Exposure of benzo[a]pyrene induces HCC exosome-circular RNA to activate lung fibroblasts and trigger organotropic metastasis  

作　　者：Wei Mu Pengfei Gu Huating Li Jinjin Zhou Yulun Jian Weiping Jia Yang Ge 

机构地区：[1]School of Public Health,Center for Single-cell Omics,Shanghai Jiao Tong University School of Medicine,Shanghai,P.R.China [2]Shanghai Key Laboratory of Diabetes Mellitus,Department of Endocrinology and Metabolism,Shanghai Diabetes Institute,Shanghai Clinical Center for Diabetes,Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,P.R.China

出　　处：《Cancer Communications》2024年第7期718-738,共21页癌症通讯（英文）

基　　金：National Nature Science Foundation,Grant/Award Numbers:82173543,81902939;Innovative Research Team of High-level Local Universities in Shanghai,Grant/Award Number:SHSMU-ZLCX20211602;Key laboratory of the Ministry of Education Foundation,Grant/Award Number:2022-MEKLLC-MS-003;Sanming Project of Medicine in Shenzhen,Grant/Award Number:SZSM202311019;Shanghai Key Discipline of Public Health,Grant/Award Number:GWVI-11.1-20;Shanghai Science and Technology Development Funds,Grant/Award Number:23QA1405700。

摘　　要：Background:Benzo[a]pyrene(B[a]P),a carcinogen pollutant produced by combustion processes,is present in the western diet with grilled meats.Chronic exposure of B[a]P in hepatocellular carcinoma(HCC)cells promotes metastasis rather than primary proliferation,implying an unknown mechanism of B[a]P-induced malignancy.Given that exosomes carry bioactive molecules to distant sites,we investigated whether and how exosomes mediate cancer-stroma communications for a toxicologically associated microenvironment.Method:Exosomes were isolated from B[a]P stimulated BEL7404 HCC cells(7404-100Bap Exo)at an environmental relevant dose(100 nmol/L).Lung preeducation animal model was prepared via injection of exosomes and cytokines.The inflammatory genes of educated lungs were evaluated using quantitative reverse transcription PCR array.HCC LM3 cells transfected with firefly luciferase were next injected to monitor tumor burdens and organotropic metastasis.Profile of B[a]P-exposed exosomes were determined by ceRNA microarray.Interactions between circular RNA(circRNA)and microRNAs(miRNAs)were detected using RNA pull-down in target lung fibroblasts.Fluorescence in situ hybridization and RNA immunoprecipitation assay was used to evaluate the“on-off”interaction of circRNA-miRNA pairs.We further developed an adenoassociated virus inhalation model to examine mRNA expression specific in lung,thereby exploring the mRNA targets of B[a]P induced circRNA-miRNA cascade.Results:Lung fibroblasts exert activation phenotypes,including focal adhesion and motility were altered by 7404-100Bap Exo.In the exosome-educated in vivo model,fibrosis factors and pro-inflammatory molecules of are up-regulated when injected with exosomes.Compared to non-exposed 7404 cells,circ_0011496 was up-regulated following B[a]P treatment and wasmainly packaged into 7404-100Bap Exo.Exosomal circ_0011496 were delivered and competitively bound to miR-486-5p in recipient fibroblasts.The down-regulation of miR-486-5p converted fibroblast to cancer-associated fibroblast via

关 键 词：benzo(a)pyrene cancer associate fibroblast circular RNA EXOSOME organotropic metastasis 

分 类 号：R73-37[医药卫生—肿瘤]