{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T22:17:07Z","timestamp":1788128227680,"version":"build-2803163510"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"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. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Lymphangiogenesis promotes tumor dissemination and may shape the immune contexture of cervical cancer, yet lymphangiogenesis-related prognostic stratification and its immunometabolic implications remain insufficiently defined in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>TCGA-CESC transcriptomes and clinical data were obtained from UCSC Xena and integrated with normal cervix tissues from the Genotype-Tissue Expression Project after batch correction. Prognostic LYMRGs were first identified from the differentially expressed set using univariable Cox proportional hazards analysis. Candidate genes were then reduced using an L1-regularized Cox model (Least Absolute Shrinkage and Selection Operator), and the remaining markers were entered into a multivariable Cox regression to obtain the final coefficients and compute an individualized risk score. The model\u2019s prognostic value was further assessed in an independent Gene Expression Omnibus dataset. In addition, expression patterns of the signature genes were leveraged for molecular subtyping of TCGA samples via non-negative matrix factorization (NMF). Immune infiltration and immunotherapy-associated characteristics were interrogated through a multi-algorithm strategy (single-sample gene set enrichment analysis, CIBERSORT, ESTIMATE, Tumor Immune Dysfunction and Exclusion (TIDE), and Immunophenoscore . Additional analyses included pathway enrichment (GSEA\/GO\/KEGG), drug sensitivity prediction (pRRophetic\/CellMiner), and ceRNA network analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A six-gene LYMRG signature robustly stratified survival. High-risk patients had significantly worse overall survival in The Cancer Genome Atlas with AUCs of 0.819\/0.801\/0.801\u00a0at 1\/3\/5 years, and in GSE52903 (P = 0.001) with AUCs of 0.733\/0.719\/0.725. NMF identified two subtypes with distinct prognosis (P = 0.01) and divergent immune landscapes. Risk groups and subtypes exhibited consistent differences in immune infiltration, checkpoint expression, TIDE\/IPS patterns, and pathway enrichment. Predicted chemosensitivity differed by risk group, and the ceRNA network suggested candidate upstream lncRNA regulators of the signature.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>A lymphangiogenesis-related six-gene model enables clinically meaningful prognostic stratification of CESC and links lymphangiogenesis programs to distinct tumor immune phenotypes and therapeutic vulnerabilities.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1835653","type":"journal-article","created":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T22:10:14Z","timestamp":1788127814000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Lymphangiogenesis-related gene signature\u2013based risk model for prognostic assessment of cervical cancer: immune\u2013metabolic characterization and molecular subtype analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Xijing","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine","place":["Jinhua, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine","place":["Jinhua, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Healthcare, Jinhua Maternal and Child Healthcare Hospital","place":["Jinhua, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunjie","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Jinhua Maternal and Child Healthcare Hospital","place":["Jinhua, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Pan","sequence":"additional","affiliation":[{"name":"Lighthouse Research Institute, University of Nottingham Ningbo China","place":["Ningbo, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine","place":["Jinhua, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1002\/ijgo.12749","article-title":"Revised FIGO staging for carcinoma of the cervix uteri","volume":"145","author":"Bhatla","year":"2019","journal-title":"Int. Journal Gynaecology Obstetrics The Official Organ Int. Fed. Gynaecol. Obstetrics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1007\/s00428-023-03552-3","article-title":"ESGO\/ESTRO\/ESP guidelines for the management of patients with cervical cancer - update 2023","volume":"33","author":"Cibula","year":"2023","journal-title":"Int. Journal Gynecological Cancer Official Journal Int. Gynecol. Cancer Soc."