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It is worth noting that the high\u2010metastatic hepatocellular carcinoma (HCC) cell\u2010derived exosomes have exhibited the ability to transform normal fibroblasts into CAFs, which further fosters the lung metastasis of low\u2010metastatic HCC cells. Yet, the mechanisms underlying this tumor exosome\u2010induced metastatic niche formation are poorly explored. In this study, the secreted protein arginyl aminopeptidase (RNPEP) was highly expressed in the plasma of patients with HCC. In addition, high\u2010metastatic HCC cells showed augmented RNPEP expression levels in their exosomes. These exosomes induced obvious CAF\u2010like properties in the human fibroblast cell line MRC\u20105, as evidenced by the increased CAF marker expression, and enhanced migratory ability. More strikingly, the secretions from high\u2010metastatic tumor exosome\u2010educated MRC\u20105 cells increased tumor stemness and promoted epithelial\u2013mesenchymal transition (EMT) in MHCC\u201097L cells, a low\u2010metastatic HCC cell line. However, the knockdown of RNPEP in exosomes from high\u2010metastatic HCC cells abated the changes described above. Animal studies in\u00a0vivo highlighted the pro\u2010tumor and pro\u2010metastatic effects of exosomal RNPEP on MHCC\u201097L cells by inducing CAF activation. Furthermore, tumor\u2010derived exosomal RNPEP induced the activation of NF\u2010\u03baB signaling in MRC\u20105 cells, a critical pathway associated with CAF activation. Collectively, these results provide novel insight into tumor\u2010derived exosomal RNPEP for its crosstalk with CAFs during HCC lung metastasis.<\/jats:p>","DOI":"10.1111\/cas.16417","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T04:13:53Z","timestamp":1733890433000},"page":"792-807","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Tumor exosomal <scp>RNPEP<\/scp> promotes lung metastasis of liver cancer via inducing cancer\u2010associated fibroblast activation"],"prefix":"10.1111","volume":"116","author":[{"given":"Yuankun","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Tropical and Liver Diseases The Second Affiliated Hospital of Hainan Medical University  Haikou China"},{"name":"Department of Clinical Laboratory The Second Affiliated Hospital of Hainan Medical University  Haikou 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