{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:25:39Z","timestamp":1787048739647,"version":"build-2736575974"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014895","name":"Southwest Medical University","doi-asserted-by":"publisher","award":["2018LZXNYD-ZK29"],"award-info":[{"award-number":["2018LZXNYD-ZK29"]}],"id":[{"id":"10.13039\/501100014895","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015375","name":"Affiliated Hospital of Southwest Medical University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100015375","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality, highlighting the need for novel biomarkers and therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The role of Olfactomedin-like 2B (OLFML2B) in HCC was investigated through multi-database analyses (The Cancer Genome Atlas, International Cancer Genome Consortium, Gene Expression Omnibus) and experimental validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>OLFML2B was significantly upregulated in HCC tissues, correlated with poor overall and disease-specific survival, clinicopathological features (tumor grade, stage, age, gender), and robust diagnostic performance (AUC &amp;gt; 0.7 across 14\/15 datasets). Transcriptomic and single-cell analyses further revealed that high OLFML2B expression was associated with an immunosuppressive tumor microenvironment, characterized by increased infiltration of M2 macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), as well as reduced abundance of cytotoxic T cells and NK cells. Knockdown of OLFML2B suppressed malignant phenotypes, including cell proliferation, migration, invasion, and angiogenesis, attenuated PI3K\/AKT-EMT signaling, and enhanced sensitivity to sorafenib, cabozantinib, and regorafenib in Huh7 and HepG2 cells. Additionally, OLFML2B knockdown suppressed tumor growth and metastasis in zebrafish xenografts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Collectively, these findings indicate that OLFML2B is required for HCC progression and represents a prognostic biomarker and potential therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1779625","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:35:34Z","timestamp":1787045734000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["OLFML2B promotes hepatocellular carcinoma malignancy via the PI3K\/AKT-EMT axis and correlates with an immunosuppressive tumor microenvironment"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaoling","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Affiliated Hospital, Southwest Medical University","place":["Luzhou, China"]},{"name":"Laboratory of Infection and Immunity, The Affiliated Hospital, Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Affiliated Hospital, Southwest Medical University","place":["Luzhou, China"]},{"name":"Laboratory of Infection and Immunity, The Affiliated Hospital, Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Affiliated Hospital, Southwest Medical University","place":["Luzhou, China"]},{"name":"Laboratory of Infection and Immunity, The Affiliated Hospital, Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cunliang","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Affiliated Hospital, Southwest Medical University","place":["Luzhou, China"]},{"name":"Laboratory of Infection and Immunity, The Affiliated Hospital, Southwest Medical University","place":["Luzhou, China"]},{"name":"Department of Tuberculosis, Affiliated Hospital, Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changfeng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Affiliated Hospital, Southwest Medical University","place":["Luzhou, China"]},{"name":"Laboratory of Infection and Immunity, The Affiliated Hospital, Southwest Medical University","place":["Luzhou, China"]},{"name":"Department of Tuberculosis, Affiliated Hospital, Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2005.08.064","article-title":"Elucidation of subfamily segregation and intramolecular coevolution of the olfactomedin-like proteins by comprehensive phylogenetic analysis and gene expression pattern assessment","volume":"579","author":"Zeng","year":"2005","journal-title":"FEBS Lett"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.molbev.a025975","article-title":"Molecular evolution of olfactomedin","volume":"15","author":"Karavanich","year":"1998","journal-title":"Mol Biol Evol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1083\/jcb.200210053","article-title":"Amassin, an olfactomedin protein, mediates the massive intercellular adhesion of sea urchin coelomocytes","volume":"160","author":"Hillier","year":"2003","journal-title":"J Cell Biol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1017\/s0016672300004584","article-title":"Characterization and differential expression of a human gene family of olfactomedin-related proteins","volume":"76","author":"Kulkarni","year":"2000","journal-title":"Genetical Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.5462-03.2004","article-title":"A conserved postsynaptic transmembrane protein affecting neuromuscular signaling in Caenorhabditis elegans","volume":"24","author":"Loria","year":"2004","journal-title":"J Neurosci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-10-219","article-title":"Sequencing and de novo analysis of a coral larval transcriptome using 454 GSFlx","volume":"10","author":"Meyer","year":"2009","journal-title":"BMC Genomics"},{"key":"B7","article-title":"Bioinformatic approaches for identification and characterization of olfactomedin related genes with a potential role in pathogenesis of ocular disorders","volume":"10","author":"Mukhopadhyay","year":"2004","journal-title":"Mol Vision"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1042\/bj20050120","article-title":"Identification and characterization of photomedins: novel olfactomedin-domain-containing proteins with chondroitin sulphate-E-binding activity","volume":"389","author":"Furutani","year":"2005","journal-title":"Biochem J"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.650678","article-title":"OLFML2B is a robust prognostic biomarker in bladder cancer through genome-wide screening: a study based on seven cohorts","volume":"11","author":"Lin","year":"2021","journal-title":"Front Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/9143695","article-title":"Identification