{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T16:47:59Z","timestamp":1794329279557,"version":"4.9.0"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24fk0210131"],"award-info":[{"award-number":["JP24fk0210131"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23H02893"],"award-info":[{"award-number":["23H02893"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031022","name":"Center for Cancer Research","doi-asserted-by":"publisher","award":["ZIABC010877"],"award-info":[{"award-number":["ZIABC010877"]}],"id":[{"id":"10.13039\/100031022","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Biomark Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Hepatocellular carcinoma (HCC) can be classified into several subtypes based on molecular traits, aiding in prognostic stratification. The subtype with a poor prognosis is often associated with stem\/progenitor features. This study focused on identifying circulating biomarkers for aggressive HCC.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We searched for secretory proteins whose expression was positively associated with the stem\/progenitor markers KRT19, EPCAM, and PROM1 in 2 independent HCC cohorts. Serum folate receptor 1 (FOLR1) levels were measured in 238 chronic liver disease and 247 HCC patients, evaluating their diagnostic and prognostic capabilities.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>FOLR1 was identified as a secretory protein that was positively correlated with all 3 stem\/progenitor markers and a poor prognosis in both the discovery and validation cohorts. Higher FOLR1 expression was detected in tumor than nontumor tissues and was associated with aggressive subtypes, and activation of p53, DNA repair, Myc, E2F, and PI3K\/AKT\/mTOR pathways. Serum FOLR1 levels correlated with tumoral FOLR1 expression in HCC patients and were significantly elevated compared with those in patients with chronic hepatitis or nonliver disease. Serum FOLR1 levels demonstrated diagnostic performance for HCC comparable to that of alpha-fetoprotein (AFP), and their combination increased the diagnostic accuracy. Elevated serum FOLR1 levels were associated with poor prognosis in HCC patients, regardless of treatment, especially in patients with early-stage disease. The multivariate analysis revealed that the serum FOLR1 level and the Gender, Age, AFP-L3, AFP, and Des-gamma-carboxy prothrombin (GALAD) score were independent predictors of a poor prognosis with their combination further stratifying prognosis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>FOLR1 is a stemness-associated biomarker for HCC, with serum levels serving as a diagnostic marker for HCC and a prognostic indicator for early-stage disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s40364-025-00752-8","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T09:28:07Z","timestamp":1741080487000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Folate receptor 1 is a stemness trait-associated diagnostic and prognostic marker for hepatocellular carcinoma"],"prefix":"10.1186","volume":"13","author":[{"given":"Yuto","family":"Shiode","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Kodama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Matsumae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumiko","family":"Shirai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Doi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Tahata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayato","family":"Hikita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohide","family":"Tatsumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moto","family":"Fukai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinobu","family":"Taketomi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathuros","family":"Ruchirawat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Takehara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,4]]},"reference":[{"issue":"1","key":"752_CR1","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","volume":"7","author":"JM