},{"key":"B3","doi-asserted-by":"publisher","first-page":"4133","DOI":"10.1158\/0008-5472.CAN-21-0633","article-title":"Lymphatic PD-L1 expression restricts tumor-specific CD8(+) T-cell responses","volume":"81","author":"Cousin","year":"2021","journal-title":"Cancer Research"},{"key":"B4","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/978-3-030-83282-7_7","article-title":"Noncoding RNAs in papillary thyroid cancer: interaction with cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) and regulators of differentiation and lymph node metastasis","volume":"1350","author":"Dadafarin","year":"2021","journal-title":"Adv. Experimental Medicine Biology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e38488","DOI":"10.1016\/j.heliyon.2024.e38488","article-title":"Identification of molecular subtypes, prognostic status and immunotherapy response in cervical cancer based on angiogenic signature genes","volume":"10","author":"Deng","year":"2024","journal-title":"Heliyon"},{"key":"B6","doi-asserted-by":"publisher","first-page":"5876","DOI":"10.1158\/0008-5472.CAN-21-1456","article-title":"ALKBH5 facilitates hypoxia-induced paraspeckle assembly and IL8 secretion to generate an immunosuppressive tumor microenvironment","volume":"81","author":"Dong","year":"2021","journal-title":"Cancer Research"},{"key":"B7","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1038\/s41419-022-04926-2","article-title":"FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis","volume":"13","author":"Du","year":"2022","journal-title":"Cell Death and Disease"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1190251","DOI":"10.3389\/fonc.2023.1190251","article-title":"Lymph node metastasis-related gene signature shows good performance in predicting prognosis and immune infiltration in cervical cancer","volume":"13","author":"Guo","year":"2023","journal-title":"Front. Oncology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2252","DOI":"10.21037\/tlcr-21-40","article-title":"Role of lymphatic endothelial cells in the tumor microenvironment-a narrative review of recent advances","volume":"10","author":"He","year":"2021","journal-title":"Transl. Lung Cancer Research"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e33547","DOI":"10.1097\/MD.0000000000033547","article-title":"Prognostic value of lymphovascular space invasion in stage IA to IIB cervical cancer: a meta-analysis","volume":"102","author":"Huang","year":"2023","journal-title":"Medicine"},{"key":"B11","doi-asserted-by":"publisher","first-page":"106863","DOI":"10.1016\/j.phrs.2023.106863","article-title":"HPV E7-drived ALKBH5 promotes cervical cancer progression by modulating m6A modification of PAK5","volume":"195","author":"Huo","year":"2023","journal-title":"Pharmacol. Research"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1081376","DOI":"10.3389\/fphys.2022.1081376","article-title":"TGF-\u03b2 signaling in lymphatic vascular vessel formation and maintenance","volume":"13","author":"Itoh","year":"2022","journal-title":"Front. Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/s41392-023-01576-4","article-title":"Lymph node metastasis in cancer progression: molecular mechanisms, clinical significance and therapeutic interventions","volume":"8","author":"Ji","year":"2023","journal-title":"Signal Transduction Targeted Therapy"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1086835","DOI":"10.3389\/fcell.2022.1086835","article-title":"Angiogenesis-related gene signatures reveal the prognosis of cervical cancer based on single cell sequencing and co-expression network analysis","volume":"10","author":"Kang","year":"2022","journal-title":"Front. Cell Developmental Biology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1038\/s41568-024-00681-y","article-title":"Lymphatic vessels in the age of cancer immunotherapy","volume":"24","author":"Karakousi","year":"2024","journal-title":"Nat. Reviews Cancer"},{"key":"B16","doi-asserted-by":"publisher","first-page":"35429","DOI":"10.1038\/s41598-025-19290-2","article-title":"Machine learning analysis of coagulation-related genes for breast cancer