{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:50:44Z","timestamp":1791222644405,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,3,5]],"date-time":"2020-03-05T00:00:00Z","timestamp":1583366400000},"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":["620009001"],"award-info":[{"award-number":["620009001"]}],"id":[{"id":"10.13039\/501100004071","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Faculty of Medicine, Khon Kaen University","award":["AS61301"],"award-info":[{"award-number":["AS61301"]}]},{"DOI":"10.13039\/501100004396","name":"Thailand Research Fund","doi-asserted-by":"publisher","award":["DBG5980004"],"award-info":[{"award-number":["DBG5980004"]}],"id":[{"id":"10.13039\/501100004396","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cholangiocarcinoma (CCA), a malignancy of biliary epithelium, is related to liver stem cell deregulation. FoxAs are a group of transcription factors that play critical roles in liver stem cell differentiation. In this study, the expression levels of FoxAs (i.e., FoxA1, FoxA2 and FoxA3) were detected in intrahepatic CCA tissues and the functions of FoxAs were studied in CCA cell lines. FoxA1 and FoxA2 were mainly localized in the nuclei of normal bile duct (NBD) cells and some of the cancer cells. Low expression of FoxA1 in CCA tissues (72%) was significantly correlated with poor prognosis. FoxA3 expression of CCA cells was localized in the nucleus and cytoplasm, whereas it was slightly detected in NBDs. High expression of FoxA3 in cancer tissues (61%) was significantly related to high metastasis status. These findings suggest the opposing roles of FoxA1 and FoxA3 in CCA. Moreover, the FoxA1-over-expressing CCA cell line exhibited a significant reduction in proliferative and invasive activities compared to control cells. Knockdown of FoxA3 in CCA cells resulted in a significant decrease in proliferative and invasive activities compared with control cells. Taken together, in CCA, FoxA1 is down-regulated and has tumor suppressive roles, whereas FoxA3 is up-regulated and has oncogenic roles.<\/jats:p>","DOI":"10.3390\/ijms21051796","type":"journal-article","created":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T09:26:41Z","timestamp":1583486801000},"page":"1796","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Opposing Roles of FoxA1 and FoxA3 in Intrahepatic Cholangiocarcinoma Progression"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9001-1197","authenticated-orcid":false,"given":"Raynoo","family":"Thanan","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waleeporn","family":"Kaewlert","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0145-8753","authenticated-orcid":false,"given":"Chadamas","family":"Sakonsinsiri","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timpika","family":"Chaiprasert","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Napat","family":"Armartmuntree","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duangkamon","family":"Muengsaen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anchalee","family":"Techasen","sequence":"additional","affiliation":[{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0209-3901","authenticated-orcid":false,"given":"Poramate","family":"Klanrit","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Worachart","family":"Lert-itthiporn","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somchai","family":"Pinlaor","sequence":"additional","affiliation":[{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, 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"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4558","DOI":"10.1242\/dev.112672","article-title":"Fox transcription factors: From development to disease","volume":"143","author":"Golson","year":"2016","journal-title":"Development"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.3892\/or.2014.3357","article-title":"Targeting forkhead box transcription factors FOXM1 and FOXO in leukemia (Review)","volume":"32","author":"Zhu","year":"2014","journal-title":"Oncol. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1042\/BSR20110046","article-title":"FOXA1: A transcription factor with parallel functions in development and cancer","volume":"32","author":"Bernardo","year":"2012","journal-title":"Biosci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1007\/s00018-006-6095-6","article-title":"The Foxa family of transcription factors in development and metabolism","volume":"63","author":"Friedman","year":"2006","journal-title":"Cell Mol. Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"44385","DOI":"10.1074\/jbc.M108214200","article-title":"Transcription factor FoxA (HNF3) on a nucleosome at an enhancer complex in liver chromatin","volume":"276","author":"Chaya","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1038\/nature03649","article-title":"The initiation of liver development is dependent on Foxa transcription factors","volume":"435","author":"Lee","year":"2005","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1053\/j.gastro.2009.05.044","article-title":"Stem cells and liver regeneration","volume":"137","author":"Duncan","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1016\/j.freeradbiomed.2013.07.034","article-title":"Inflammation-related DNA damage and expression of CD133 and Oct3\/4 in cholangiocarcinoma patients with poor prognosis","volume":"65","author":"Thanan","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/hep.24351","article-title":"Risk factors for cholangiocarcinoma","volume":"54","author":"Tyson","year":"2011","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e89","DOI":"10.1016\/j.canep.2011.11.007","article-title":"Risk factors for cholangiocarcinoma in high-risk area of Thailand: Role of lifestyle, diet and methylenetetrahydrofolate reductase polymorphisms","volume":"36","author":"Songserm","year":"2012","journal-title":"Cancer Epidemiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.biocel.2009.11.006","article-title":"The role