Llovet","year":"2021","unstructured":"Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6.","journal-title":"Nat Rev Dis Primers"},{"issue":"4","key":"752_CR2","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1001\/jamasurg.2022.7989","volume":"158","author":"ZJ Brown","year":"2023","unstructured":"Brown ZJ, Tsilimigras DI, Ruff SM, Mohseni A, Kamel IR, Cloyd JM, et al. Management of hepatocellular carcinoma: a review. JAMA Surg. 2023;158(4):410\u201320.","journal-title":"JAMA Surg"},{"key":"752_CR3","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.ejca.2021.11.023","volume":"161","author":"H Rumgay","year":"2022","unstructured":"Rumgay H, Ferlay J, de Martel C, Georges D, Ibrahim AS, Zheng R, et al. Global, regional and national burden of primary liver cancer by subtype. Eur J Cancer. 2022;161:108\u201318.","journal-title":"Eur J Cancer"},{"issue":"10","key":"752_CR4","doi-asserted-by":"publisher","first-page":"101130","DOI":"10.1016\/j.jhepr.2024.101130","volume":"6","author":"A Childs","year":"2024","unstructured":"Childs A, Aidoo-Micah G, Maini MK, Meyer T. Immunotherapy for hepatocellular carcinoma. JHEP Rep. 2024;6(10):101130.","journal-title":"JHEP Rep"},{"issue":"2","key":"752_CR5","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1002\/hep.29913","volume":"68","author":"JA Marrero","year":"2018","unstructured":"Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723\u201350.","journal-title":"Hepatology"},{"issue":"3","key":"752_CR6","doi-asserted-by":"publisher","first-page":"e445","DOI":"10.1002\/onco.13535","volume":"26","author":"LJ Chen","year":"2021","unstructured":"Chen LJ, Chang YJ. Survival predictability between the American Joint Committee on Cancer 8th edition staging system and the Barcelona clinic liver cancer classification in patients with hepatocellular carcinoma. Oncologist. 2021;26(3):e445\u201353.","journal-title":"Oncologist."},{"issue":"9","key":"752_CR7","doi-asserted-by":"publisher","first-page":"100806","DOI":"10.1016\/j.jhepr.2023.100806","volume":"5","author":"XP Meng","year":"2023","unstructured":"Meng XP, Tang TY, Zhou Y, Xia C, Xia T, Shi Y, et al. Predicting post-resection recurrence by integrating imaging-based surrogates of distinct vascular patterns of hepatocellular carcinoma. JHEP Rep. 2023;5(9):100806.","journal-title":"JHEP Rep"},{"issue":"1","key":"752_CR8","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1002\/hep.21467","volume":"45","author":"S Boyault","year":"2007","unstructured":"Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S, Jeannot E, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45(1):42\u201352.","journal-title":"Hepatology"},{"issue":"3","key":"752_CR9","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1002\/hep.20375","volume":"40","author":"JS Lee","year":"2004","unstructured":"Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40(3):667\u201376.","journal-title":"Hepatology"},{"issue":"4","key":"752_CR10","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1038\/nm843","volume":"9","author":"QH Ye","year":"2003","unstructured":"Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003;9(4):416\u201323.","journal-title":"Nat Med"},{"issue":"10","key":"752_CR11","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1158\/2159-8290.CD-17-0368","volume":"7","author":"A Jusakul","year":"2017","unstructured":"Jusakul A, Cutcutache I, Yong CH, Lim JQ, Huang MN, Padmanabhan N, et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov. 2017;7(10):1116\u201335.","journal-title":"Cancer Discov"},{"issue":"2","key":"752_CR12","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.jhep.2019.08.017","volume":"72","author":"S Rebouissou","year":"2020","unstructured":"Rebouissou S, Nault JC. Advances in molecular classification and precision oncology in hepatocellular carcinoma. J Hepatol. 