{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:44:27Z","timestamp":1786977867301,"version":"build-2736575974"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T00:00:00Z","timestamp":1606348800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T00:00:00Z","timestamp":1606348800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>The wide prevalence of chemoresistance and compromised early diagnosis of gallbladder cancer (GBC) has led to poor patient prognosis, requiring sustained efforts for the identification of effective biomarkers and therapeutic intervention. Ceramides have emerged as intracellular signaling molecules linked to tumorigenesis and therapeutic response in cancers. However, the clinical relevance of ceramides with GBC has not been investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      In the present study, we revealed aberrant gene expressions (e.g., serine palmitoyltransferase 1 [SPTLC1] and ceramide synthase 2 [CERS2]) of\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      ceramide biosynthesis and length\u2010specific ceramide production in GBC tissues. Analyses of serum ceramide pattern in healthy controls, gallbladder stone, and GBC patients identified C24\u2010Ceramide as a potential diagnostic biomarker for patients with GBC. Importantly, elevation of SPTLC1, CERS2, and its product, C24\u2010Ceramide, was associated with tumor staging, distal metastasis, and worse prognosis. In line with this, C\n                      <jats:sub>24<\/jats:sub>\n                      \u2010Ceramide promoted GBC cell proliferation and migration\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      . Mechanistically, C24\u2010Ceramide directly bound to phosphatidylinositol 5\u2010phosphate 4\u2010kinase type\u20102 gamma (PIP4K2C), a regulator of mammalian target of rapamycin (mTOR), to facilitate mTOR complex formation and activation. C6\u2010Ceramide, an analogue of natural ceramide, competed with C24\u2010Ceramide for PIP4K2C binding, thereby abrogating C24\u2010Ceramide\u2013mediated mTOR signaling activation and oncogenic activity. Furthermore, stimulation with C6\u2010Ceramide significantly suppressed the proliferative and metastatic capacity of GBC cells\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      , which was dependent on PIP4K2C.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings highlight the clinical relevance of ceramide metabolism with GBC progression and identify C24\u2010Ceramide as a diagnostic biomarker for GBC. We propose that PIP4K2C is indispensable for C6\u2010Ceramide as a potential therapeutic intervention for GBC through a direct competition with C24\u2010Ceramide.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.31304","type":"journal-article","created":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T16:56:44Z","timestamp":1588784204000},"page":"692-712","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":35,"title":["C24\u2010Ceramide Drives Gallbladder Cancer Progression Through Directly Targeting Phosphatidylinositol 5\u2010Phosphate 4\u2010Kinase Type\u20102 Gamma to Facilitate Mammalian Target of Rapamycin Signaling Activation"],"prefix":"10.1097","volume":"73","author":[{"given":"Yonglong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Biliary\u2010Pancreatic Surgery,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biliary\u2010Pancreatic Surgery,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biliary\u2010Pancreatic Surgery,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haolu","family":"Wang","sequence":"additional","affiliation":[{"name":"The University of Queensland Diamantina Institute,The University of Queensland,Brisbane,Queensland,Australia"},{"name":"Gallipoli Medical Research Institute,Greenslopes Private Hospital,Brisbane,Queensland,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowen","family":"Liang","sequence":"additional","affiliation":[{"name":"The University of Queensland Diamantina Institute,The University of Queensland,Brisbane,Queensland,Australia"},{"name":"Gallipoli Medical Research Institute,Greenslopes Private Hospital,Brisbane,Queensland,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":",","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biliary\u2010Pancreatic Surgery,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlin","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Pathology Affiliated Tongren Hospital,School of Medicine,Shanghai