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<p>Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer. Unfortunately, this knowledge has not yet led to any breakthrough in cancer therapy. Thrombin is the key enzyme of blood coagulation system. The identification of a direct link between thrombin and the tumor progression remains unknown. We illustrated thrombin expression in lung adenocarcinoma (LUAD) was closely related to clinicopathological features, prognosis, and chemotherapy outcome of patients via TCGA and clinical pathological analysis. Using genetic and pharmacological approaches, we showed a direct link between thrombin catalytic activity and lung cancer progression in vitro and in vivo. Furthermore, we revealed that thrombin cleaves epidermal growth factor receptor (EGFR) at a GRG motif perfectly conserved across disparate species, indicating functional importance, which results in activation of EGFR/AKT/mTOR signaling pathway. Last we found the mutual interaction between thrombin and chemotherapy resistance. Combination therapy of thrombin inhibitor and chemotherapy results in improved anti-tumor efficacy. Together, our data firstly revealed a mechanism of cancer progression and chemotherapy resistance that involves thrombin-mediated EGFR cleavage. We propose that thrombin could be a prognostic biomarker for lung cancer, blockade of thrombin is a valuable therapeutic strategy to overcome cancer’s resistance to chemotherapy.</p>

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The coagulation and tumor system are directly linked through the proteolysis and activation of epidermal growth factor receptor by thrombin

  • 期刊论文

  • 发表日期：

    2025年2月5日

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  • Tianfa Wang,
  • Zhiyuan Shen,
  • Liu Yang,
  • Xiaohan Zhang,
  • Min Yu,
  • Sanjian Yu,
  • Bing Zhao

摘要

Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer. Unfortunately, this knowledge has not yet led to any breakthrough in cancer therapy. Thrombin is the key enzyme of blood coagulation system. The identification of a direct link between thrombin and the tumor progression remains unknown. We illustrated thrombin expression in lung adenocarcinoma (LUAD) was closely related to clinicopathological features, prognosis, and chemotherapy outcome of patients via TCGA and clinical pathological analysis. Using genetic and pharmacological approaches, we showed a direct link between thrombin catalytic activity and lung cancer progression in vitro and in vivo. Furthermore, we revealed that thrombin cleaves epidermal growth factor receptor (EGFR) at a GRG motif perfectly conserved across disparate species, indicating functional importance, which results in activation of EGFR/AKT/mTOR signaling pathway. Last we found the mutual interaction between thrombin and chemotherapy resistance. Combination therapy of thrombin inhibitor and chemotherapy results in improved anti-tumor efficacy. Together, our data firstly revealed a mechanism of cancer progression and chemotherapy resistance that involves thrombin-mediated EGFR cleavage. We propose that thrombin could be a prognostic biomarker for lung cancer, blockade of thrombin is a valuable therapeutic strategy to overcome cancer’s resistance to chemotherapy.