2020;72(2):215\u201329.","journal-title":"J Hepatol"},{"issue":"6","key":"752_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2023.100754","volume":"5","author":"S Luo","year":"2023","unstructured":"Luo S, Jia Y, Zhang Y, Zhang X. A transcriptomic intratumour heterogeneity-free signature overcomes sampling bias in prognostic risk classification for hepatocellular carcinoma. JHEP Rep. 2023;5(6): 100754.","journal-title":"JHEP Rep"},{"issue":"18","key":"752_CR14","doi-asserted-by":"publisher","first-page":"7385","DOI":"10.1158\/0008-5472.CAN-09-1089","volume":"69","author":"Y Hoshida","year":"2009","unstructured":"Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69(18):7385\u201392.","journal-title":"Cancer Res"},{"issue":"16","key":"752_CR15","doi-asserted-by":"publisher","first-page":"6779","DOI":"10.1158\/0008-5472.CAN-08-0742","volume":"68","author":"DY Chiang","year":"2008","unstructured":"Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, Minguez B, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 2008;68(16):6779\u201388.","journal-title":"Cancer Res"},{"issue":"1","key":"752_CR16","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1002\/hep.32573","volume":"77","author":"H Murai","year":"2023","unstructured":"Murai H, Kodama T, Maesaka K, Tange S, Motooka D, Suzuki Y, et al. Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma. Hepatology. 2023;77(1):77\u201391.","journal-title":"Hepatology"},{"issue":"7","key":"752_CR17","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1016\/j.cell.2017.05.046","volume":"169","author":"Cancer Genome Atlas Research Network. Electronic address wbe, Cancer Genome Atlas Research N","year":"2017","unstructured":"Cancer Genome Atlas Research Network. Electronic address wbe, Cancer Genome Atlas Research N. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017;169(7):1327-41 e23.","journal-title":"Cell."},{"issue":"7","key":"752_CR18","doi-asserted-by":"publisher","first-page":"101094","DOI":"10.1016\/j.jhepr.2024.101094","volume":"6","author":"F Peeters","year":"2024","unstructured":"Peeters F, Cappuyns S, Pique-Gili M, Phillips G, Verslype C, Lambrechts D, et al. Applications of single-cell multi-omics in liver cancer. JHEP Rep. 2024;6(7):101094.","journal-title":"JHEP Rep"},{"issue":"3","key":"752_CR19","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1053\/j.gastro.2008.12.004","volume":"136","author":"T Yamashita","year":"2009","unstructured":"Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem\/progenitor cell features. Gastroenterology. 2009;136(3):1012\u201324.","journal-title":"Gastroenterology"},{"issue":"4","key":"752_CR20","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1080\/15384047.2021.1916381","volume":"22","author":"F Liu","year":"2021","unstructured":"Liu F, Qian Y. The role of CD133 in hepatocellular carcinoma. Cancer Biol Ther. 2021;22(4):291\u2013300.","journal-title":"Cancer Biol Ther"},{"issue":"4","key":"752_CR21","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1136\/gutjnl-2012-304351","volume":"63","author":"O Govaere","year":"2014","unstructured":"Govaere O, Komuta M, Berkers J, Spee B, Janssen C, de Luca F, et al. Keratin 19: a key role player in the invasion of human hepatocellular carcinomas. Gut. 2014;63(4):674\u201385.","journal-title":"Gut"},{"issue":"7","key":"752_CR22","doi-asserted-by":"publisher","first-page":"4101","DOI":"10.21873\/anticanres.12700","volume":"38","author":"CK Noh","year":"2018","unstructured":"Noh CK, Wang HJ, Kim CM, Kim J, Yoon SY, Lee GH, et al. EpCAM as a predictive marker of tumor recurrence and survival in patients who underwent surgical resection for hepatocellular carcinoma. Anticancer Res. 2018;38(7):4101\u20139.","journal-title":"Anticancer Res"},{"issue":"15","key":"752_CR23","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1016\/j.clinbiochem.2013.03.010","volume":"46","author":"F Leung","year":"2013","unstructured":"Leung F, Dimitromanolakis A, Kobayashi H, Diamandis EP, Kulasingam V. Folate-receptor 1 (FOLR1) protein is elevated in the serum of ovarian cancer patients. Clin Biochem. 