diagnosis and prognosis prediction","volume":"15","author":"Li","year":"2025","journal-title":"Sci. Reports"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1709260","DOI":"10.3389\/fimmu.2025.1709260","article-title":"Decoding the immunoregulatory functions of ALKBH5 in the tumor microenvironment","volume":"16","author":"Li","year":"2025","journal-title":"Front. Immunology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1186\/s13046-022-02462-7","article-title":"ALKBH5-mediated m6A modification of circCCDC134 facilitates cervical cancer metastasis by enhancing HIF1A transcription","volume":"41","author":"Liang","year":"2022","journal-title":"J. Experimental and Clinical Cancer Research CR"},{"key":"B19","doi-asserted-by":"publisher","first-page":"923263","DOI":"10.3389\/fgene.2022.923263","article-title":"Construction of a six-gene prognostic risk model related to hypoxia and angiogenesis for cervical cancer","volume":"13","author":"Liu","year":"2022","journal-title":"Front. Genetics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.celrep.2012.01.005","article-title":"VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics","volume":"1","author":"Lund","year":"2012","journal-title":"Cell Reports"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2771","DOI":"10.1007\/s12094-024-03604-3","article-title":"SEOM-GEICO clinical guidelines on cervical cancer","volume":"26","author":"Manso","year":"2024","journal-title":"Clin. and Translational Oncology Official Publication Fed. Span. Oncol. Soc."},{"key":"B22","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1038\/s41419-023-06265-2","article-title":"The roles of m6A methylation in cervical cancer: functions, molecular mechanisms, and clinical applications","volume":"14","author":"Mao","year":"2023","journal-title":"Cell Death and Disease"},{"key":"B23","doi-asserted-by":"publisher","first-page":"591","DOI":"10.3390\/ijms27020591","article-title":"Cholesterol metabolism: an ally in the development and progression of cervical cancer","volume":"27","author":"Mart\u00ednez-Ram\u00edrez","year":"2026","journal-title":"Int. Journal Molecular Sciences"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e29907","DOI":"10.1080\/23723556.2015.1024821","article-title":"Role of hypoxia and vascular endothelial growth factors in lymphangiogenesis","volume":"1","author":"Morfoisse","year":"2014","journal-title":"Mol. Cell Oncol."},{"key":"B25","first-page":"462","article-title":"Lymphangiogenesis and tumor metastasis: myth or reality?","volume":"7","author":"Pepper","year":"2001","journal-title":"Clin. Cancer Research An Official Journal Am. Assoc. Cancer Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e197","DOI":"10.1016\/s2214-109x(22)00501-0","article-title":"Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO global cervical cancer elimination initiative","volume":"11","author":"Singh","year":"2023","journal-title":"Lancet Glob. Health"},{"key":"B27","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1007\/s12282-020-01079-y","article-title":"Tumor-infiltrating regulatory T cells, CD8\/Treg ratio, and cancer stem cells are correlated with lymph node metastasis in patients with early breast cancer","volume":"27","author":"Solis-Castillo","year":"2020","journal-title":"Breast Cancer (Tokyo, Jpn.)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1039\/c5mb00685f","article-title":"Down-regulation of MALAT1 inhibits cervical cancer cell invasion and metastasis by inhibition of epithelial-mesenchymal transition","volume":"12","author":"Sun","year":"2016","journal-title":"Mol. Biosyst."},{"key":"B29","doi-asserted-by":"publisher","first-page":"4196","DOI":"10.1158\/0008-5472.CAN-18-3657","article-title":"Activation of the VEGFC\/VEGFR3 pathway induces tumor immune escape in colorectal cancer","volume":"79","author":"Tacconi","year":"2019","journal-title":"Cancer Research"},{"key":"B30","doi-asserted-by":"publisher","first-page":"3989","DOI":"10.1038\/ncomms4989","article-title":"Antigen capture and archiving by lymphatic endothelial cells following vaccination or viral infection","volume":"5","author":"Tamburini","year":"2014","journal-title":"Nat. Communications"},{"key":"B31","doi-asserted-by":"publisher","first-page":"212","DOI":"10.3390\/cancers14010212","article-title":"Lymph node involvement in early-stage