{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:51:54Z","timestamp":1791597114129,"version":"4.3.4"},"reference-count":42,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","award":["ORF-2026-1725"],"award-info":[{"award-number":["ORF-2026-1725"]}],"id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]},{"award":["ORF-2026-1725"],"award-info":[{"award-number":["ORF-2026-1725"]}],"id":[{"id":"https:\/\/ror.org\/02f81g417","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Annexin A2 (ANXA2) is involved in cell-surface fibrinolysis and has been associated with hepatocellular carcinoma (HCC). We examined ANXA2 expression in HCC and its associations with survival and immune\u2013hemostatic gene expression. ANXA2 transcript expression was assessed in The Cancer Genome Atlas liver cancer cohort (TCGA-LIHC) and an independent HCC dataset (GSE25097). Public protein datasets were used to examine ANXA2 abundance. We analyzed clinicopathological associations, overall survival, tumor\u2013normal tissue discrimination, and correlations with selected immune, coagulation, fibrinolytic, and inflammatory genes. ANXA2 expression was higher in HCC than in non-tumor liver tissue in the transcriptomic analyses and was elevated in the protein analyses. Higher ANXA2 expression was associated with poorer overall survival after adjustment for age, sex, and pathological stage (hazard ratio, 1.26; 95% confidence interval, 1.07\u20131.49; p = 0.006). Within TCGA-LIHC, ANXA2 expression discriminated tumor from normal tissue (area under the curve, 0.895; 95% confidence interval, 0.852\u20130.933); this performance was not independently validated. ANXA2 expression also correlated with selected fibrinolytic, inflammatory, and immune-related genes. GSE25097 supported the differential-expression finding. ANXA2 is overexpressed in HCC and is associated with poorer survival and an immune\u2013hemostatic transcriptional pattern. The correlations do not establish that ANXA2 regulates these processes.<\/jats:p>","DOI":"10.3390\/ijms27198915","type":"journal-article","created":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:40:17Z","timestamp":1791596417000},"page":"8915","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ANXA2 as a Candidate Molecular Hub Linking Fibrinolysis, Coagulation, and Immune Remodeling in Hepatocellular Carcinoma: An Integrative Multi-Omics Analysis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8922-0143","authenticated-orcid":false,"given":"Esra\u2019a","family":"Abudouleh","sequence":"first","affiliation":[{"name":"Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasha","family":"Elsayim","sequence":"additional","affiliation":[{"name":"Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1908-9469","authenticated-orcid":false,"given":"Heba W.","family":"Alhamdi","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Sciences, King Khalid University, P.O. Box 960, Abha 61413, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Nada Fahad","family":"Almebairik","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Science, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8847-323X","authenticated-orcid":false,"given":"Noorah A.","family":"Alkubaisi","sequence":"additional","affiliation":[{"name":"Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.livres.2023.11.004","article-title":"Hepatocellular carcinoma recurrence: Predictors and management","volume":"7","author":"Abdelhamed","year":"2023","journal-title":"Liver Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1002\/hep4.1923","article-title":"Global and regional long-term survival following resection for HCC in the recent decade: A meta-analysis of 110 studies","volume":"6","author":"Teng","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.3748\/wjg.v26.i18.2126","article-title":"Annexin A2 promotion of hepatocellular carcinoma tumorigenesis via the immune microenvironment","volume":"26","author":"Qiu","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lopez-Gonzalez, L., Sanchez Cendra, A., Sanchez Cendra, C., Roberts Cervantes, E.D., Espinosa, J.C., Pekarek, T., Fraile-Martinez, O., Garcia-Montero, C., Rodriguez-Slocker, A.M., and Jimenez-Alvarez, L. (2024). Exploring Biomarkers in Breast Cancer: Hallmarks of Diagnosis, Treatment, and Follow-Up in Clinical Practice. Medicina, 60.","DOI":"10.3390\/medicina60010168"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"115027","DOI":"10.1016\/j.addr.2023.115027","article-title":"The role of coagulome in the tumor immune microenvironment","volume":"200","author":"Wahab","year":"2023","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lim, H.I., and Hajjar, K.A. (2021). Annexin A2 in fibrinolysis, inflammation and fibrosis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22136836"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1186\/s12967-025-07177-9","article-title":"ANXA2 in hepatocellular carcinoma: Orchestrating tumorigenesis, progression, and therapeutic resistance toward precision targeting","volume":"23","author":"Chen","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/ijc.34048","article-title":"Annexin A2: The diversity of pathological effects in tumorigenesis and immune response","volume":"151","author":"Huang","year":"2022","journal-title":"Int. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dallacasagrande, V., and Hajjar, K.A. (2020). Annexin A2 in inflammation and host defense. Cells, 9.","DOI":"10.3390\/cells9061499"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41420-025-02469-x","article-title":"ANXA2 in cancer: Aberrant regulation of tumour cell apoptosis and its immune interactions","volume":"11","author":"Huang","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s40364-023-00535-z","article-title":"Biomarkers and prognostic factors of PD-1\/PD-L1 inhibitor-based therapy in patients with advanced hepatocellular carcinoma","volume":"12","author":"Zhang","year":"2024","journal-title":"Biomark. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.vph.2011.03.003","article-title":"The annexin A2 system and vascular homeostasis","volume":"54","author":"Flood","year":"2011","journal-title":"Vasc. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e38831","DOI":"10.1016\/j.heliyon.2024.e38831","article-title":"Blood hypercoagulability and thrombosis mechanisms in cancer patients\u2013A brief review","volume":"10","author":"Peng","year":"2024","journal-title":"Heliyon"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10760296211056637","DOI":"10.1177\/10760296211056637","article-title":"Longitudinal dynamics of coagulation and angiogenesis markers in cancer patients during and after chemotherapy","volume":"27","author":"Beleva","year":"2021","journal-title":"Clin. Appl. Thromb."