Acylcarnitines promote gallbladder cancer metastasis through lncBCL2L11-THOC5-JNK axis

作者：Yang Yang, Huaifeng Li, Ke Liu, Lu Zou, Shanshan Xiang, Yajun Geng, Xuechuan Li, Shimei Qiu, Jiahua Yang, Xuya Cui, Lin Li, Yang Li, Weijian Li, Siyuan Yan, Liguo Liu, Xiangsong Wu, Fatao Liu, Wenguang Wu, Shili Chen, Yingbin Liu · 发表于：Journal of Translational Medicine · 年份：2024 · DOI：10.1186/s12967-024-05091-0 · 被引用次数：11 · 研究领域：Cancer, Lipids, and Metabolism、RNA modifications and cancer、Peroxisome Proliferator-Activated Receptors

Abstract Background The progression of gallbladder cancer (GBC) is accompanied by abnormal fatty acid β-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 acylcarnitine...