{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T14:04:38Z","timestamp":1788012278449,"version":"build-2784847793"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T00:00:00Z","timestamp":1621987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Methyltransferase-like 18 (METTL18), a METTL family member, is abundant in hepatocellular carcinoma (HCC). Studies have indicated the METTL family could regulate the progress of diverse malignancies while the role of METTL18 in HCC remains unclear. Data of HCC patients were acquired from the cancer genome atlas (TCGA) and gene expression omnibus (GEO). The expression level of METTL18 in HCC patients was compared with normal liver tissues by Wilcoxon test. Then, the logistic analysis was used to estimate the correlation between METTL18 and clinicopathological factors. Besides, Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA) were used to explore relevant functions and quantify the degree of immune infiltration for METTL18. Univariate and Multivariate Cox analyses and Kaplan\u2013Meier analysis were used to estimate the association between METTL18 and prognosis. Besides, by cox multivariate analysis, a nomogram was conducted to forecast the influence of METTL18 on survival rates. METTL18-high was associated with Histologic grade, T stage, Pathologic stage, BMI, Adjacent hepatic tissue inflammation, AFP, Vascular invasion, and TP53 status (P &amp;lt; 0.05). HCC patients with METTL18-high had a poor Overall-Survival [OS; hazard ratio (HR): 1.87, P &amp;lt; 0.001), Disease-Specific Survival (DSS, HR: 1.76, P = 0.015), and Progression-Free Interval (PFI, HR: 1.51, P = 0.006). Multivariate analysis demonstrated that METTL18 was an independent factor for OS (HR: 2.093, P &amp;lt; 0.001), DSS (HR: 2.404, P = 0.015), and PFI (HR: 1.133, P = 0.006). Based on multivariate analysis, the calibration plots and C-indexes of nomograms showed an efficacious predictive effect for HCC patients. GSEA demonstrated that METTL18-high could activate G2M checkpoint, E2F targets, KRAS signaling pathway, and Mitotic Spindle. There was a positive association between the METTL18 and abundance of innate immunocytes (T helper 2 cells) and a negative relation to the abundance of adaptive immunocytes (Dendritic cells, Cytotoxic cells <jats:italic>etc.<\/jats:italic>). Finally, we uncovered knockdown of METTL18 significantly suppressed the proliferation, invasion, and migration of HCC cells <jats:italic>in vitro<\/jats:italic>. This research indicates that METTL18 could be a novel biomarker to evaluate HCC patients\u2019 prognosis and an important regulator of immune responses in HCC.<\/jats:p>","DOI":"10.3389\/fonc.2021.665192","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T06:18:24Z","timestamp":1622009904000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Identification METTL18 as a Potential Prognosis Biomarker and Associated With Immune Infiltrates in Hepatocellular Carcinoma"],"prefix":"10.3389","volume":"11","author":[{"given":"Tian-Hao","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bang-Bo","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Tao","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Ying","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze-Ru","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-Tong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Bin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,26]]},"reference":[{"key":"B1","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":"B2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.canlet.2013.12.024","article-title":"Multiple Interactive Factors in Hepatocarcinogenesis","volume":"346","author":"Ding","year":"2014","journal-title":"Cancer Lett"},{"key":"B3","doi-asserted-by":"publisher","first-page":"486","DOI":"10.3390\/cancers11040486","article-title":"Diagnostic and Prognostic Potential of AKR1B10 in Human Hepatocellular Carcinoma","volume":"11","author":"DiStefano","year":"2019","journal-title":"Cancers"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2017.07.041","article-title":"Cost Effectiveness of Nivolumab in Advanced Renal Cell Carcinoma","volume":"73","author":"Sarfaty","year":"2018","journal-title":"Eur Urol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/S0016-5085(03)00689-9","article-title":"Glypican-3: A Novel Serum and Histochemical Marker for Hepatocellular Carcinoma","volume":"125","author":"Capurro","year":"2003","journal-title":"Gastroenterology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-0223","article-title":"Molecular Pathways: Protein Methyltransferases in Cancer","volume":"19","author":"Copeland","year":"2013","journal-title":"Clin Cancer Res:  Off J Am Assoc Cancer Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-43624-1_6","article-title":"Genetic Studies on Mammalian Dna Methyltransferases","volume":"945","author":"Dan","year":"2016","journal-title":"Adv Exp Med Biol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/nrg3863","article-title":"RNA-Mediated Epigenetic Regulation of Gene Expression","volume":"16","author":"Holoch","year":"2015","journal-title":"Nat