{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:50:59Z","timestamp":1785408659520,"version":"3.56.0"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004071","name":"Khon Kaen University","doi-asserted-by":"publisher","award":["Centre for Research and Development of Medical Diagnostic Laboratories"],"award-info":[{"award-number":["Centre for Research and Development of Medical Diagnostic Laboratories"]}],"id":[{"id":"10.13039\/501100004071","id-type":"DOI","asserted-by":"publisher"}]},{"award":["Centre for Research and Development of Medical Diagnostic Laboratories"],"award-info":[{"award-number":["Centre for Research and Development of Medical Diagnostic Laboratories"]}],"id":[{"id":"https:\/\/ror.org\/03cq4gr50","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012389","name":"National Institute of Information and Communications Technology","doi-asserted-by":"publisher","award":["ASEAN IVO"],"award-info":[{"award-number":["ASEAN IVO"]}],"id":[{"id":"10.13039\/501100012389","id-type":"DOI","asserted-by":"publisher"}]},{"award":["ASEAN IVO"],"award-info":[{"award-number":["ASEAN IVO"]}],"id":[{"id":"https:\/\/ror.org\/016bgq349","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cholangiocarcinoma (CCA) in Northeast Thailand is characterized by late diagnosis and poor prognosis, creating a critical need for effective early-detection biomarkers. This study utilized a multi-omics approach to identify novel diagnostic targets and improve CCA screening. Initial serum proteomic and transcriptomic analyses revealed significant upregulation of the luteinizing hormone\/choriogonadotropin receptor (LHCGR) in CCA patients, correlating with advanced disease stages. Interaction network analysis subsequently identified its circulating ligand, beta-human chorionic gonadotropin (\u03b2-hCG), as a highly translatable clinical target. The protein expression of \u03b2-hCG was assessed via immunohistochemistry (IHC) in 100 tissue samples, and serum levels of \u03b2-hCG, alongside routine markers (CA19-9, AFP, and CEA), were quantified in a cohort of 405 individuals, including 153 CCA patients. IHC confirmed significantly higher \u03b2-hCG expression in tumor tissues compared to adjacent areas (p &lt; 0.0001). Serum \u03b2-hCG levels were significantly elevated in CCA patients and correlated with tumor volume and reduced overall survival. Diagnostically, a combined multiparameter panel (\u03b2-hCG, carbohydrate antigen 19-9, carcinoembryonic antigen, and alpha-fetoprotein) yielded excellent accuracy in distinguishing CCA from healthy controls (AUC: 0.962) and hepatocellular carcinoma cases (AUC: 0.890). However, discriminatory efficiency was notably lower when differentiating CCA from benign biliary diseases (AUC: 0.680) and liver metastases (AUC: 0.705). In conclusion, activation of the LHCGR signaling axis is a novel pathophysiological feature in CCA. When integrated into a multi-marker blood panel, circulating \u03b2-hCG serves as a valuable complementary risk-stratification and prognostic tool, though further optimization is required to overcome limited specificity in the presence of confounding liver pathologies before routine clinical implementation.<\/jats:p>","DOI":"10.3390\/ijms27125438","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T03:27:21Z","timestamp":1781666841000},"page":"5438","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Serum \u03b2-hCG Combined with Traditional Tumor Markers Improves Detection Efficacy and Prognostic Prediction in Cholangiocarcinoma"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6276-5765","authenticated-orcid":false,"given":"Suppakrit","family":"Kongsintaweesuk","sequence":"first","affiliation":[{"name":"Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4999-1038","authenticated-orcid":false,"given":"Thatsanapong","family":"Pongking","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keerapach","family":"Tunbenjasiri","sequence":"additional","affiliation":[{"name":"Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9735-028X","authenticated-orcid":false,"given":"Pakornkiat","family":"Tanasuka","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3696-8390","authenticated-orcid":false,"given":"Sittiruk","family":"Roytrakul","sequence":"additional","affiliation":[{"name":"National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudarat","family":"Onsurathum","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chawalit","family":"Pairojkul","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kitti","family":"Intuyod","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vor","family":"Luvira","sequence":"additional","affiliation":[{"name":"Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8187-7247","authenticated-orcid":false,"given":"Somchai","family":"Pinlaor","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4658-3251","authenticated-orcid":false,"given":"David","family":"Blair","sequence":"additional","affiliation":[{"name":"College of Science and Engineering, James Cook University, Townsville, QLD 4811, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7436-3355","authenticated-orcid":false,"given":"Porntip","family":"Pinlaor","sequence":"additional","affiliation":[{"name":"Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"School of Medical Technology, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"448","DOI":"10.21037\/jtd.2017.02.75","article-title":"Cancer prevention from the perspective of global cancer burden patterns","volume":"9","author":"Nagai","year":"2017","journal-title":"J. Thorac. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S158","DOI":"10.1016\/j.actatropica.2010.07.006","article-title":"Opisthorchiasis and Opisthorchis-associated cholangiocarcinoma in Thailand and Laos","volume":"120","author":"Sripa","year":"2011","journal-title":"Acta Trop."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1007\/s11894-011-0178-8","article-title":"Cholangiocarcinoma: Epidemiology, risk factors, pathogenesis, and diagnosis","volume":"13","author":"Charbel","year":"2011","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1097\/MOG.0b013e3282fbf9b3","article-title":"Cholangiocarcinoma: Lessons from Thailand","volume":"24","author":"Sripa","year":"2008","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kamsa-Ard, S., Santong, C., Kamsa-Ard, S., Luvira, V., Luvira, V., Suwanrungruang, K., and Bhudhisawasdi, V. (2021). Decreasing trends in cholangiocarcinoma incidence and relative survival in Khon Kaen, Thailand: An updated, inclusive, population-based cancer registry analysis for 1989\u20132018. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0246490"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.critrevonc.2008.09.008","article-title":"Cholangiocarcinoma","volume":"69","author":"Mosconi","year":"2009","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.soncn.2017.02.002","article-title":"Cancer Screening and Early Detection in the 21(st) Century","volume":"33","author":"Loud","year":"2017","journal-title":"Semin. Oncol. Nurs."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41572-021-00300-2","article-title":"Cholangiocarcinoma","volume":"7","author":"Brindley","year":"2021","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/s41392-024-01823-2","article-title":"Tumor biomarkers for diagnosis, prognosis and targeted therapy","volume":"9","author":"Zhou","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.4269\/ajtmh.17-0879","article-title":"Biomarkers for the Diagnosis of Cholangiocarcinoma: A Systematic Review","volume":"98","author":"Tshering","year":"2018","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/978-94-017-7215-0_11","article-title":"The Role of Human Chorionic Gonadotropin as Tumor Marker: Biochemical and Clinical Aspects","volume":"867","author":"Sisinni","year":"2015","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_12","first-page":"580709","article-title":"Management of nonpregnant women with elevated human chorionic gonadotropin","volume":"2013","author":"Schmid","year":"2013","journal-title":"Case Rep. Obstet. Gynecol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1080\/15384101.2018.1558869","article-title":"beta-hCG promotes epithelial ovarian cancer metastasis through ERK\/MMP2 signaling pathway","volume":"18","author":"Wu","year":"2019","journal-title":"Cell Cycle"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/BF00708253","article-title":"Human chorionic gonadotropin in primary liver carcinoma in adults. An immunohistochemical study","volume":"409","author":"Nakanuma","year":"1986","journal-title":"Virchows Arch. A Pathol. Anat. Histopathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"99","DOI":"10.4103\/0971-5851.64254","article-title":"Expression of human chorionic gonadotropin beta in gastric carcinoma: A retrospective immunohistochemical study","volume":"30","author":"Murhekar","year":"2009","journal-title":"Indian J. Med. Paediatr. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/bjc.1989.289","article-title":"Human chorionic gonadotropin in colorectal cancer and its relationship to prognosis","volume":"60","author":"Yamaguchi","year":"1989","journal-title":"Br. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.clinbiochem.2004.05.008","article-title":"Human chorionic gonadotropin in cancer","volume":"37","author":"Stenman","year":"2004","journal-title":"Clin. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"322","DOI":"10.3390\/livers1040025","article-title":"Biliary hCG\u03b2 Is a Potential Novel Marker for Prediction of Biliary Neoplasia in Primary Sclerosing Cholangitis Patients","volume":"1","author":"Koistinen","year":"2021","journal-title":"Livers"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10161","DOI":"10.1007\/s00432-023-04935-4","article-title":"Differential diagnosis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma based on spatial and channel attention mechanisms","volume":"149","author":"Huang","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lorenzen, M., Nielsen, J.E., Andreassen, C.H., Juul, A., Toft, B.G., Rajpert-De Meyts, E., Daugaard, G., and Blomberg Jensen, M. (2020). Luteinizing Hormone Receptor Is Expressed in Testicular Germ Cell Tumors: Possible Implications for Tumor Growth and Prognosis. Cancers, 12.","DOI":"10.3390\/cancers12061358"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.3892\/ol.2016.4906","article-title":"Influence of VEGFR and LHCGR on endometrial adenocarcinoma","volume":"12","author":"Kolbl","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8624","DOI":"10.1038\/s41598-022-12495-9","article-title":"Expression and function of the luteinizing hormone choriogonadotropin receptor in human endometrial stromal cells","volume":"12","author":"Mann","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Nwabuobi, C., Arlier, S., Schatz, F., Guzeloglu-Kayisli, O., Lockwood, C.J., and Kayisli, U.A. (2017). hCG: Biological Functions and Clinical Applications. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102037"},{"key":"ref_24","first-page":"715","article-title":"Usefulness of beta hCG as tumor marker in the diagnosis and follow up of patients with ovarian cancer","volume":"16","author":"Djurdjevic","year":"2011","journal-title":"J. BUON"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s40001-016-0204-2","article-title":"An update on the clinical diagnostic value of \u03b2-hCG and AFP for intracranial germ cell tumors","volume":"21","author":"Hu","year":"2016","journal-title":"Eur. J. Med. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1477-7827-7-8","article-title":"New discoveries on the biology and detection of human chorionic gonadotropin","volume":"7","author":"Cole","year":"2009","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1016\/j.ajpath.2011.05.018","article-title":"Overexpression of the beta subunit of human chorionic gonadotropin promotes the transformation of human ovarian epithelial cells and ovarian tumorigenesis","volume":"179","author":"Guo","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1136\/jcp.49.4.329","article-title":"beta hCG as a prognostic marker in adenocarcinoma of the prostate","volume":"49","author":"Sheaff","year":"1996","journal-title":"J. Clin. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/bs.acr.2020.10.005","article-title":"Intrahepatic cholangiocarcinoma: Morpho-molecular pathology, tumor reactive microenvironment, and malignant progression","volume":"149","author":"Sirica","year":"2021","journal-title":"Adv. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11406","DOI":"10.1038\/s41598-023-38307-2","article-title":"Gut dysbiosis in Thai intrahepatic cholangiocarcinoma and hepatocellular carcinoma","volume":"13","author":"Pomyen","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"197","DOI":"10.2188\/jea.JE20180007","article-title":"Cholangiocarcinoma Trends, Incidence, and Relative Survival in Khon Kaen, Thailand from 1989 Through 2013: A Population-Based Cancer Registry Study","volume":"29","author":"Luvira","year":"2019","journal-title":"J. Epidemiol."},{"key":"ref_32","first-page":"85","article-title":"The Evaluation of Joint Detection of CA19-9, AFP and CEA in Identification and Diagnosis of Cholangiocarcinoma","volume":"45","author":"Lagampan","year":"2020","journal-title":"Chonburi Hosp. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"761","DOI":"10.5306\/wjco.v11.i10.761","article-title":"Colorectal liver metastases: Current management and future perspectives","volume":"11","author":"Martin","year":"2020","journal-title":"World J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"D730","DOI":"10.1093\/nar\/gkae1113","article-title":"The STRING database in 2025: Protein networks with directionality of regulation","volume":"53","author":"Szklarczyk","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e3465","DOI":"10.21769\/BioProtoc.3465","article-title":"Semi-quantitative Determination of Protein Expression using Immunohistochemistry Staining and Analysis: An Integrated Protocol","volume":"9","author":"Crowe","year":"2019","journal-title":"Bio Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5438\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T04:21:00Z","timestamp":1782102060000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5438"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,16]]},"references-count":35,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125438"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125438","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,16]]}}}