{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T01:22:23Z","timestamp":1790558543163,"version":"4.1.0"},"reference-count":44,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"7","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Nature Science Foundation","award":["82173543"],"award-info":[{"award-number":["82173543"]}]},{"name":"National Nature Science Foundation","award":["81902939"],"award-info":[{"award-number":["81902939"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Commun"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">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\u2010induced malignancy. Given that exosomes carry bioactive molecules to distant sites, we investigated whether and how exosomes mediate cancer\u2010stroma communications for a toxicologically associated microenvironment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Method<\/jats:title>\n                    <jats:p xml:lang=\"en\">Exosomes were isolated from B[a]P stimulated BEL7404 HCC cells (7404\u2010100Bap Exo) at an environmental relevant dose (100 nmol\/L). Lung pre\u2010education 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\u2010exposed exosomes were determined by ceRNA microarray. Interactions between circular RNA (circRNA) and microRNAs (miRNAs) were detected using RNA pull\u2010down in target lung fibroblasts. Fluorescence in situ hybridization and RNA immunoprecipitation assay was used to evaluate the \u201con\u2010off\u201d interaction of circRNA\u2010miRNA pairs. We further developed an adeno\u2010associated virus inhalation model to examine mRNA expression specific in lung, thereby exploring the mRNA targets of B[a]P induced circRNA\u2010miRNA cascade.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">Lung fibroblasts exert activation phenotypes, including focal adhesion and motility were altered by 7404\u2010100Bap Exo. In the exosome\u2010educated in vivo model, fibrosis factors and pro\u2010inflammatory molecules of are up\u2010regulated when injected with exosomes. Compared to non\u2010exposed 7404 cells, circ_0011496 was up\u2010regulated following B[a]P treatment and was mainly packaged into 7404\u2010100Bap Exo. Exosomal circ_0011496 were delivered and competitively bound to miR\u2010486\u20105p in recipient fibroblasts. The down\u2010regulation of miR\u2010486\u20105p converted fibroblast to cancer\u2010associated fibroblast via regulating the downstream of Twinfilin\u20101 (TWF1) and matrix metalloproteinase\u20109 (MMP9) cascade. Additionally, increased TWF1, specifically in exosomal circ_0011496 educated lungs, could promote cancer\u2010stroma crosstalk via activating vascular endothelial growth factor (VEGF). These modulated fibroblasts promoted endothelial cells angiogenesis and recruited primary HCC cells invasion, as a consequence of a pre\u2010metastatic niche formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p xml:lang=\"en\">We demonstrated that B[a]P\u2010induced tumor exosomes can deliver circ_0011496 to activate miR\u2010486\u20105p\/TWF1\/MMP9 cascade in the lung fibroblasts, generating a feedback loop that promoted HCC metastasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.12574","type":"journal-article","created":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T02:58:20Z","timestamp":1717642700000},"page":"718-738","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Exposure of benzo[a]pyrene induces HCC exosome\u2010circular RNA to activate lung fibroblasts and trigger organotropic metastasis"],"prefix":"10.34133","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2828-8096","authenticated-orcid":false,"given":"Wei","family":"Mu","sequence":"first","affiliation":[{"name":"Shanghai Jiao Tong University School of Medicine","place":["Shanghai, P. 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