Jiaotong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenjiao","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Biliary\u2010Pancreatic Surgery,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Qiao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology (MOE & MOH),Shanghai Medical College,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences of Shanghai Medical School,Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2633-4765","authenticated-orcid":false,"given":"Yanfeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Clinical Stem Cell Center,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biliary\u2010Pancreatic Surgery,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2020,11,26]]},"reference":[{"key":"hep31304-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrc.2017.96","article-title":"Sphingolipid metabolism in cancer signalling and therapy","volume":"18","year":"2018","journal-title":"Nat Rev Cancer"},{"key":"hep31304-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/hep.510300146","article-title":"Ceramide induces caspase\u2010independent apoptosis in rat hepatocytes sensitized by inhibition of RNA synthesis","volume":"30","year":"1999","journal-title":"Hepatology"},{"key":"hep31304-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/nrm2329","article-title":"Principles of bioactive lipid signalling: lessons from sphingolipids","volume":"9","year":"2008","journal-title":"Nat Rev Mol Cell Biol"},{"key":"hep31304-bib-0004-20250824","doi-asserted-by":"crossref","first-page":"21025","DOI":"10.1074\/jbc.M112.363580","article-title":"Modulation of ceramide synthase activity via dimerization","volume":"287","year":"2012","journal-title":"J Biol Chem"},{"key":"hep31304-bib-0005-20250824","doi-asserted-by":"crossref","first-page":"25001","DOI":"10.1074\/jbc.R600010200","article-title":"When do Lasses (longevity assurance genes) become CerS (ceramide synthases)? Insights into the regulation of ceramide synthesis","volume":"281","year":"2006","journal-title":"J Biol Chem"},{"key":"hep31304-bib-0006-20250824","doi-asserted-by":"crossref","first-page":"35642","DOI":"10.1074\/jbc.M205211200","article-title":"Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N\u2010stearoyl\u2010sphinganine (C18\u2010(dihydro)ceramide) synthesis in a fumonisin B1\u2010independent manner in mammalian cells","volume":"277","year":"2002","journal-title":"J Biol Chem"},{"key":"hep31304-bib-0007-20250824","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nrc3398","article-title":"Ceramide\u2010orchestrated signalling in cancer cells","volume":"13","year":"2013","journal-title":"Nat Rev Cancer"},{"key":"hep31304-bib-0008-20250824","doi-asserted-by":"crossref","first-page":"6097","DOI":"10.1158\/1078-0432.CCR-11-0930","article-title":"Results of a phase II trial of gemcitabine plus doxorubicin in patients with recurrent head and neck cancers: serum C(1)(8)\u2010ceramide as a novel biomarker for monitoring response","volume":"17","year":"2011","journal-title":"Clin Cancer Res"},{"key":"hep31304-bib-0009-20250824","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.bbrc.2009.11.035","article-title":"Increased ceramide synthase 2 and 6 mRNA levels in breast cancer tissues and correlation with sphingosine kinase expression","volume":"391","year":"2010","journal-title":"Biochem Biophys Res Comm"},{"key":"hep31304-bib-0010-20250824","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1093\/carcin\/bgp061","article-title":"Ceramide synthases and ceramide levels are increased in breast cancer tissue","volume":"30","year":"2009","journal-title":"Carcinogenesis"},{"key":"hep31304-bib-0011-20250824","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.canlet.2007.06.003","article-title":"Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): attenuation of C(18)\u2010ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis","volume":"256","year":"2007","journal-title":"Cancer Lett"},{"key":"hep31304-bib-0012-20250824","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1053\/j.gastro.2017.10.050","article-title":"Nanoliposome C6\u2010ceramide increases the anti\u2010tumor immune response and slows growth of liver tumors in mice","volume":"154","year":"2018","journal-title":"Gastroenterology"},{"key":"hep31304-bib-0013-20250824","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1136\/gut.2010.216671","article-title":"Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma","volume":"60","year":"2011","journal-title":"Gut"},{"key":"hep31304-bib-0014-20250824","doi-asserted-by":"crossref","first-page":"6557","DOI":"10.1038\/onc.2010.379","article-title":"Exogenous