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.critrevonc.2017.08.003","article-title":"Mechanisms and risk factors of thrombosis in cancer","volume":"118","author":"Falanga","year":"2017","journal-title":"Crit. Rev. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1055\/s-0033-1334143","article-title":"Annexin A2 system in human biology: Cell surface and beyond","volume":"39","author":"Luo","year":"2013","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_17","first-page":"144","article-title":"The biology of annexin A2: From vascular fibrinolysis to innate immunity","volume":"126","author":"Hajjar","year":"2015","journal-title":"Trans. Am. Clin. Climatol. Assoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6259","DOI":"10.3390\/ijms14036259","article-title":"Annexin A2 heterotetramer: Structure and function","volume":"14","author":"Bharadwaj","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1182\/blood.2020008123","article-title":"Reduced expression of annexin A2 is associated with impaired cell surface fibrinolysis and venous thromboembolism","volume":"137","author":"Fassel","year":"2021","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"19192","DOI":"10.1074\/jbc.M800100200","article-title":"Endothelial cell annexin A2 regulates polyubiquitination and degradation of its binding partner S100A10\/p11","volume":"283","author":"He","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_21","first-page":"5","article-title":"Annexin A2 and cancer: A systematic review","volume":"52","author":"Christensen","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Huang, S.-W., Chen, Y.-C., Lin, Y.-H., and Yeh, C.-T. (2021). Clinical Limitations of Tissue Annexin A2 Level as a Predictor of Postoperative Overall Survival in Patients with Hepatocellular Carcinoma. J. Clin. Med., 10.","DOI":"10.3390\/jcm10184158"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9373","DOI":"10.1007\/s13277-015-3678-6","article-title":"Up-regulation of annexin A2 expression predicates advanced clinicopathological features and poor prognosis in hepatocellular carcinoma","volume":"36","author":"Zhang","year":"2015","journal-title":"Tumor Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"zyaf017","DOI":"10.1093\/intbio\/zyaf017","article-title":"diagnosis and prognostic value and biological function of annexin A2 in hepatocellular carcinoma: A bioinformatic and experimental study","volume":"17","author":"Li","year":"2025","journal-title":"Integr. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"39","DOI":"10.2174\/1381612043453559","article-title":"The urokinase plasminogen activator system: Role in malignancy","volume":"10","author":"Duffy","year":"2004","journal-title":"Curr. Pharm. Des."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s000180050497","article-title":"The plasminogen activation system in tumor growth, invasion, and metastasis","volume":"57","author":"Andreasen","year":"2000","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1055\/s-0039-1688495","article-title":"Fibrin and fibrinolysis in cancer","volume":"45","author":"Kwaan","year":"2019","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1111\/jth.12075","article-title":"Coagulation and cancer: Biological and clinical aspects","volume":"11","author":"Falanga","year":"2013","journal-title":"J. Thromb. Haemost."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"587","DOI":"10.3892\/ijo.2014.2761","article-title":"Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2\/STAT3\/Snail pathway","volume":"46","author":"Fu","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/j.jhep.2016.02.004","article-title":"IL-6 pathway in the liver: From physiopathology to therapy","volume":"64","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s40364-025-00785-z","article-title":"PAQR5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the NF-\u03baB signaling","volume":"13","author":"Yang","year":"2025","journal-title":"Biomark. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5897","DOI":"10.3748\/wjg.v18.i41.5897","article-title":"Expression characteristics and diagnostic value of annexin A2 in hepatocellular carcinoma","volume":"18","author":"Zhang","year":"2012","journal-title":"World J. Gastroenterol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"469","DOI":"10.4254\/wjh.v9.i9.469","article-title":"Annexin A2 as a biomarker for hepatocellular carcinoma in Egyptian patients","volume":"9","author":"Shaker","year":"2017","journal-title":"World J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e108","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":"ref_35","doi-asserted-by":"crossref","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":"ref_36","doi-asserted-by":"crossref","first-page":"649","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"},{"key":"ref_37","unstructured":"(2025, October 07). The Human Protein Atlas. Available online: https:\/\/www.proteinatlas.org\/."},{"key":"ref_38","unstructured":"(2025, October 07). Kaplan-Meier Plotter. Available online: https:\/\/kmplot.com\/analysis\/."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"D956","DOI":"10.1093\/nar\/gkx1090","article-title":"LinkedOmics: Analyzing multi-omics data within and across 32 cancer types","volume":"46","author":"Vasaikar","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_40","unstructured":"(2026, February 11). Gene Expression Omnibus Series GSE25097. Gene Expression Omnibus Series GSE25097, Available online: https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE25097."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/ahg.12441","article-title":"Effect of high variation in transcript expression on identifying differentially expressed genes in RNA-seq analysis","volume":"85","author":"Cui","year":"2021","journal-title":"Ann. Hum. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Yang, W., Rosenstiel, P.C., and Schulenburg, H. (2016). ABSSeq: A new RNA-Seq analysis method based on modelling absolute expression differences. BMC Genom., 17.","DOI":"10.1186\/s12864-016-2848-2"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8915\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:45:27Z","timestamp":1791596727000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8915"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":42,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198915"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198915","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]}}}