{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T11:54:52Z","timestamp":1773662092675,"version":"3.50.1"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T00:00:00Z","timestamp":1625616000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T00:00:00Z","timestamp":1625616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002345","name":"Eberhard Karls Universit\u00e4t T\u00fcbingen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002345","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cancer Res Clin Oncol"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Glutamine plays an important role in cell viability and growth of various tumors. For the fetal subtype of hepatoblastoma, growth inhibition through glutamine depletion was shown. We studied glutamine depletion in embryonal cell lines of hepatoblastoma carrying different mutations. Since asparagine synthetase was identified as a prognostic factor and potential therapeutic target in adult hepatocellular carcinoma, we investigated the expression of its gene <jats:italic>ASNS<\/jats:italic> and of the gene <jats:italic>GLUL,<\/jats:italic> encoding for glutamine synthetase, in hepatoblastoma specimens and cell lines and investigated the correlation with overall survival.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We correlated <jats:italic>GLUL<\/jats:italic> and <jats:italic>ASNS<\/jats:italic> expression with overall survival using publicly available microarray and clinical data. We examined <jats:italic>GLUL<\/jats:italic> and <jats:italic>ASNS<\/jats:italic> expression by RT-qPCR and by Western blot analysis in the embryonal cell lines Huh-6 and HepT1, and in five hepatoblastoma specimens. In the same cell lines, we investigated the effects of glutamine depletion. Hepatoblastoma biopsies were examined for histology and <jats:italic>CTNNB1<\/jats:italic> mutations.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>High <jats:italic>GLUL<\/jats:italic> expression was associated with a higher median survival time. Independent of mutations and histology, hepatoblastoma samples showed strong <jats:italic>GLUL<\/jats:italic> expression and glutamine synthesis. Glutamine depletion resulted in the inhibition of proliferation and of cell viability in both embryonal hepatoblastoma cell lines. <jats:italic>ASNS<\/jats:italic> expression did not correlate with overall survival.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Growth inhibition resulting from glutamine depletion, as described for the hepatoblastoma fetal subtype, is also detected in established embryonal hepatoblastoma cell lines carrying different mutations. At variance with adult hepatocellular carcinoma, in hepatoblastoma asparagine synthetase has no prognostic significance.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00432-021-03713-4","type":"journal-article","created":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T19:03:14Z","timestamp":1625684594000},"page":"3169-3181","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Hepatoblastoma: glutamine depletion hinders cell viability in the embryonal subtype but high GLUL expression is associated with better overall survival"],"prefix":"10.1007","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7631-0609","authenticated-orcid":false,"given":"Andreas","family":"Schmidt","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Armento","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ovidio","family":"Bussolati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Chiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verena","family":"Ellerkamp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus O.","family":"Scharpf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Sander","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evi","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven W.","family":"Warmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00f6rg","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,7,7]]},"reference":[{"key":"3713_CR1","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.humpath.2008.10.022","volume":"40","author":"AM Adesina","year":"2009","unstructured":"Adesina AM et al (2009) Gene expression profiling reveals signatures characterizing histologic subtypes of hepatoblastoma and global deregulation in cell growth and survival pathways. Hum Pathol 40:843\u2013853. https:\/\/doi.org\/10.1016\/j.humpath.2008.10.022","journal-title":"Hum Pathol"},{"key":"3713_CR2","doi-asserted-by":"publisher","first-page":"4839","DOI":"10.1038\/sj.onc.1207634","volume":"23","author":"M Al-Fageeh","year":"2004","unstructured":"Al-Fageeh M, Li Q, Dashwood WM, Myzak MC, Dashwood RH (2004) Phosphorylation and ubiquitination of oncogenic mutants of beta-catenin containing substitutions at Asp32. Oncogene 23:4839\u20134846. https:\/\/doi.org\/10.1038\/sj.onc.1207634","journal-title":"Oncogene"},{"key":"3713_CR3","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/0092-8674(76)90190-2","volume":"8","author":"G Arad","year":"1976","unstructured":"Arad G, Freikopf A, Kulka RG (1976) Glutamine-stimulated modification and degradation of glutamine synthetase in hepatoma tissue culture cells. Cell 8:95\u2013101. https:\/\/doi.org\/10.1016\/0092-8674(76)90190-2","journal-title":"Cell"},{"key":"3713_CR4","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.biocel.2009.07.012","volume":"43","author":"C Armengol","year":"2011","unstructured":"Armengol C, Cairo S, Fabre M, Buendia MA (2011) Wnt signaling and hepatocarcinogenesis: the hepatoblastoma model. Int J Biochem Cell Biol 43:265\u2013270. https:\/\/doi.org\/10.1016\/j.biocel.2009.07.012","journal-title":"Int J Biochem Cell Biol"},{"key":"3713_CR5","doi-asserted-by":"publisher","first-page":"8293","DOI":"10.1038\/sj.onc.1206118","volume":"21","author":"A Cadoret","year":"2002","unstructured":"Cadoret A et al (2002) New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene 21:8293\u20138301. https:\/\/doi.org\/10.1038\/sj.onc.1206118","journal-title":"Oncogene"},{"key":"3713_CR6","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.ccr.2008.11.002","volume":"14","author":"S Cairo","year":"2008","unstructured":"Cairo S et al (2008) Hepatic stem-like phenotype and interplay of Wnt\/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell 14:471\u2013484. https:\/\/doi.org\/10.1016\/j.ccr.2008.11.002","journal-title":"Cancer Cell"},{"key":"3713_CR7","doi-asserted-by":"publisher","DOI":"10.3390\/genes9020108","author":"A Castegna","year":"2018","unstructured":"Castegna A, Menga A (2018) Glutamine synthetase: localization dictates outcome. Genes (basel). https:\/\/doi.org\/10.3390\/genes9020108","journal-title":"Genes (basel)"},{"key":"3713_CR8","doi-asserted-by":"publisher","first-page":"311","DOI":"10.3748\/wjg.v21.i1.311","volume":"21","author":"D Cevik","year":"2015","unstructured":"Cevik D, Yildiz G, Ozturk M (2015) Common telomerase reverse transcriptase promoter mutations in hepatocellular carcinomas from different geographical locations. World J Gastroenterol 21:311\u2013317. https:\/\/doi.org\/10.3748\/wjg.v21.i1.311","journal-title":"World J Gastroenterol"},{"key":"3713_CR9","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1038\/bjc.2014.425","volume":"111","author":"M Chiu","year":"2014","unstructured":"Chiu M et al (2014) Glutamine depletion by crisantaspase hinders the growth of human hepatocellular carcinoma xenografts. Br J Cancer 111:1159\u20131167. https:\/\/doi.org\/10.1038\/bjc.2014.425","journal-title":"Br J Cancer"},{"key":"3713_CR10","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.3389\/fonc.2019.01480","volume":"9","author":"M Chiu","year":"2019","unstructured":"Chiu M, Taurino G, Bianchi MG, Kilberg MS, Bussolati O (2019) Asparagine synthetase in cancer: beyond acute lymphoblastic leukemia front. Oncol 9:1480. https:\/\/doi.org\/10.3389\/fonc.2019.01480","journal-title":"Oncol"},{"key":"3713_CR11","unstructured":"COSMIC (2021) Catalogue of Somatic Mutations in Cancer httpn :\/\/cancersangeracuk\/cosmic\/gene\/analysis?ln=CTNNB1 Accessed 5 June 2021"},{"key":"3713_CR12","doi-asserted-by":"publisher","first-page":"4","DOI":"10.2174\/157489212798358001","volume":"7","author":"D Covini","year":"2012","unstructured":"Covini D et al (2012) Expanding targets for a metabolic therapy of cancer: L-asparaginase. Recent Pat Anticancer Drug Discov 