of prognosis-related genes in bladder cancer microenvironment across TCGA database","volume":"2020","author":"Zhao","year":"2020","journal-title":"BioMed Res Int"},{"key":"B11","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1186\/s12885-019-5406-x","article-title":"Bioinformatic exploration of OLFML2B overexpression in gastric cancer base on multiple analyzing tools","volume":"19","author":"Liu","year":"2019","journal-title":"BMC Cancer"},{"key":"B12","doi-asserted-by":"publisher","first-page":"736","DOI":"10.3390\/biom13050736","article-title":"Epigenetic and tumor microenvironment for prognosis of patients with gastric cancer","volume":"13","author":"Wu","year":"2023","journal-title":"Biomolecules"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.6504","article-title":"Integrating bioinformatic analysis and detailed experiments reveal an EMT-related biomarker for clear cell renal cell carcinoma","volume":"12","author":"Ge","year":"2023","journal-title":"Cancer Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2021108647","article-title":"Dynamic EMT: a multi-tool for tumor progression","volume":"40","author":"Brabletz","year":"2021","journal-title":"EMBO J"},{"key":"B15","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1186\/s12964-025-02369-8","article-title":"Senescent fibroblasts secrete CTHRC1 to promote cancer stemness in hepatocellular carcinoma","volume":"23","author":"Huang","year":"2025","journal-title":"Cell Commun Signal"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1151800","article-title":"Model for predicting immunotherapy based on M2 macrophage infiltration in TNBC","volume":"14","author":"Wu","year":"2023","journal-title":"Front Immunol"},{"key":"B17","article-title":"Landscape of active enhancers developed de novo in cirrhosis and conserved in hepatocellular carcinoma","volume":"10","author":"Yang","year":"2020","journal-title":"Am J Cancer Res"},{"key":"B18","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":"PNAS"},{"key":"B19","doi-asserted-by":"publisher","first-page":"bbae116","DOI":"10.32614\/cran.package.reporterscore","article-title":"Generalized reporter score-based enrichment analysis for omics data","volume":"25","author":"Peng","year":"2024","journal-title":"Briefings Bioinf"},{"key":"B20","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.jhep.2011.12.001","article-title":"EASL clinical practice guidelines: Management of hepatocellular carcinoma","volume":"69","year":"2018","journal-title":"J Hepatol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"199","DOI":"10.46883\/onc.2021.3504.0199","article-title":"How to radiologically assess and follow response after treatment of hepatocellular carcinoma","volume":"35","author":"Gabutti","year":"2021","journal-title":"Oncol (Williston Park NY)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-023-13228-6","article-title":"Disease-free interval and tumor stage complementarily predict the biological behavior of recurrent hepatocellular carcinoma","volume":"30","author":"Shindoh","year":"2023","journal-title":"Ann Surg Oncol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1186\/s12893-024-02642-6","article-title":"Prognostic significance of early and multiple recurrences after curative resection for hepatocellular carcinoma","volume":"24","author":"Tanemura","year":"2024","journal-title":"BMC Surg"},{"key":"B24","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1007\/s13304-020-00931-2","article-title":"Six months as a cutoff time point to define early recurrence after liver resection of hepatocellular carcinoma based on post-recurrence survival","volume":"73","author":"Liu","year":"2021","journal-title":"Updates Surg"},{"key":"B25","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1186\/s12876-023-02827-y","article-title":"Comprehensive analysis of candidate signatures of long non-coding RNA LINC01116 and related protein-coding genes in patients with hepatocellular carcinoma","volume":"23","author":"Wang","year":"2023","journal-title":"BMC Gastroenterol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"110","DOI":"10.21203\/rs.3.rs-2832772\/v1","article-title":"Analysis of prognostic value of lactate metabolism-related genes in ovarian cancer based on bioinformatics","volume":"17","author":"Sun","year":"2024","journal-title":"J Ovarian Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1089\/dna.2020.5512","article-title":"A five-gene signature based on stromal\/immune scores in the tumor microenvironment and its clinical implications for liver cancer","volume":"39","author":"Liu","year":"2020","journal-title":"DNA Cell Biol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.939460","article-title":"Pro-metastatic and mesenchymal gene expression signatures characterize circulating tumor cells of neuroblastoma patients with bone marrow metastases and relapse","volume":"12","author":"Loh","year":"2022","journal-title":"Front Oncol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.882794","article-title":"Pan-cancer analysis of OLFML2B expression and its association with prognosis and immune infiltration","volume":"13","author":"Hu","year":"2022","journal-title":"Front Genet"},{"key":"B30","doi-asserted-by":"publisher","first-page":"BSR20200980","DOI":"10.1042\/bsr20200980","article-title":"Identification of prognosis-related genes in the tumor microenvironment of stomach adenocarcinoma by TCGA and GEO datasets","volume":"40","author":"Ren","year":"2020","journal-title":"Biosci Rep"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1529525","article-title":"Development and pan-cancer validation of an epigenetics-based random survival forest model for prognosis prediction and drug response in OS","volume":"16","author":"Yin","year":"2025","journal-title":"Front Pharmacol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1779625\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:35:37Z","timestamp":1787045737000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1779625\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":31,"alternative-id":["10.3389\/fimmu.2026.1779625"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1779625","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]},"article-number":"1779625"}}