Plasmin promotes hepatocellular carcinoma invasion and metastasis via CXCR4-mediated activation of PI3K/AKT/mTOR signaling.

Cancer-associated hyperfibrinolysis are potentially fatal outcomes of advanced cancer. Unfortunately, this knowledge has not yet led to any breakthrough in cancer therapy. Plasmin is the key enzyme of fibrinolytic system. The identification of a direct link between plasmin and the tumor progression remains unknown. Here, we demonstrated that plasmin expression was significantly upregulated in HCC tissue, especially tumor tissues from patients who had received chemotherapy. Through in vitro and in vivo models, we showed that plasmin enhanced HCC cell invasion and migration. Pharmacological inhibition of plasmin with tranexamic acid (TXA) suppressed tumor invasion and metastasis. Mechanistically, we identified plasmin could directly bind to CXCR4, which potentiated the CXCL12/CXCR4 interaction and activated the PI3K/AKT/mTOR signaling pathway. Moreover, CDDP-resistant cells had higher expression of plasmin and stronger invasion and metastasis ability, which were effectively suppressed by plasmin inhibitor, and combining TXA with CDDP synergistically inhibited tumor progression and metastasis in mouse model and human HCC organoids. Our findings reveal a novel plasmin-CXCR4 axis driving HCC dissemination and suggest that targeting plasmin may enhance the efficacy of conventional chemotherapy.