function: Revisiting the Th1\/Th2 Paradigm","volume":"38","author":"Ruterbusch","year":"2020","journal-title":"Annu Rev Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1080\/08916930500124122","article-title":"Immunosteroid as a Regulator for Th1\/Th2 Balance: Its Possible Role in Autoimmune Diseases","volume":"38","author":"Matsuzaki","year":"2005","journal-title":"Autoimmunity"}],"updated-by":[{"DOI":"10.3389\/fonc.2021.801970","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T00:00:00Z","timestamp":1636416000000}}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.721644\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T10:59:42Z","timestamp":1636455582000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.721644\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,24]]},"references-count":39,"alternative-id":["10.3389\/fonc.2021.721644"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.721644","relation":{"corrigendum":[{"id-type":"doi","id":"10.3389\/fonc.2021.801970","asserted-by":"object"}]},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,24]]},"article-number":"721644"}}