Rev Genet"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b07830","article-title":"Chemical Proteomic Profiling of Human Methyltransferases","volume":"138","author":"Horning","year":"2016","journal-title":"J Am Chem Soc"},{"key":"B10","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s13072-017-0130-8","article-title":"DNA Methylation and DNA Methyltransferases","volume":"10","author":"Edwards","year":"2017","journal-title":"Epigenet Chromatin"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1089\/clo.2006.8.200","article-title":"Inhibitors of Histone Deacetylases and DNA Methyltransferases Alter Imprinted Gene Regulation in Embryonic Stem Cells","volume":"8","author":"Baqir","year":"2006","journal-title":"Cloning Stem Cells"},{"key":"B12","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/nrc3409","article-title":"Protein Arginine Methyltransferases and Cancer","volume":"13","author":"Yang","year":"2013","journal-title":"Nat Rev Cancer"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1177\/1073858417707457","article-title":"Neuronal DNA Methyltransferases: Epigenetic Mediators Between Synaptic Activity and Gene Expression","volume":"24","author":"Bayraktar","year":"2018","journal-title":"Neuroscientist"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.798298","article-title":"Three Distinct 3-Methylcytidine (M(3)C) Methyltransferases Modify tRNA and mRNA in Mice and Humans","volume":"292","author":"Xu","year":"2017","journal-title":"J Biol Chem"},{"key":"B15","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1016\/j.cell.2017.05.003","article-title":"The U6 snRNA M(6)a Methyltransferase Mettl16 Regulates Sam Synthetase Intron Retention","volume":"169","author":"Pendleton","year":"2017","journal-title":"Cell"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-018-0034-6","article-title":"Rna N(6)-methyladenosine Modification in Cancers: Current Status and Perspectives","volume":"28","author":"Deng","year":"2018","journal-title":"Cell Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28885","article-title":"METTL14 Suppresses the Metastatic Potential of Hepatocellular Carcinoma by Modulating N(6) -Methyladenosine-Dependent Primary MicroRNA Processing","volume":"65","author":"Ma","year":"2017","journal-title":"Hepatology"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29683","article-title":"Rna N6-methyladenosine Methyltransferase-Like 3 Promotes Liver Cancer Progression Through YTHDF2-dependent Posttranscriptional Silencing of SOCS2","volume":"67","author":"Chen","year":"2018","journal-title":"Hepatology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1.30.1","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr Protoc Bioinf"},{"key":"B20","doi-asserted-by":"publisher","first-page":"D158","DOI":"10.1093\/nar\/gkw1099","volume":"45","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"B21","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":"B22","doi-asserted-by":"publisher","first-page":"D607","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":"B23","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":"B24","doi-asserted-by":"publisher","first-page":"6584","DOI":"10.1038\/s41598-019-43010-2","article-title":"The Interactome of a Family of Potential Methyltransferases in HeLa Cells","volume":"9","author":"Ignatova","year":"2019","journal-title":"Sci Rep"},{"key":"B25","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1038\/nature21073","article-title":"Corrigendum: Structural Basis of N(6)-adenosine Methylation by the METTL3-METTL14 Complex","volume":"542","author":"Wang","year":"2017","journal-title":"Nature"},{"key":"B26","article-title":"N6-Methyladenosine Methyltransferase METTL3 Promotes Colorectal Cancer Cell Proliferation Through Enhancing MYC Expression","volume":"12","author":"Xiang","year":"2020","journal-title":"Am J Transl Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0538-8","article-title":"mRNA Circularization by METTL3-eIF3h Enhances Translation and Promotes Oncogenesis","volume":"561","author":"Choe","year":"2018","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s10787-017-0309-4","article-title":"Antioxidant and Anti-Inflammatory Effects of Zinc. Zinc-dependent Nf-\u03bab Signaling","volume":"25","author":"Jarosz","year":"2017","journal-title":"Inflammopharmacology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3732","DOI":"10.3390\/nu12123732","article-title":"The Role of Zinc and Copper in Gynecological Malignancies","volume":"12","author":"Michalczyk","year":"2020","journal-title":"Nutrients"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.3390\/nu9121286","article-title":"Zinc as a Gatekeeper of Immune Function","volume":"9","author":"Wessels","year":"2017","journal-title":"Nutrients"},{"key":"B31","doi-asserted-by":"publisher","first-page":"126629","DOI":"10.1016\/j.jtemb.2020.126629","article-title":"Serum Copper and Zinc Levels in Breast Cancer: A Meta-Analysis","volume":"62","author":"Feng","year":"2020","journal-title":"J Trace Elements Med Biol: Organ Soc Minerals Trace Elements (GMS)"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1039\/C5MT00149H","article-title":"Targeting Copper in Cancer Therapy: \u2018Copper That Cancer\u2019","volume":"7","author":"Denoyer","year":"2015","journal-title":"Metallomics: Integrated Biometal Sci"},{"key":"B33","doi-asserted-by":"publisher","first-page":"152843","DOI":"10.1016\/j.phymed.2019.152843","article-title":"Aloperine Induces Apoptosis and G2\/M Cell Cycle Arrest in Hepatocellular Carcinoma Cells Through the PI3K\/Akt Signaling Pathway","volume":"61","author":"Liu","year":"2019","journal-title":"Phytomed: Int J Phytother Phytopharmacol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2019.11.001","article-title":"Macrophages-Induced Long Noncoding RNA H19 Up-Regulation Triggers and Activates the miR-193b\/MAPK1 Axis and Promotes Cell Aggressiveness in Hepatocellular Carcinoma","volume":"469","author":"Ye","year":"2020","journal-title":"Cancer Lett"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-313114","article-title":"CHK2 Overexpression and Mislocalisation Within Mitotic Structures Enhances Chromosomal Instability and Hepatocellular Carcinoma Progression","volume":"67","author":"Carloni","year":"2018","journal-title":"Gut"},{"key":"B36","doi-asserted-by":"publisher","first-page":"103195","DOI":"10.1016\/j.ebiom.2020.103195","article-title":"The RNA Methyltransferase NSUN6 Suppresses Pancreatic Cancer Development by Regulating Cell Proliferation","volume":"63","author":"Yang","year":"2021","journal-title":"EBioMedicine"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/ijms12128947","article-title":"The Role of the E2F Transcription Factor Family in UV-induced Apoptosis","volume":"12","author":"Hazar-Rethinam","year":"2011","journal-title":"Int J Mol Sci"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e0127951","DOI":"10.1371\/journal.pone.0127951","article-title":"E2f1-Mediated Induction of NFYB Attenuates Apoptosis Via Joint Regulation of a Pro-Survival Transcriptional Program","volume":"10","author":"Jiang","year":"2015","journal-title":"PloS One"},{"key":"B39","doi-asserted-by":"publisher","first-page":"795","DOI":"10.3748\/wjg.v20.i3.795","article-title":"Bortezomib Effect on E2F and Cyclin Family Members in Human Hepatocellular Carcinoma Cell Lines","volume":"20","author":"Baiz","year":"2014","journal-title":"World J Gastroenterol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bbi.2015.07.019","article-title":"Tumor Infiltrating Immune Cells in Gliomas and Meningiomas","volume":"53","author":"Domingues","year":"2016","journal-title":"Brain Behav Immun"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1016\/j.cell.2017.05.035","article-title":"Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing","volume":"169","author":"Zheng","year":"2017","journal-title":"Cell"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0757","article-title":"Accumulation of Tumor-Infiltrating Cd49a(+) NK Cells Correlates With Poor Prognosis for Human Hepatocellular Carcinoma","volume":"7","author":"Sun","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B43","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41577-019-0210-z","article-title":"Dendritic Cells in Cancer Immunology and Immunotherapy","volume":"20","author":"Wculek","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/bs.ircmb.2019.07.008","article-title":"Interplay Between Dendritic Cells and Cancer Cells","volume":"348","author":"Martinek","year":"2019","journal-title":"Int Rev Cell Mol Biol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2015.01.007","article-title":"Insulin-Like Growth Factors Inhibit Dendritic Cell-Mediated Anti-Tumor Immunity Through Regulating ERK1\/2 Phosphorylation and p38 Dephosphorylation","volume":"359","author":"Huang","year":"2015","journal-title":"Cancer Lett"},{"key":"B46","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1186\/s40425-018-0399-6","article-title":"Resident Memory T Cells, Critical Components in Tumor Immunology","volume":"6","author":"Mami-Chouaib","year":"2018","journal-title":"J Immunother Cancer"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.03.074","article-title":"Hepatocellular Carcinoma Cells Up-regulate Pvrl1, Stabilizing PVR and Inhibiting the Cytotoxic T-Cell Response Via TIGIT to Mediate Tumor Resistance to PD1 Inhibitors in Mice","volume":"159","author":"Chiu","year":"2020","journal-title":"Gastroenterology"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1038\/s41467-018-04006-0","article-title":"The LINC01138 Drives Malignancies Via Activating Arginine Methyltransferase 5 in Hepatocellular Carcinoma","volume":"9","author":"Li","year":"2018","journal-title":"Nat Commun"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.665192\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T06:18:29Z","timestamp":1622009909000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.665192\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,26]]},"references-count":48,"alternative-id":["10.3389\/fonc.2021.665192"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.665192","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,26]]},"article-number":"665192"}}