{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T05:03:44Z","timestamp":1784610224130,"version":"3.55.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"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:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Oral squamous cell carcinoma (OSCC) shows marked biological heterogeneity, but markers that connect malignant epithelial states with the tumor immune context remain limited. Origin recognition complex subunit 6 (ORC6) participates in DNA replication licensing, but its disease-specific role in OSCC is not well defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated anatomically filtered bulk transcriptomic data, external validation cohorts, single-cell transcriptomic profiling, immune-context analyses, proliferation-adjusted sensitivity analyses, virtual perturbation, and in vitro ORC6-knockdown assays to evaluate the clinical and biological relevance of ORC6 in OSCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>After reconstruction of a strictly defined TCGA oral cavity OSCC cohort excluding base of tongue and other non-oral cavity subsites, ORC6 remained upregulated in OSCC tissues and cell lines and was associated with adverse clinicopathological features and poorer survival. Exploratory analysis in the HPV-negative GSE41613 cohort further supported the adverse survival association of ORC6. Single-cell analysis showed preferential enrichment of ORC6 in malignant epithelial cells. Within this compartment, high ORC6 expression marked a replication-active state characterized by activation of DNA-replication and cell-cycle programs and weaker transcriptional signatures of interferon response and antigen presentation. These differences were directionally preserved in donor-matched pseudobulk comparisons and after cell-cycle-score regression. At the bulk-tumor level, proliferation-adjusted models showed that ORC6 retained directionally inverse associations with selected immune-related features, including cytolytic activity, IFN-\u03b3 response, and MHC-I\/antigen-presentation signatures. ORC6 knockdown in CAL27 cells reduced cell growth, migration, invasion, and S-phase fraction while increasing antigen-presentation-associated transcripts and surface HLA-A\/B\/C expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings support ORC6 as a marker of a replication-active malignant epithelial state associated with attenuated immune-related features in OSCC, particularly antigen-presentation-related programs. Further functional immune-recognition studies and independent clinical validation are warranted.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1882429","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T04:19:43Z","timestamp":1784607583000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ORC6 marks a replication-active malignant epithelial state and is associated with immune-low features in oral squamous cell carcinoma"],"prefix":"10.3389","volume":"16","author":[{"given":"Shaofu","family":"Yan","sequence":"first","affiliation":[{"name":"Shanxi Medical University School and Hospital of Stomatology","place":["Taiyuan, China"]},{"name":"The Fifth Clinical Medical College of Shanxi Medical University","place":["Taiyuan, China"]},{"name":"Shanxi Oral Health Prevention and Control Technology Innovation Center","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqi","family":"Tan","sequence":"additional","affiliation":[{"name":"Shanxi Medical University School and Hospital of Stomatology","place":["Taiyuan, China"]},{"name":"The Fifth Clinical Medical College of Shanxi Medical University","place":["Taiyuan, China"]},{"name":"Shanxi Oral Health Prevention and Control Technology Innovation Center","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanxi Medical University School and Hospital of Stomatology","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyan","family":"Si","sequence":"additional","affiliation":[{"name":"The Fifth Clinical Medical College of Shanxi Medical University","place":["Taiyuan, China"]},{"name":"Shanxi Oral Health Prevention and Control Technology Innovation Center","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiehua","family":"Guo","sequence":"additional","affiliation":[{"name":"Shanxi Medical University School and Hospital of Stomatology","place":["Taiyuan, China"]},{"name":"The Fifth Clinical Medical College of Shanxi Medical University","place":["Taiyuan, China"]},{"name":"Shanxi Oral Health Prevention and Control Technology Innovation Center","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yang","sequence":"additional","affiliation":[{"name":"Shanxi Medical University School and Hospital of Stomatology","place":["Taiyuan, China"]},{"name":"The Fifth Clinical Medical College of Shanxi Medical University","place":["Taiyuan, China"]},{"name":"Shanxi Oral Health Prevention and Control Technology Innovation Center","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Shi","sequence":"additional","affiliation":[{"name":"Shanxi Medical University School and Hospital of Stomatology","place":["Taiyuan, China"]},{"name":"The Fifth Clinical Medical College of Shanxi Medical University","place":["Taiyuan, China"]},{"name":"Shanxi Oral Health Prevention and Control Technology Innovation Center","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","article-title":"Head and neck squamous cell carcinoma","volume":"6","author":"Johnson","year":"2020","journal-title":"Nat Rev Dis Primers"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1602252","article-title":"Nivolumab for recurrent squamous-cell carcinoma of the head and neck","volume":"375","author":"Ferris","year":"2016","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32591-7","article-title":"Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (KEYNOTE-048): a randomised, open-label, phase 3 study","volume":"394","author":"Burtness","year":"2019","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0014-x","article-title":"Understanding the tumor immune microenvironment (TIME) for effective therapy","volume":"24","author":"Binnewies","year":"2018","journal-title":"Nat Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/nrc3245","article-title":"The immune contexture in human tumours: impact on clinical outcome","volume":"12","author":"Fridman","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2018.11","article-title":"The molecular landscape of head and neck