Tumor exosomal RNPEP promotes lung metastasis of liver cancer via inducing cancer‐associated fibroblast activation

Abstract

Cancer‐associated fibroblasts (CAFs) are essential players in the tumor microenvironment (TME) due to their roles in facilitating tumor progression and metastasis. It is worth noting that the high‐metastatic hepatocellular carcinoma (HCC) cell‐derived exosomes have exhibited the ability to transform normal fibroblasts into CAFs, which further fosters the lung metastasis of low‐metastatic HCC cells. Yet, the mechanisms underlying this tumor exosome‐induced 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‐metastatic HCC cells showed augmented RNPEP expression levels in their exosomes. These exosomes induced obvious CAF‐like properties in the human fibroblast cell line MRC‐5, as evidenced by the increased CAF marker expression, and enhanced migratory ability. More strikingly, the secretions from high‐metastatic tumor exosome‐educated MRC‐5 cells increased tumor stemness and promoted epithelial–mesenchymal transition (EMT) in MHCC‐97L cells, a low‐metastatic HCC cell line. However, the knockdown of RNPEP in exosomes from high‐metastatic HCC cells abated the changes described above. Animal studies in vivo highlighted the pro‐tumor and pro‐metastatic effects of exosomal RNPEP on MHCC‐97L cells by inducing CAF activation. Furthermore, tumor‐derived exosomal RNPEP induced the activation of NF‐κB signaling in MRC‐5 cells, a critical pathway associated with CAF activation. Collectively, these results provide novel insight into tumor‐derived exosomal RNPEP for its crosstalk with CAFs during HCC lung metastasis.