7:4\u201313. https:\/\/doi.org\/10.2174\/157489212798358001","journal-title":"Recent Pat Anticancer Drug Discov"},{"key":"3713_CR13","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.15252\/emmm.201707814","volume":"9","author":"S Crippa","year":"2017","unstructured":"Crippa S et al (2017) Mutant CTNNB1 and histological heterogeneity define metabolic subtypes of hepatoblastoma. EMBO Mol Med 9:1589\u20131604. https:\/\/doi.org\/10.15252\/emmm.201707814","journal-title":"EMBO Mol Med"},{"key":"3713_CR14","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1042\/bj1760047","volume":"176","author":"RB Crook","year":"1978","unstructured":"Crook RB, Tomkins GM (1978) Effect of glutamine on the degradation of glutamine synthetase in hepatoma tissue-culture cells. Biochem J 176:47\u201352. https:\/\/doi.org\/10.1042\/bj1760047","journal-title":"Biochem J"},{"key":"3713_CR15","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1097\/MOP.0000000000000046","volume":"26","author":"P Czauderna","year":"2014","unstructured":"Czauderna P, Lopez-Terrada D, Hiyama E, Haberle B, Malogolowkin MH, Meyers RL (2014) Hepatoblastoma state of the art: pathology, genetics, risk stratification, and chemotherapy. Curr Opin Pediatr 26:19\u201328. https:\/\/doi.org\/10.1097\/MOP.0000000000000046","journal-title":"Curr Opin Pediatr"},{"key":"3713_CR16","doi-asserted-by":"publisher","first-page":"8847","DOI":"10.1073\/pnas.95.15.8847","volume":"95","author":"A de La Coste","year":"1998","unstructured":"de La Coste A et al (1998) Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 95:8847\u20138851. https:\/\/doi.org\/10.1073\/pnas.95.15.8847","journal-title":"Proc Natl Acad Sci USA"},{"key":"3713_CR17","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/onc.2009.358","volume":"29","author":"RJ DeBerardinis","year":"2010","unstructured":"DeBerardinis RJ, Cheng T (2010) Q\u2019s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29:313\u2013324. https:\/\/doi.org\/10.1038\/onc.2009.358","journal-title":"Oncogene"},{"key":"3713_CR18","first-page":"1","volume":"67","author":"I Doi","year":"1976","unstructured":"Doi I (1976) Establishment of a cell line and its clonal sublines from a patient with hepatoblastoma. Gan 67:1\u201310","journal-title":"Gan"},{"key":"3713_CR19","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1016\/j.jhep.2014.08.009","volume":"61","author":"M Eichenmuller","year":"2014","unstructured":"Eichenmuller M et al (2014) The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol 61:1312\u20131320. https:\/\/doi.org\/10.1016\/j.jhep.2014.08.009","journal-title":"J Hepatol"},{"key":"3713_CR20","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1002\/1097-0142(19890901)64:5<1082::aid-cncr2820640520>3.0.co;2-g","volume":"64","author":"JE Haas","year":"1989","unstructured":"Haas JE, Muczynski KA, Krailo M, Ablin A, Land V, Vietti TJ, Hammond GD (1989) Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer 64:1082\u20131095. https:\/\/doi.org\/10.1002\/1097-0142(19890901)64:5%3c1082::aid-cncr2820640520%3e3.0.co;2-g","journal-title":"Cancer"},{"key":"3713_CR21","doi-asserted-by":"publisher","first-page":"3130","DOI":"10.1002\/1097-0142(20011215)92:12<3130::aid-cncr10115>3.0.co;2-#","volume":"92","author":"JE Haas","year":"2001","unstructured":"Haas JE, Feusner JH, Finegold MJ (2001) Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Cancer 92:3130\u20133134. https:\/\/doi.org\/10.1002\/1097-0142(20011215)92:12%3c3130::aid-cncr10115%3e3.0.co;2-#","journal-title":"Cancer"},{"key":"3713_CR22","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1038\/modpathol.2016.122","volume":"29","author":"G Hale","year":"2016","unstructured":"Hale G et al (2016) Correlation of exon 3 beta-catenin mutations with glutamine synthetase staining patterns in hepatocellular adenoma and hepatocellular carcinoma. Mod Pathol 29:1370\u20131380. https:\/\/doi.org\/10.1038\/modpathol.2016.122","journal-title":"Mod Pathol"},{"key":"3713_CR23","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/j.jfma.2016.09.013","volume":"116","author":"WJ Huang","year":"2017","unstructured":"Huang WJ, Tsai JH, Jeng YM (2017) Complementary roles of beta-catenin and glutamine synthetase