PMID- 38519939 OWN - NLM STAT- MEDLINE DCOM- 20240325 LR - 20240325 IS - 1479-5876 (Electronic) IS - 1479-5876 (Linking) VI - 22 IP - 1 DP - 2024 Mar 22 TI - Acylcarnitines promote gallbladder cancer metastasis through lncBCL2L11-THOC5-JNK axis. PG - 299 LID - 10.1186/s12967-024-05091-0 [doi] LID - 299 AB - BACKGROUND: The progression of gallbladder cancer (GBC) is accompanied by abnormal fatty acid beta-oxidation (FAO) metabolism. Different types of lipids perform various biological functions. This study aimed to determine the role of acyl carnitines in the molecular mechanisms of GBC progression. METHODS: Distribution of lipids in GBC was described by LC-MS-based lipidomics. Cellular localization, expression level and full-length of lncBCL2L11 were detected using fluorescence in situ hybridization (FISH) assays, subcellular fractionation assay and 5' and 3' rapid amplification of the cDNA ends (RACE), respectively. In vitro and in vivo experiments were used to verify the biological function of lncBCL2L11 in GBC cells. Methylated RNA Immunoprecipitation (MeRIP) was performed to detect the methylation levels of lncBCL2L11. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were used to identify lncBCL2L11 interacting proteins. Co-Immunoprecipitation (Co-IP) and Western blot assay were performed to validate the regulatory mechanism of lncBCL2L11 and THO complex. RESULTS: Acylcarnitines were significantly up-regulated in GBC tissues. High serum triglycerides correlated to decreased survival in GBC patients and promoted tumor migration. LncBCL2L11 was identified in the joint analysis of highly metastatic cells and RNA sequencing data. LncBCl2L11 prevented the binding of THOC6 and THOC5 and causes the degradation of THOC5, thus promoting the accumulation of acylcarnitines in GBC cells, leading to the malignant progression of cancer cells. In addition, highly expressed acylcarnitines stabilized the expression of lncBCL2L11 through N(6)-methyladenosine methylation (m6A), forming a positive feedback regulation in tumor dissemination. CONCLUSIONS: LncBCL2L11 is involved in gallbladder cancer metastasis through FAO metabolism. High lipid intake is associated with poor prognosis of GBC. Therefore, targeting lncBCL2L11 and its pathway-related proteins or reducing lipid intake may be significant for the treatment of GBC patients. CI - (c) 2024. The Author(s). FAU - Yang, Yang AU - Yang Y AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. FAU - Li, Huaifeng AU - Li H AD - Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. FAU - Liu, Ke AU - Liu K AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. FAU - Zou, Lu AU - Zou L AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. FAU - Xiang, Shanshan AU - Xiang S AD - Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. FAU - Geng, Yajun AU - Geng Y AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. FAU - Li, Xuechuan AU - Li X AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. FAU - Qiu, Shimei AU - Qiu S AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. AD - University of Shanghai for Science and Technology, Shanghai, 200093, China. FAU - Yang, Jiahua AU - Yang J AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. FAU - Cui, Xuya AU - Cui X AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. FAU - Li, Lin AU - Li L AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. FAU - Li, Yang AU - Li Y AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. FAU - Li, Weijian AU - Li W AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. FAU - Yan, Siyuan AU - Yan S AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. FAU - Liu, Liguo AU - Liu L AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. FAU - Wu, Xiangsong AU - Wu X AD - Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. FAU - Liu, Fatao AU - Liu F AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. fasterliu@163.com. FAU - Wu, Wenguang AU - Wu W AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. wuwenguang08@126.com. FAU - Chen, Shili AU - Chen S AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. chenshilichem@163.com. AD - Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. chenshilichem@163.com. FAU - Liu, Yingbin AU - Liu Y AUID- ORCID: 0000-0001-6110-0185 AD - Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. laoniulyb@shsmu.edu.cn. LA - eng GR - 82173048/Innovative Research Group Project of the National Natural Science Foundation of China/ GR - 81874181/National Natural Science Foundation of China/ GR - 82103253/National Natural Science Foundation of China/ GR - 2022XD010/Shanghai Municipal Health Commission/ GR - 22Y1908000/Science and Technology Innovation Plan Of Shanghai Science and Technology Commission/ PT - Journal Article DEP - 20240322 PL - England TA - J Transl Med JT - Journal of translational medicine JID - 101190741 RN - 0 (acylcarnitine) RN - 63231-63-0 (RNA) RN - 0 (Lipids) RN - 0 (THOC5 protein, human) RN - 0 (Nuclear Proteins) RN - 0 (THOC6 protein, human) RN - 0 (RNA-Binding Proteins) RN - S7UI8SM58A (Carnitine) SB - IM MH - Humans MH - *Gallbladder Neoplasms/genetics MH - In Situ Hybridization, Fluorescence MH - RNA MH - Lipids MH - Cell Line, Tumor MH - Cell Proliferation MH - Gene Expression Regulation, Neoplastic MH - Nuclear Proteins/metabolism MH - RNA-Binding Proteins/genetics MH - Carnitine/*analogs & derivatives PMC - PMC10958842 OTO - NOTNLM OT - Acylcarnitine OT - Gallbladder cancer OT - Lipid OT - lncBCL2L11 COIS- The authors declare no potential competing interests. EDAT- 2024/03/23 20:43 MHDA- 2024/03/25 06:44 PMCR- 2024/03/22 CRDT- 2024/03/23 01:26 PHST- 2023/10/03 00:00 [received] PHST- 2024/03/13 00:00 [accepted] PHST- 2024/03/25 06:44 [medline] PHST- 2024/03/23 20:43 [pubmed] PHST- 2024/03/23 01:26 [entrez] PHST- 2024/03/22 00:00 [pmc-release] AID - 10.1186/s12967-024-05091-0 [pii] AID - 5091 [pii] AID - 10.1186/s12967-024-05091-0 [doi] PST - epublish SO - J Transl Med. 2024 Mar 22;22(1):299. doi: 10.1186/s12967-024-05091-0.