of stem cells in liver repair and fibrosis","volume":"43","author":"Greenbaum","year":"2011","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.redox.2017.11.011","article-title":"Prolonged oxidative stress down-regulates Early B cell factor 1 with inhibition of its tumor suppressive function against cholangiocarcinoma genesis","volume":"14","author":"Armartmuntree","year":"2018","journal-title":"Redox Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.bbrc.2015.06.112","article-title":"Development and characterization of a hydrogen peroxide-resistant cholangiocyte cell line: A novel model of oxidative stress-related cholangiocarcinoma genesis","volume":"464","author":"Thanan","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Rangel, N., Fortunati, N., Osella-Abate, S., Annaratone, L., Isella, C., Catalano, M.G., Rinella, L., Metovic, J., Boldorini, R., and Balmativola, D. (2018). FOXA1 and AR in invasive breast cancer: New findings on their co-expression and impact on prognosis in ER-positive patients. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4624-y"},{"key":"ref_15","first-page":"133","article-title":"FOXA2 promotes the proliferation, migration and invasion, and epithelial mesenchymal transition in colon cancer","volume":"16","author":"Wang","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.gene.2018.11.022","article-title":"Expression and prognosis analyses of forkhead box A (FOXA) family in human lung cancer","volume":"685","author":"Huang","year":"2019","journal-title":"Gene"},{"key":"ref_17","first-page":"4351","article-title":"Upregulated forkhead-box A3 elevates the expression of forkhead-box A1 and forkhead-box A2 to promote metastasis in esophageal cancer","volume":"17","author":"Chen","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1007\/s12672-018-0349-2","article-title":"The Importance of CYP19A1 in Estrogen Receptor-Positive Cholangiocarcinoma","volume":"9","author":"Kaewlert","year":"2018","journal-title":"Horm. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.jhep.2016.09.010","article-title":"Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks","volume":"66","author":"Vaquero","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1177\/1066896907304519","article-title":"Aberrant expression of alpha-fetoprotein in intrahepatic cholangiocarcinoma: An exceptional occurrence","volume":"16","author":"Vij","year":"2008","journal-title":"Int. J. Surg. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.3748\/wjg.14.2251","article-title":"Clinicopathologic characteristics of intrahepatic cholangiocarcinoma in patients with positive serum a-fetoprotein","volume":"14","author":"Zhou","year":"2008","journal-title":"World J. Gastroenterol"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/ng.2764","article-title":"The Cancer Genome Atlas Pan-Cancer analysis project","volume":"45","author":"Weinstein","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"3526","DOI":"10.1038\/onc.2009.211","article-title":"Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties","volume":"28","author":"Coulouarn","year":"2009","journal-title":"Oncogene"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1158\/0008-5472.CAN-09-2979","article-title":"Loss of FOXA1\/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer","volume":"70","author":"Song","year":"2010","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1038\/sj.onc.1208344","article-title":"Distinct gene expression patterns associated with FLT3- and NRAS-activating mutations in acute myeloid leukemia with normal karyotype","volume":"24","author":"Neben","year":"2005","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4415","DOI":"10.1158\/1078-0432.CCR-07-0122","article-title":"FOXA1 expression in breast cancer--correlation with luminal subtype A and survival","volume":"13","author":"Badve","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1111\/j.1365-2559.2011.03796.x","article-title":"High-level expression of forkhead-box protein A1 in metastatic prostate cancer","volume":"58","author":"Jain","year":"2011","journal-title":"Histopathology"},{"key":"ref_29","first-page":"5273","article-title":"The hepatocyte nuclear factor 3 alpha gene, HNF3alpha (FOXA1), on chromosome band 14q13 is amplified and overexpressed in esophageal and lung adenocarcinomas","volume":"62","author":"Lin","year":"2002","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1159\/000492702","article-title":"miR-122-5p Inhibits the Proliferation, Invasion and Growth of Bile Duct Carcinoma Cells by Targeting ALDOA","volume":"48","author":"Xu","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14289","DOI":"10.1073\/pnas.1407640111","article-title":"Role of forkhead box protein A3 in age-associated metabolic decline","volume":"111","author":"Ma","year":"2014","journal-title":"Proc. Natl. Acad Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3543","DOI":"10.1111\/cas.13798","article-title":"Prolonged inhibition of hepatocellular carcinoma cell proliferation by combinatorial expression of defined transcription factors","volume":"109","author":"Takashima","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.3748\/wjg.v11.i22.3392","article-title":"Establishment and characterization of an opisthorchiasis-associated cholangiocarcinoma cell line (KKU-100)","volume":"11","author":"Sripa","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Foty, R. (2011). A simple hanging drop cell culture protocol for generation of 3D spheroids. J. Vis. Exp.","DOI":"10.3791\/2720-v"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/5\/1796\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:04:33Z","timestamp":1760173473000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/5\/1796"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,5]]},"references-count":34,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["ijms21051796"],"URL":"https:\/\/doi.org\/10.3390\/ijms21051796","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,5]]}}}