2013;46(15):1462\u20138.","journal-title":"Clin Biochem"},{"issue":"7","key":"752_CR24","doi-asserted-by":"publisher","first-page":"2542","DOI":"10.1053\/j.gastro.2007.04.025","volume":"132","author":"S Ma","year":"2007","unstructured":"Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, et al. Identification and characterization of tumorigenic liver cancer stem\/progenitor cells. Gastroenterology. 2007;132(7):2542\u201356.","journal-title":"Gastroenterology"},{"issue":"4","key":"752_CR25","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1038\/nm1377","volume":"12","author":"JS Lee","year":"2006","unstructured":"Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med. 2006;12(4):410\u20136.","journal-title":"Nat Med"},{"issue":"1","key":"752_CR26","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.ccell.2017.05.009","volume":"32","author":"J Chaisaingmongkol","year":"2017","unstructured":"Chaisaingmongkol J, Budhu A, Dang H, Rabibhadana S, Pupacdi B, Kwon SM, et al. Common molecular subtypes among Asian hepatocellular carcinoma and cholangiocarcinoma. Cancer Cell. 2017;32(1):57-70 E3.","journal-title":"Cancer Cell."},{"issue":"3","key":"752_CR27","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.tem.2021.12.003","volume":"33","author":"FZ Nawaz","year":"2022","unstructured":"Nawaz FZ, Kipreos ET. Emerging roles for folate receptor FOLR1 in signaling and cancer. Trends Endocrinol Metab. 2022;33(3):159\u201374.","journal-title":"Trends Endocrinol Metab"},{"issue":"3","key":"752_CR28","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1016\/j.molonc.2011.11.010","volume":"6","author":"YL Chen","year":"2012","unstructured":"Chen YL, Chang MC, Huang CY, Chiang YC, Lin HW, Chen CA, et al. Serous ovarian carcinoma patients with high alpha-folate receptor had reducing survival and cytotoxic chemo-response. Mol Oncol. 2012;6(3):360\u20139.","journal-title":"Mol Oncol"},{"issue":"5","key":"752_CR29","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1080\/1354750X.2020.1771420","volume":"25","author":"Y Liu","year":"2020","unstructured":"Liu Y, Lian T, Yao Y. A systematic review and meta-analysis of higher expression of folate receptor alpha (FOLR1) predicts poor cancer prognosis. Biomarkers. 2020;25(5):367\u201374.","journal-title":"Biomarkers"},{"issue":"7","key":"752_CR30","doi-asserted-by":"publisher","first-page":"e6292","DOI":"10.1371\/journal.pone.0006292","volume":"4","author":"E Basal","year":"2009","unstructured":"Basal E, Eghbali-Fatourechi GZ, Kalli KR, Hartmann LC, Goodman KM, Goode EL, et al. Functional folate receptor alpha is elevated in the blood of ovarian cancer patients. PLoS ONE. 2009;4(7):e6292.","journal-title":"PLoS ONE"},{"key":"752_CR31","doi-asserted-by":"publisher","first-page":"11187","DOI":"10.1038\/srep11187","volume":"5","author":"CT Kuo","year":"2015","unstructured":"Kuo CT, Chang C, Lee WS. Folic acid inhibits COLO-205 colon cancer cell proliferation through activating the FRalpha\/c-SRC\/ERK1\/2\/NFkappaB\/TP53 pathway: in vitro and in vivo studies. Sci Rep. 2015;5:11187.","journal-title":"Sci Rep"},{"key":"752_CR32","doi-asserted-by":"crossref","unstructured":"Liu Z, Jin X, Pi W, Liu S. Folic acid inhibits nasopharyngeal cancer cell proliferation and invasion via activation of FRalpha\/ERK1\/2\/TSLC1 pathway. Biosci Rep. 2017;37(6):BSR20170772.","DOI":"10.1042\/BSR20170772"},{"issue":"7","key":"752_CR33","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1016\/j.cellsig.2015.03.020","volume":"27","author":"MF Hansen","year":"2015","unstructured":"Hansen MF, Greibe E, Skovbjerg S, Rohde S, Kristensen AC, Jensen TR, et al. Folic acid mediates activation of the pro-oncogene STAT3 via the Folate Receptor alpha. Cell Signal. 2015;27(7):1356\u201368.","journal-title":"Cell Signal"},{"issue":"17","key":"752_CR34","doi-asserted-by":"publisher","first-page":"8817","DOI":"10.1093\/nar\/gky585","volume":"46","author":"L Su","year":"2018","unstructured":"Su L, Xia W, Shen T, Liang Q, Wang W, Li H, et al. H2A.Z.1 crosstalk with H3K56-acetylation controls gliogenesis through the transcription of folate receptor. Nucleic Acids Res. 2018;46(17):8817\u201331.","journal-title":"Nucleic Acids Res."