cell\u2010permeable C6 ceramide sensitizes multiple cancer cell lines to doxorubicin\u2010induced apoptosis by promoting AMPK activation and mTORC1 inhibition","volume":"29","year":"2010","journal-title":"Oncogene"},{"key":"hep31304-bib-0015-20250824","doi-asserted-by":"crossref","first-page":"6959","DOI":"10.1073\/pnas.93.14.6959","article-title":"Ceramide\u2010binding and activation defines protein kinase c\u2010Raf as a ceramide\u2010activated protein kinase","volume":"93","year":"1996","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep31304-bib-0016-20250824","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1074\/mcp.M115.055954","article-title":"Proteome\u2010wide identification of novel ceramide\u2010binding proteins by yeast surface cDNA display and deep sequencing","volume":"15","year":"2016","journal-title":"Mol Cell Proteomics"},{"key":"hep31304-bib-0017-20250824","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1194\/jlr.M082354","article-title":"A search for ceramide binding proteins using bifunctional lipid analogs yields CERT\u2010related protein StarD7","volume":"59","year":"2018","journal-title":"J Lipid Res"},{"key":"hep31304-bib-0018-20250824","doi-asserted-by":"crossref","first-page":"5252","DOI":"10.1093\/emboj\/18.19.5252","article-title":"Cathepsin D targeted by acid sphingomyelinase\u2010derived ceramide","volume":"18","year":"1999","journal-title":"EMBO J"},{"key":"hep31304-bib-0019-20250824","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.bbalip.2003.08.010","article-title":"Differential binding of ceramide to MEKK1 in glomerular endothelial and mesangial cells","volume":"1636","year":"2004","journal-title":"Biochim Biophys Acta"},{"key":"hep31304-bib-0020-20250824","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1136\/gutjnl-2014-308900","article-title":"Ceramide\u2010CD300f binding suppresses experimental colitis by inhibiting ATP\u2010mediated mast cell activation","volume":"65","year":"2016","journal-title":"Gut"},{"key":"hep31304-bib-0021-20250824","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1096\/fj.08-120550","article-title":"Direct interaction between the inhibitor 2 and ceramide via sphingolipid\u2010protein binding is involved in the regulation of protein phosphatase 2A activity and signaling","volume":"23","year":"2009","journal-title":"FASEB J"},{"key":"hep31304-bib-0022-20250824","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.1074\/jbc.M116.768366","article-title":"Ceramide\u2010CD300f binding inhibits lipopolysaccharide\u2010induced skin inflammation","volume":"292","year":"2017","journal-title":"J Biol Chem"},{"key":"hep31304-bib-0023-20250824","doi-asserted-by":"crossref","first-page":"26415","DOI":"10.1074\/jbc.M501492200","article-title":"Direct binding to ceramide activates protein kinase Czeta before the formation of a pro\u2010apoptotic complex with PAR\u20104 in differentiating stem cells","volume":"280","year":"2005","journal-title":"J Biol Chem"},{"key":"hep31304-bib-0024-20250824","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1002\/hep.30861","article-title":"A metallomic approach to assess associations of serum metal levels with gallstones and gallbladder cancer","volume":"71","year":"2020","journal-title":"Hepatology"},{"key":"hep31304-bib-0025-20250824","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1007\/s00432-019-03030-x","article-title":"Eukaryotic translation initiation factor 6 overexpression plays a major role in the translational control of gallbladder cancer","volume":"145","year":"2019","journal-title":"J Cancer Res Clin Oncol"},{"key":"hep31304-bib-0026-20250824","doi-asserted-by":"crossref","first-page":"89736","DOI":"10.18632\/oncotarget.21116","article-title":"IMP2\/IGF2BP2 expression, but not IMP1 and IMP3, predicts poor outcome in patients and high tumor growth rate in xenograft models of gallbladder cancer","volume":"8","year":"2017","journal-title":"Oncotarget"},{"key":"hep31304-bib-0027-20250824","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1002\/hep.27016","article-title":"Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer","volume":"60","year":"2014","journal-title":"Hepatology"},{"key":"hep31304-bib-0028-20250824","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.jhep.2010.06.039","article-title":"Trends in the incidence and management of