immunostaining in diagnosis of chemotherapy-treated and untreated hepatoblastoma. J Formos Med Assoc 116:549\u2013553. https:\/\/doi.org\/10.1016\/j.jfma.2016.09.013","journal-title":"J Formos Med Assoc"},{"key":"3713_CR24","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1002\/hep.27243","volume":"60","author":"D Jia","year":"2014","unstructured":"Jia D et al (2014) Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex. Hepatology 60:1686\u20131696. https:\/\/doi.org\/10.1002\/hep.27243","journal-title":"Hepatology"},{"key":"3713_CR25","doi-asserted-by":"publisher","first-page":"8","DOI":"10.14348\/molcells.2018.0436","volume":"42","author":"S Kim","year":"2019","unstructured":"Kim S, Jeong S (2019) Mutation hotspots in the \u03b2-catenin gene: lessons from the human cancer genome databases. Mol Cells 42:8\u201316. https:\/\/doi.org\/10.14348\/molcells.2018.0436","journal-title":"Mol Cells"},{"key":"3713_CR26","first-page":"269","volume":"59","author":"A Koch","year":"1999","unstructured":"Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T (1999) Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res 59:269\u2013273","journal-title":"Cancer Res"},{"key":"3713_CR27","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1002\/path.1662","volume":"204","author":"A Koch","year":"2004","unstructured":"Koch A et al (2004) Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas. J Pathol 204:546\u2013554. https:\/\/doi.org\/10.1002\/path.1662","journal-title":"J Pathol"},{"key":"3713_CR28","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1038\/modpathol.2014.161","volume":"28","author":"J Lasota","year":"2015","unstructured":"Lasota J, Felisiak-Golabek A, Aly FZ, Wang ZF, Thompson LD, Miettinen M (2015) Nuclear expression and gain-of-function beta-catenin mutation in glomangiopericytoma (sinonasal-type hemangiopericytoma): insight into pathogenesis and a diagnostic marker. Mod Pathol 28:715\u2013720. https:\/\/doi.org\/10.1038\/modpathol.2014.161","journal-title":"Mod Pathol"},{"key":"3713_CR29","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"KJ Livak","year":"2001","unstructured":"Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402\u2013408. https:\/\/doi.org\/10.1006\/meth.2001.1262","journal-title":"Methods"},{"key":"3713_CR30","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1016\/j.humpath.2009.07.003","volume":"40","author":"D Lopez-Terrada","year":"2009","unstructured":"Lopez-Terrada D, Cheung SW, Finegold MJ, Knowles BB (2009a) Hep G2 is a hepatoblastoma-derived cell line. Hum Pathol 40:1512\u20131515. https:\/\/doi.org\/10.1016\/j.humpath.2009.07.003","journal-title":"Hum Pathol"},{"key":"3713_CR31","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/j.humpath.2008.07.022","volume":"40","author":"D Lopez-Terrada","year":"2009","unstructured":"Lopez-Terrada D et al (2009b) Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors. Hum Pathol 40:783\u2013794. https:\/\/doi.org\/10.1016\/j.humpath.2008.07.022","journal-title":"Hum Pathol"},{"key":"3713_CR32","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1038\/modpathol.2013.80","volume":"27","author":"D Lopez-Terrada","year":"2014","unstructured":"Lopez-Terrada D et al (2014) Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Mod Pathol 27:472\u2013491. https:\/\/doi.org\/10.1038\/modpathol.2013.80","journal-title":"Mod Pathol"},{"key":"3713_CR33","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.4155\/fmc.13.130","volume":"5","author":"MJ Lukey","year":"2013","unstructured":"Lukey MJ, Wilson KF, Cerione RA (2013) Therapeutic strategies impacting cancer cell glutamine metabolism. Future Med Chem 5:1685\u20131700. https:\/\/doi.org\/10.4155\/fmc.13.130","journal-title":"Future Med Chem"},{"key":"3713_CR34","doi-asserted-by":"publisher","first-page":"3301","DOI":"10.1200\/JCO.2010.29.3837","volume":"29","author":"MH Malogolowkin","year":"2011","unstructured":"Malogolowkin MH, Katzenstein HM, Meyers RL, Krailo MD, Rowland JM, Haas J, Finegold MJ (2011) Complete surgical resection is curative for children with hepatoblastoma with pure fetal histology: a report from the Children\u2019s Oncology Group. J Clin Oncol 