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 · 发表于：癌症：英文版 · 年份：2024 · DOI：10.1002/cac2.12574 · 被引用次数：45 · 研究领域：Extracellular vesicles in disease、Circular RNAs in diseases、Toxic Organic Pollutants Impact

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 pre-education 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 adeno-associated virus inhalation model to examine mRNA expression specific in lung, thereby exploring the mRNA targets of B[a]P induced circRNA-miRNA cascade. RESULT...