},{"key":"752_CR35","doi-asserted-by":"publisher","first-page":"153303382211444","DOI":"10.1177\/15330338221144446","volume":"21","author":"J Quevedo-Ocampo","year":"2022","unstructured":"Quevedo-Ocampo J, Escobedo-Calvario A, Souza-Arroyo V, Miranda-Labra RU, Bucio-Ortiz L, Gutierrez-Ruiz MC, et al. Folate metabolism in hepatocellular carcinoma. What do we know so far? Technol Cancer Res Treat. 2022;21:15330338221144446.","journal-title":"Technol Cancer Res Treat."},{"issue":"2","key":"752_CR36","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1007\/s10735-020-09955-9","volume":"52","author":"R Sharma","year":"2021","unstructured":"Sharma R, Ali T, Negi I, Das A, Duseja A, Kaur J. Dietary modulations of folic acid affect the development of diethylnitrosamine induced hepatocellular carcinoma in a rat model. J Mol Histol. 2021;52(2):335\u201350.","journal-title":"J Mol Histol"},{"key":"752_CR37","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1038\/srep00980","volume":"2","author":"V Boshnjaku","year":"2012","unstructured":"Boshnjaku V, Shim KW, Tsurubuchi T, Ichi S, Szany EV, Xi G, et al. Nuclear localization of folate receptor alpha: a new role as a transcription factor. Sci Rep. 2012;2:980.","journal-title":"Sci Rep"},{"issue":"11","key":"752_CR38","doi-asserted-by":"publisher","first-page":"2721","DOI":"10.1002\/stem.2421","volume":"34","author":"V Mohanty","year":"2016","unstructured":"Mohanty V, Shah A, Allender E, Siddiqui MR, Monick S, Ichi S, et al. Folate receptor alpha upregulates Oct4, Sox2 and Klf4 and downregulates miR-138 and miR-let-7 in cranial neural crest cells. Stem Cells. 2016;34(11):2721\u201332.","journal-title":"Stem Cells"},{"key":"752_CR39","doi-asserted-by":"crossref","unstructured":"Pinero F, Dirchwolf M, Pessoa MG. Biomarkers in hepatocellular carcinoma: diagnosis, prognosis and treatment response assessment. Cells. 2020;9(6):cells9061370.","DOI":"10.3390\/cells9061370"},{"issue":"6","key":"752_CR40","doi-asserted-by":"publisher","first-page":"1922","DOI":"10.1097\/HEP.0000000000000466","volume":"78","author":"AG Singal","year":"2023","unstructured":"Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023;78(6):1922\u201365.","journal-title":"Hepatology"},{"key":"752_CR41","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.3389\/fonc.2020.01316","volume":"10","author":"T Wang","year":"2020","unstructured":"Wang T, Zhang KH. New blood biomarkers for the diagnosis of AFP-negative hepatocellular carcinoma. Front Oncol. 2020;10:1316.","journal-title":"Front Oncol"},{"issue":"1","key":"752_CR42","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.jhep.2018.03.019","volume":"69","author":"easloffice@easloffice.eu EAftSotLEa, Liver EAftSot","year":"2018","unstructured":"easloffice@easloffice.eu EAftSotLEa, Liver EAftSot. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182\u2013236.","journal-title":"J Hepatol."},{"issue":"9","key":"752_CR43","doi-asserted-by":"publisher","first-page":"2481","DOI":"10.1038\/bjc.2013.564","volume":"109","author":"KC Chang","year":"2013","unstructured":"Chang KC, Wu YY, Hung CH, Lu SN, Lee CM, Chiu KW, et al. Clinical-guide risk prediction of hepatocellular carcinoma development in chronic hepatitis C patients after interferon-based therapy. Br J Cancer. 2013;109(9):2481\u20138.","journal-title":"Br J Cancer"},{"key":"752_CR44","doi-asserted-by":"publisher","first-page":"7243","DOI":"10.12659\/MSM.918784","volume":"25","author":"X Li","year":"2019","unstructured":"Li X, Xu H, Gao P. Fibrosis Index Based on 4 Factors (FIB-4) predicts liver cirrhosis and hepatocellular carcinoma in chronic Hepatitis C Virus (HCV) patients. Med Sci Monit. 2019;25:7243\u201350.","journal-title":"Med Sci Monit"},{"issue":"6","key":"752_CR45","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1038\/bjc.2013.481","volume":"109","author":"AM Attallah","year":"2013","unstructured":"Attallah AM, Omran MM, Attallah AA, Abdallah SO, Farid K, Darwish H, et al. HCC-ART score, a simple, highly sensitive and specific test for early diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Br J Cancer. 