biliary tract cancer: a French population\u2010based study","volume":"54","year":"2011","journal-title":"J Hepatol"},{"key":"hep31304-bib-0029-20250824","article-title":"Limited use of adjuvant therapy in patients with resected gallbladder cancer despite a strong association with survival","volume":"109","year":"2017","journal-title":"J Natl Cancer Inst"},{"key":"hep31304-bib-0030-20250824","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.jhep.2010.10.010","article-title":"Combination of gemcitabine and cisplatin for biliary tract cancer: a platform to build on","volume":"54","year":"2011","journal-title":"J Hepatol"},{"key":"hep31304-bib-0031-20250824","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.1080\/15384101.2019.1676581","article-title":"Cholesterol depletion sensitizes gallbladder cancer to cisplatin by impairing DNA damage response","volume":"18","year":"2019","journal-title":"Cell Cycle"},{"key":"hep31304-bib-0032-20250824","article-title":"C6\u2010ceramide synergistically potentiates the anti\u2010tumor effects of histone deacetylase inhibitors via AKT dephosphorylation and alpha\u2010tubulin hyperacetylation both in vitro and in vivo","volume":"2","year":"2011","journal-title":"Cell Death Dis"},{"key":"hep31304-bib-0033-20250824","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1002\/hep.28395","article-title":"Hippocalcin\u2010like 1 suppresses hepatocellular carcinoma progression by promoting p21(Waf\/Cip1) stabilization by activating the ERK1\/2\u2010MAPK pathway","volume":"63","year":"2016","journal-title":"Hepatology"},{"key":"hep31304-bib-0034-20250824","doi-asserted-by":"crossref","first-page":"4810","DOI":"10.1021\/pr9005316","article-title":"The proapoptotic C16\u2010ceramide\u2010dependent pathway requires the death\u2010promoting factor Btf in colon adenocarcinoma cells","volume":"8","year":"2009","journal-title":"J Proteome Res"},{"key":"hep31304-bib-0035-20250824","first-page":"ra104","article-title":"PIP4k\u03b3 is a substrate for mTORC1 that maintains basal mTORC1 signaling during starvation","volume":"7","year":"2014","journal-title":"Sci Signal"},{"key":"hep31304-bib-0036-20250824","first-page":"E1983","article-title":"PI5P4K\u03b3 functions in DTX1\u2010mediated Notch signaling","volume":"115","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep31304-bib-0037-20250824","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.suronc.2019.09.006","article-title":"Molecular pathways and potential biomarkers in gallbladder cancer: a comprehensive review","volume":"31","year":"2019","journal-title":"Surg Oncol"},{"key":"hep31304-bib-0038-20250824","first-page":"70","article-title":"Brief commentary: largest randomized trial of biliary tract cancer treatment with cisplatin plus gemcitabine versus gemcitabine alone: an excellent opportunity to evaluate the prognostic value of tumor marker CA 19\u20109","volume":"10","year":"2011","journal-title":"Clin Colorectal Cancer"},{"key":"hep31304-bib-0039-20250824","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1245\/s10434-010-1529-7","article-title":"Preoperative serum CA 19\u20139 level as a predictive factor for recurrence after curative resection in biliary tract cancer","volume":"18","year":"2011","journal-title":"Ann Surg Oncol"},{"key":"hep31304-bib-0040-20250824","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.cell.2017.03.035","article-title":"mTOR signaling in growth, metabolism, and disease","volume":"169","year":"2017","journal-title":"Cell"},{"key":"hep31304-bib-0041-20250824","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1139\/y59-099","article-title":"A rapid method of total lipid extraction and purification","volume":"37","year":"1959","journal-title":"Can J Biochem Physiol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.31304","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.31304","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.31304","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31304","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T23:04:22Z","timestamp":1756076662000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31304"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,26]]},"references-count":41,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.31304","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,26]]},"assertion":[{"value":"2019-12-16","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-08","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}