29:3301\u20133306. https:\/\/doi.org\/10.1200\/JCO.2010.29.3837","journal-title":"J Clin Oncol"},{"key":"3713_CR35","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/nrclinonc.2016.60","volume":"14","author":"UE Martinez-Outschoorn","year":"2017","unstructured":"Martinez-Outschoorn UE, Peiris-Pages M, Pestell RG, Sotgia F, Lisanti MP (2017) Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 14:11\u201331. https:\/\/doi.org\/10.1038\/nrclinonc.2016.60","journal-title":"Nat Rev Clin Oncol"},{"key":"3713_CR36","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.semcdb.2019.05.012","volume":"98","author":"JM Mates","year":"2020","unstructured":"Mates JM, Di Paola FJ, Campos-Sandoval JA, Mazurek S, Marquez J (2020) Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer. Semin Cell Dev Biol 98:34\u201343. https:\/\/doi.org\/10.1016\/j.semcdb.2019.05.012","journal-title":"Semin Cell Dev Biol"},{"key":"3713_CR37","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1016\/j.ajpath.2019.02.002","volume":"189","author":"Q Min","year":"2019","unstructured":"Min Q et al (2019) Beta-catenin and yes-associated protein 1 cooperate in hepatoblastoma pathogenesis. Am J Pathol 189:1091\u20131104. https:\/\/doi.org\/10.1016\/j.ajpath.2019.02.002","journal-title":"Am J Pathol"},{"key":"3713_CR38","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1053\/j.gastro.2015.02.056","volume":"148","author":"SP Monga","year":"2015","unstructured":"Monga SP (2015) Beta-Catenin signaling and roles in liver homeostasis injury, and tumorigenesis. Gastroenterology 148:1294\u20131310. https:\/\/doi.org\/10.1053\/j.gastro.2015.02.056","journal-title":"Gastroenterology"},{"key":"3713_CR39","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","volume":"65","author":"T Mosmann","year":"1983","unstructured":"Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55\u201363. https:\/\/doi.org\/10.1016\/0022-1759(83)90303-4","journal-title":"J Immunol Methods"},{"key":"3713_CR40","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.molcel.2016.02.032","volume":"61","author":"TV Nguyen","year":"2016","unstructured":"Nguyen TV et al (2016) Glutamine triggers acetylation-dependent degradation of glutamine synthetase via the thalidomide receptor cereblon. Mol Cell 61:809\u2013820. https:\/\/doi.org\/10.1016\/j.molcel.2016.02.032","journal-title":"Mol Cell"},{"key":"3713_CR41","first-page":"809","volume":"74","author":"T Pietsch","year":"1996","unstructured":"Pietsch T, Fonatsch C, Albrecht S, Maschek H, Wolf HK, von Schweinitz D (1996) Characterization of the continuous cell line HepT1 derived from a human hepatoblastoma. Lab Invest 74:809\u2013818","journal-title":"Lab Invest"},{"key":"3713_CR42","doi-asserted-by":"publisher","unstructured":"Schmid E, Xuan NT, Zahir N, Russo A, Yang W, Kuhl D, Faggio C, Shumilina E, Lang F (2014) Cell Physiol Biochem 34(3):943\u201354. https:\/\/doi.org\/10.1159\/000366311","DOI":"10.1159\/000366311"},{"key":"3713_CR43","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/nm.4464","volume":"24","author":"ML Schulte","year":"2018","unstructured":"Schulte ML et al (2018) Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med 24:194\u2013202. https:\/\/doi.org\/10.1038\/nm.4464","journal-title":"Nat Med"},{"key":"3713_CR44","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1186\/1471-2164-10-269","volume":"10","author":"X She","year":"2009","unstructured":"She X, Rohl CA, Castle JC, Kulkarni AV, Johnson JM, Chen R (2009) Definition, conservation and epigenetics of housekeeping and tissue-enriched genes. BMC Genomics 10:269. https:\/\/doi.org\/10.1186\/1471-2164-10-269","journal-title":"BMC Genomics"},{"key":"3713_CR45","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1038\/bjc.2017.113","volume":"116","author":"ER Still","year":"2017","unstructured":"Still ER, Yuneva MO (2017) Hopefully devoted to Q: targeting glutamine addiction in cancer. Br J Cancer 116:1375\u20131381. https:\/\/doi.org\/10.1038\/bjc.2017.113","journal-title":"Br J Cancer"},{"key":"3713_CR46","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1002\/hep.28888","volume":"65","author":"P Sumazin","year":"2017","unstructured":"Sumazin P et al (2017) Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups. Hepatology 65:104\u2013121. https:\/\/doi.org\/10.1002\/hep.28888","journal-title":"Hepatology"},{"key":"3713_CR47","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1053\/j.gastro.2014.05.004","volume":"147","author":"J Tao","year":"2014","unstructured":"Tao J et al (2014) Activation of beta-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. Gastroenterology 147:690\u2013701. https:\/\/doi.org\/10.1053\/j.gastro.2014.05.004","journal-title":"Gastroenterology"},{"key":"3713_CR48","doi-asserted-by":"publisher","first-page":"929","DOI":"10.2174\/156800911797264725","volume":"11","author":"S Tardito","year":"2011","unstructured":"Tardito S et al (2011) L-Asparaginase and inhibitors of glutamine synthetase disclose glutamine addiction of beta-catenin-mutated human hepatocellular carcinoma cells. Curr Cancer Drug Targets 11:929\u2013943","journal-title":"Curr Cancer Drug Targets"},{"key":"3713_CR49","doi-asserted-by":"publisher","first-page":"6583","DOI":"10.1038\/sj.onc.1203051","volume":"18","author":"B Terris","year":"1999","unstructured":"Terris B et al (1999) Close correlation between beta-catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas. Oncogene 18:6583\u20136588. https:\/\/doi.org\/10.1038\/sj.onc.1203051","journal-title":"Oncogene"},{"key":"3713_CR50","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/s0959-437x(98)80068-3","volume":"8","author":"K Willert","year":"1998","unstructured":"Willert K, Nusse R (1998) Beta-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev 8:95\u2013102. https:\/\/doi.org\/10.1016\/s0959-437x(98)80068-3","journal-title":"Curr Opin Genet Dev"},{"key":"3713_CR51","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1007\/s00432-018-2605-9","volume":"144","author":"J Ye","year":"2018","unstructured":"Ye J et al (2018) Targeting of glutamine transporter ASCT2 and glutamine synthetase suppresses gastric cancer cell growth. J Cancer Res Clin Oncol 144:821\u2013833. https:\/\/doi.org\/10.1007\/s00432-018-2605-9","journal-title":"J Cancer Res Clin Oncol"},{"key":"3713_CR52","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1038\/bjc.2013.293","volume":"109","author":"B Zhang","year":"2013","unstructured":"Zhang B et al (2013) Asparagine synthetase is an independent predictor of surgical survival and a potential therapeutic target in hepatocellular carcinoma. Br J Cancer 109:14\u201323. https:\/\/doi.org\/10.1038\/bjc.2013.293","journal-title":"Br J Cancer"},{"key":"3713_CR53","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1016\/j.ejca.2005.02.035","volume":"41","author":"A Zimmermann","year":"2005","unstructured":"Zimmermann A (2005) The emerging family of hepatoblastoma tumours: from ontogenesis to oncogenesis. Eur J Cancer 41:1503\u20131514. https:\/\/doi.org\/10.1016\/j.ejca.2005.02.035","journal-title":"Eur J Cancer"}],"container-title":["Journal of Cancer Research and Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-021-03713-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00432-021-03713-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-021-03713-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T17:11:33Z","timestamp":1633021893000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00432-021-03713-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,7]]},"references-count":53,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["3713"],"URL":"https:\/\/doi.org\/10.1007\/s00432-021-03713-4","relation":{},"ISSN":["0171-5216","1432-1335"],"issn-type":[{"value":"0171-5216","type":"print"},{"value":"1432-1335","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,7]]},"assertion":[{"value":"20 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 July 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was approved by the Ethical Committee of the Medical Faculty of the University of Tuebingen and the University Hospital Tuebingen, Germany (Ref. 354\/2018BO2).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Written informed consent for the use of hepatoblastoma tissue samples for scientific purposes was obtained\u00a0for\u00a0all individual participants included in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}]}}