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

Oncogene (2026)Cite this article

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Abstract

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.

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Fig. 1: The protein level of plasmin in HCC is closely related to clinicopathological features and the prognosis of patients.
Fig. 2: Plasmin plays an important role in the invasion and metastasis of HCC cells.
Fig. 3: Plasmin plays an important role in the progression of HCC in mouse model.
Fig. 4: Plasmin inhibitor exerts anti-invasion and anti-metastatic abilities in vitro and in vivo.
Fig. 5: CXCR4 is a receptor for plasmin.
Fig. 6: Plasmin promotes HCC progression via PI3K/AKT/mTOR signaling pathway.
Fig. 7: Combination therapy of plasmin inhibitor and chemotherapy results in improved anti-tumor efficacy.

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Data availability

The datasets utilized and/or analyzed during this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (NSFC 82273293), Shanghai Municipal Health Commission Health Industry Clinical Research Project (20224Y0120).

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Authors and Affiliations

  1. Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Qidong-Fudan Innovative Institute of Medical Sciences, Fudan University, Shanghai, China

    Zhiyuan Shen, Tianyu Mao, Fangyan Wu, Fengming Li, Liu Yang, Min Yu & Bing Zhao

  2. Department of Basic Medical Sciences, Qinghai University Medical College, Qinghai University, Xining, Qinghai, China

    Yuexing Yang

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Contributions

ZB and SZ and YM performed all of the experiments. YY, MT, and YL participated in the research. ZB and SZ designed experiments, analyzed data, and wrote the paper. WF and LF collected the clinical samples. All authors read and approved the final manuscript.

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Correspondence to Min Yu or Bing Zhao.

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The authors declare no competing interests.

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The animal experiments were conducted in strict accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) of Fudan University Shanghai Cancer Center. Approval for these experiments was obtained under the following permission numbers: FUSCC-IACUC-20220228-169 (Shanghai, China). All experiments using human tissues were performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Fudan University, Approval for these experiments was obtained under the following permission numbers: FUSCC-IACUC-2022-C016 (Shanghai, China). All methods were performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Fudan University.

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Shen, Z., Yang, Y., Mao, T. et al. Plasmin promotes hepatocellular carcinoma invasion and metastasis via CXCR4-mediated activation of PI3K/AKT/mTOR signaling. Oncogene (2026). https://doi.org/10.1038/s41388-026-03775-z

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