Leptin-mediated suppression of lipoprotein lipase cleavage enhances lipid uptake and facilitates lymph node metastasis in gastric cancer  

作　　者：Jian Xiao Shuqing Cao Jiawei Wang Pengyu Li Quan Cheng Xinyi Zhou Jiacheng Dong Yuan Li Xinyu Zhao Zekuan Xu Li Yang 

机构地区：[1]Department of General Surgery,The First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu,P.R.China

出　　处：《Cancer Communications》2024年第8期855-878,共24页癌症通讯（英文）

基　　金：National Natural Science Foundation of China,Grant/Award Number:81874219;Jiangsu Province Capability Improvement Project through Science,Technology,and Education,Grant/Award Number:ZDXK202222。

摘　　要：Background:Lymph node metastasis(LNM)is the primary mode of metastasis in gastric cancer(GC).However,the precise mechanisms underlying this process remain elusive.Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis,yet the role of lipoprotein lipase(LPL),a pivotal enzyme involved in exogenous lipid uptake,remains uncertain in tumor metastasis.Therefore,the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process.Methods:Intracellular lipid levels were quantified using oil red O staining,BODIPY 493/503 staining,and flow cytometry.Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown.Protein expression levels were assessed through immunohistochemistry,Western blotting,and enzyme-linked immunosorbent assays.The mouse popliteal LNM model was utilized to investigate differences in LNM.Immunoprecipitation and mass spectrometry were employed to examine protein associations.In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4(ANGPTL4)phosphorylation.Results:We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive(N+)GC and further demonstrated that a high-fat diet can expedite LNM.LPL was found to be significantly overexpressed in N+GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells.Leptin,an obesity-related hormone,intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage.Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1(IRE1)kinase,leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL.Moreover,our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid,which then tri

关 键 词：angiopoietin-like protein 4 LEPTIN lipoprotein lipase lymph node metastasis prostaglandin E2 

分 类 号：R733[医药卫生—肿瘤]