2013;109(6):1657\u201365.","journal-title":"Br J Cancer"},{"key":"752_CR46","doi-asserted-by":"crossref","unstructured":"Guan MC, Zhang SY, Ding Q, Li N, Fu TT, Zhang GX, et al. The performance of GALAD score for diagnosing hepatocellular carcinoma in patients with chronic liver diseases: a systematic review and meta-analysis. J Clin Med. 2023;12(3):PMC9918029.","DOI":"10.3390\/jcm12030949"},{"issue":"5","key":"752_CR47","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1007\/s00432-024-05760-z","volume":"150","author":"W Qiao","year":"2024","unstructured":"Qiao W, Li J, Xiong Y, Zheng J, Jin R, Hu C. GALAD score as a prognostic model for recurrence of hepatocellular carcinoma after local ablation. J Cancer Res Clin Oncol. 2024;150(5):241.","journal-title":"J Cancer Res Clin Oncol"},{"key":"752_CR48","doi-asserted-by":"crossref","unstructured":"Cagnin S, Donghia R, Martini A, Pesole PL, Coletta S, Shahini E, et al. Galad score as a prognostic marker for patients with hepatocellular carcinoma. Int J Mol Sci. 2023;24(22):ijms242216485.","DOI":"10.3390\/ijms242216485"},{"issue":"2","key":"752_CR49","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/s00432-023-05526-z","volume":"150","author":"A Olbrich","year":"2024","unstructured":"Olbrich A, Niemeyer J, Seiffert H, Ebel S, Gros O, Lordick F, et al. The GALAD score and the BALAD-2 score correlate with transarterial and systemic treatment response and survival in patients with hepatocellular carcinoma. J Cancer Res Clin Oncol. 2024;150(2):81.","journal-title":"J Cancer Res Clin Oncol"},{"issue":"17","key":"752_CR50","doi-asserted-by":"publisher","first-page":"2343","DOI":"10.3748\/wjg.v30.i17.2343","volume":"30","author":"O Jitpraphawan","year":"2024","unstructured":"Jitpraphawan O, Ruamtawee W, Treewatchareekorn M, Sethasine S. Diagnostic and prognostic performances of GALAD score in staging and 1-year mortality of hepatocellular carcinoma: A prospective study. World J Gastroenterol. 2024;30(17):2343\u201353.","journal-title":"World J Gastroenterol"}],"container-title":["Biomarker Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40364-025-00752-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40364-025-00752-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40364-025-00752-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T09:28:12Z","timestamp":1741080492000},"score":1,"resource":{"primary":{"URL":"https:\/\/biomarkerres.biomedcentral.com\/articles\/10.1186\/s40364-025-00752-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,4]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["752"],"URL":"https:\/\/doi.org\/10.1186\/s40364-025-00752-8","relation":{},"ISSN":["2050-7771"],"issn-type":[{"value":"2050-7771","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,4]]},"assertion":[{"value":"23 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 February 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 March 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was conducted in accordance with the Declaration of Helsinki. The validation cohort data were derived from the Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC) consortium, which included patients diagnosed with hepatocellular carcinoma (HCC). Institutional Review Board (IRB) approval was obtained from each participating center in Thailand, namely: Maharaj Nakorn Chiang Mai Hospital, Roi Et Hospital, Chulabhorn Hospital-Bangkok, National Cancer Institute of Thailand and Srinagarind Hospital. All participants provided written informed consent. Additionally, this study included a retrospective cohort of patients admitted to Osaka University Hospital (2014\u20132018) and Hokkaido University Hospital (2007\u20132018). The study protocol was approved by the Institutional Review Board Committee of Osaka University Hospital (IRB No. 17097). Informed consent was obtained from all patients prior to their participation. The study adhered to ethical guidelines consistent with the principles of the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"37"}}