PMID- 32374916 OWN - NLM STAT- MEDLINE DCOM- 20210809 LR - 20230309 IS - 1527-3350 (Electronic) IS - 0270-9139 (Linking) VI - 73 IP - 2 DP - 2021 Feb TI - C24-Ceramide Drives Gallbladder Cancer Progression Through Directly Targeting Phosphatidylinositol 5-Phosphate 4-Kinase Type-2 Gamma to Facilitate Mammalian Target of Rapamycin Signaling Activation. PG - 692-712 LID - 10.1002/hep.31304 [doi] AB - BACKGROUND AND AIMS: 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. APPROACH AND RESULTS: In the present study, we revealed aberrant gene expressions (e.g., serine palmitoyltransferase 1 [SPTLC1] and ceramide synthase 2 [CERS2]) of de novo ceramide biosynthesis and length-specific ceramide production in GBC tissues. Analyses of serum ceramide pattern in healthy controls, gallbladder stone, and GBC patients identified C24-Ceramide as a potential diagnostic biomarker for patients with GBC. Importantly, elevation of SPTLC1, CERS2, and its product, C24-Ceramide, was associated with tumor staging, distal metastasis, and worse prognosis. In line with this, C(24) -Ceramide promoted GBC cell proliferation and migration in vitro and in vivo. Mechanistically, C24-Ceramide directly bound to phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C), a regulator of mammalian target of rapamycin (mTOR), to facilitate mTOR complex formation and activation. C6-Ceramide, an analogue of natural ceramide, competed with C24-Ceramide for PIP4K2C binding, thereby abrogating C24-Ceramide-mediated mTOR signaling activation and oncogenic activity. Furthermore, stimulation with C6-Ceramide significantly suppressed the proliferative and metastatic capacity of GBC cells in vitro and in vivo, which was dependent on PIP4K2C. CONCLUSIONS: Our findings highlight the clinical relevance of ceramide metabolism with GBC progression and identify C24-Ceramide as a diagnostic biomarker for GBC. We propose that PIP4K2C is indispensable for C6-Ceramide as a potential therapeutic intervention for GBC through a direct competition with C24-Ceramide. CI - (c) 2020 by the American Association for the Study of Liver Diseases. FAU - Zhang, Yonglong AU - Zhang Y AD - Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina. FAU - Wang, Hui AU - Wang H AD - Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina. FAU - Chen, Tao AU - Chen T AD - Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina. FAU - Wang, Haolu AU - Wang H AD - The University of Queensland Diamantina InstituteThe University of QueenslandBrisbaneQueenslandAustralia. AD - Gallipoli Medical Research InstituteGreenslopes Private HospitalBrisbaneQueenslandAustralia. FAU - Liang, Xiaowen AU - Liang X AD - The University of Queensland Diamantina InstituteThe University of QueenslandBrisbaneQueenslandAustralia. AD - Gallipoli Medical Research InstituteGreenslopes Private HospitalBrisbaneQueenslandAustralia. FAU - Zhang, Yuchen AU - Zhang Y AD - Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina. FAU - Duan, Jinlin AU - Duan J AD - Department of Pathology Affiliated Tongren HospitalSchool of MedicineShanghai Jiaotong UniversityShanghaiChina. FAU - Qian, Shenjiao AU - Qian S AD - Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina. FAU - Qiao, Ke AU - Qiao K AD - Key Laboratory of Medical Molecular Virology (MOE & MOH)Shanghai Medical CollegeFudan UniversityShanghaiChina. FAU - Zhang, Lei AU - Zhang L AD - Institutes of Biomedical Sciences of Shanghai Medical SchoolFudan UniversityShanghaiChina. FAU - Liu, Yanfeng AU - Liu Y AUID- ORCID: 0000-0003-2633-4765 AD - Clinical Stem Cell CenterRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina. FAU - Wang, Jian AU - Wang J AD - Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201126 PL - United States TA - Hepatology JT - Hepatology (Baltimore, Md.) JID - 8302946 RN - 0 (Biomarkers, Tumor) RN - 0 (Ceramides) RN - 0 (Membrane Proteins) RN - 0 (Tumor Suppressor Proteins) RN - EC 2.3.1.24 (CERS2 protein, human) RN - EC 2.3.1.24 (Sphingosine N-Acyltransferase) RN - EC 2.3.1.50 (SPTLC1 protein, human) RN - EC 2.3.1.50 (Serine C-Palmitoyltransferase) RN - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.149 (PIP4K2C protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Biomarkers, Tumor/*metabolism MH - Ceramides/*metabolism MH - Female MH - Gallbladder/pathology MH - Gallbladder Neoplasms/diagnosis/genetics/mortality/*pathology MH - Humans MH - Male MH - Membrane Proteins/metabolism MH - Mice MH - Neoplasm Staging MH - Phosphotransferases (Alcohol Group Acceptor)/*metabolism MH - Prognosis MH - Serine C-Palmitoyltransferase/metabolism MH - Sphingosine N-Acyltransferase/metabolism MH - TOR Serine-Threonine Kinases/metabolism MH - Tumor Suppressor Proteins/metabolism MH - Xenograft Model Antitumor Assays EDAT- 2020/05/07 06:00 MHDA- 2021/08/10 06:00 CRDT- 2020/05/07 06:00 PHST- 2019/12/16 00:00 [received] PHST- 2020/03/05 00:00 [revised] PHST- 2020/04/08 00:00 [accepted] PHST- 2020/05/07 06:00 [pubmed] PHST- 2021/08/10 06:00 [medline] PHST- 2020/05/07 06:00 [entrez] AID - 01515467-202102000-00018 [pii] AID - 10.1002/hep.31304 [doi] PST - ppublish SO - Hepatology. 2021 Feb;73(2):692-712. doi: 10.1002/hep.31304. Epub 2020 Nov 26.