cervical cancer: is lymphangiogenesis a risk factor? Results from the MICROCOL study","volume":"14","author":"Tantari","year":"2022","journal-title":"Cancers"},{"key":"B32","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1016\/j.ygyno.2015.09.076","article-title":"The sentinel node procedure in early stage cervical cancer, taking the next step; a diagnostic review","volume":"139","author":"Tax","year":"2015","journal-title":"Gynecol. Oncology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1056\/NEJMoa1309748","article-title":"Improved survival with bevacizumab in advanced cervical cancer","volume":"370","author":"Tewari","year":"2014","journal-title":"N. Engl. Journal Medicine"},{"key":"B34","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1016\/j.immuni.2018.03.023","article-title":"The immune landscape of cancer","volume":"48","author":"Thorsson","year":"2018","journal-title":"Immunity"},{"key":"B35","doi-asserted-by":"publisher","first-page":"486","DOI":"10.3892\/etm.2023.12185","article-title":"Role of the tumor microenvironment in the lymphatic metastasis of cervical cancer","volume":"26","author":"Wang","year":"2023","journal-title":"Exp. Therapeutic Medicine"},{"key":"B36","doi-asserted-by":"publisher","first-page":"42703","DOI":"10.1038\/s41598-025-26740-4","article-title":"Classifying the tumor immune microenvironment in cervical cancer based on nuclear cytoplasmic consistent genes","volume":"15","author":"Wang","year":"2025","journal-title":"Sci. Reports"},{"key":"B37","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1097\/CM9.0000000000003407","article-title":"DDX24 promotes lymphangiogenesis and lymph node metastasis via AGRN production in cervical squamous cell carcinoma","volume":"138","author":"Wang","year":"2025","journal-title":"Chin. Medical Journal"},{"key":"B38","doi-asserted-by":"publisher","first-page":"3839","DOI":"10.7150\/ijms.118912","article-title":"PRDX3 promotes lymph node metastasis in cervical cancer by activating NF-\u03baB signaling pathway and anoikis resistance","volume":"22","author":"Wen","year":"2025","journal-title":"Int. Journal Medical Sciences"},{"key":"B39","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1038\/s41420-025-02782-5","article-title":"CREB5 promotes nodal metastasis of cervical cancer by regulation of APLN-induced lymphangiogenesis","volume":"11","author":"Xia","year":"2025","journal-title":"Cell Death Discovery"},{"key":"B40","doi-asserted-by":"publisher","first-page":"632","DOI":"10.3390\/cells9030632","article-title":"MicroRNA-361-Mediated inhibition of HSP90 expression and EMT in cervical cancer is counteracted by oncogenic lncRNA NEAT1","volume":"9","author":"Xu","year":"2020","journal-title":"Cells"},{"key":"B41","doi-asserted-by":"publisher","first-page":"2151","DOI":"10.7150\/thno.94161","article-title":"FSH induces EMT in ovarian cancer via ALKBH5-regulated snail m6A demethylation","volume":"14","author":"Xu","year":"2024","journal-title":"Theranostics"},{"key":"B42","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1186\/s12967-025-06896-3","article-title":"Targeting immune microenvironment in cervical cancer: current research and advances","volume":"23","author":"Zhang","year":"2025","journal-title":"J. Translational Medicine"},{"key":"B43","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1080\/1061186X.2020.1815210","article-title":"New insights into the role of co-receptor neuropilins in tumour angiogenesis and lymphangiogenesis and targeted therapy strategies","volume":"29","author":"Zhao","year":"2021","journal-title":"J. Drug Targeting"},{"key":"B44","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1186\/s12943-025-02424-5","article-title":"CircZFR\/YTHDF3 axis drives lymph node metastasis in cervical cancer via FASN translation","volume":"24","author":"Zhou","year":"2025","journal-title":"Mol. Cancer"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1835653\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T22:10:15Z","timestamp":1788127815000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1835653\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":44,"alternative-id":["10.3389\/fgene.2026.1835653"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2026.1835653","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]},"article-number":"1835653"}}