cancer","volume":"18","author":"Leemans","year":"2018","journal-title":"Nat Rev Cancer"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1016\/j.cell.2017.10.044","article-title":"Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer","volume":"171","author":"Puram","year":"2017","journal-title":"Cell"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.18108","article-title":"Unravelling the heterogeneity of oral squamous cell carcinoma by integrative analysis of single-cell and bulk transcriptome data","volume":"28","author":"Li","year":"2024","journal-title":"J Cell Mol Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2121406119","article-title":"Orc6 is a component of the replication fork and enables efficient mismatch repair","volume":"119","author":"Lin","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa751","article-title":"Structural basis of DNA replication origin recognition by human Orc6 protein binding with DNA","volume":"48","author":"Xu","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"B12","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1186\/s12885-023-10763-z","article-title":"ORC6, a novel prognostic biomarker, correlates with T regulatory cell infiltration in prostate adenocarcinoma: a pan-cancer analysis","volume":"23","author":"Lin","year":"2023","journal-title":"BMC Cancer"},{"key":"B13","doi-asserted-by":"publisher","first-page":"96","DOI":"10.3892\/ol.2024.14229","article-title":"ORC6 acts as an effective prognostic predictor for non-small cell lung cancer and is closely associated with tumor progression","volume":"27","author":"Chen","year":"2024","journal-title":"Oncol Lett"},{"key":"B14","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.cell.2018.02.052","article-title":"An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics","volume":"173","author":"Liu","year":"2018","journal-title":"Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat Methods"},{"key":"B17","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/s41587-020-00795-2","article-title":"Delineating copy number and clonal substructure in human tumors from single-cell transcriptomes","volume":"39","author":"Gao","year":"2021","journal-title":"Nat Biotechnol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1038\/s41698-025-01177-0","article-title":"Comprehensive molecular characterization of high-stemness gastric cancer cells using single-cell transcriptomics, spatial mapping, and machine learning","volume":"9","author":"Wang","year":"2025","journal-title":"NPJ Precis Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan2507","article-title":"A pathology atlas of the human cancer transcriptome","volume":"357","author":"Uhl\u00e9n","year":"2017","journal-title":"Science"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf8399","article-title":"Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy","volume":"355","author":"Davoli","year":"2017","journal-title":"Science"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1412212","article-title":"Altered extracellular matrix correlates with an immunosuppressive tumor microenvironment and disease progression in younger adults with oral cavity squamous cell carcinoma","volume":"14","author":"Estephan","year":"2024","journal-title":"Front Oncol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1714877115","article-title":"Identification of cancer genes that are independent of dominant proliferation and lineage programs","volume":"114","author":"Selfors","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20180139","article-title":"The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer","volume":"215","author":"Li","year":"2018","journal-title":"J Exp Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06889-6","article-title":"MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis","volume":"625","author":"Cho","year":"2024","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2022.01.044","article-title":"cGAS\/STING cross-talks with cell cycle and potentiates cancer immunotherapy","volume":"30","author":"Long","year":"2022","journal-title":"Mol Ther"},{"key":"B26","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/s41568-021-00339-z","article-title":"Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion","volume":"21","author":"Jhunjhunwala","year":"2021","journal-title":"Nat Rev Cancer"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2023.102329","article-title":"Tumor immune evasion through loss of MHC class-I antigen presentation","volume":"83","author":"Sari","year":"2023","journal-title":"Curr Opin Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0238-1","article-title":"A framework for advancing our understanding of cancer-associated fibroblasts","volume":"20","author":"Sahai","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12982","article-title":"Cancer-associated fibroblasts: key players in shaping the tumor immune microenvironment","volume":"302","author":"Desbois","year":"2021","journal-title":"Immunol Rev"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2023.101717","article-title":"Heterogeneity of cancer-associated fibroblasts in head and neck squamous cell carcinoma","volume":"35","author":"Mou","year":"2023","journal-title":"Transl Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2025.102024","article-title":"Immune-featured stromal niches associate with response to neoadjuvant immunotherapy in oral squamous cell carcinoma","volume":"6","author":"Liu","year":"2025","journal-title":"Cell Rep Med"},{"key":"B32","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1186\/s12943-023-01860-5","article-title":"Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials","volume":"22","author":"Zhang","year":"2023","journal-title":"Mol Cancer"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nature21349","article-title":"Elements of cancer immunity and the cancer-immune set point","volume":"541","author":"Chen","year":"2017","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of cancer: new dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1882429\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T04:19:45Z","timestamp":1784607585000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1882429\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":34,"alternative-id":["10.3389\/fonc.2026.1882429"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1882429","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]},"article-number":"1882429"}}