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Nevertheless, thrombin expression in non\u2010small cell lung cancer (NSCLC) primary tumour tissues and the association between prognosis of NSCLC patients remain largely unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Clinical pathological analysis was performed to determine the relationship between thrombin and tumour progression. Effects of r\u2010hirudin and direct thrombin inhibitor peptide (DTIP) on cancer progression were evaluated. Western blotting, immunohistochemistry, and immunofluorescence were used to explore the inhibition mechanism of r\u2010hirudin and DTIP. The therapeutic effect of the combination of DTIP and chemotherapy was determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Thrombin expression in NSCLC tissues was closely related to clinicopathological features and the prognosis of patients. Thrombin deficiency inhibited tumour progression. The novel thrombin inhibitors, r\u2010hirudin and DTIP, inhibited cell invasion and metastasis in vitro. They inhibited tumour growth and metastasis in orthotopic lung cancer model, inhibited cell invasion, and prolonged survival after injection of tumour cells via the tail vein. They also inhibited angiogenesis and spontaneous metastases from subcutaneously inoculated tumours. The promotion by thrombin of invasion and metastasis was abolished in PAR\u20101\u2010deficient NSCLC cells. r\u2010hirudin and DTIP inhibited tumour progression through the thrombin\u2010PAR\u20101\u2010mediated RhoA and NF\u2010\u03baB signalling cascades via inhibiting MMP9 and IL6 expression. DTIP potentiated chemotherapy\u2010induced growth and metastatic inhibition and inhibited chemotherapy\u2010induced resistance in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Thrombin makes a substantial contribution, together with PAR\u20101, to NSCLC malignancy. The anti\u2010coagulants, r\u2010hirudin and DTIP, could be used in anti\u2010tumour therapy and a combination of DTIP and chemotherapy might improve therapeutic effects.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15384","type":"journal-article","created":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T03:44:51Z","timestamp":1611373491000},"page":"5056-5073","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["A novel oncotherapy strategy: Direct thrombin inhibitors suppress progression, dissemination and spontaneous metastasis in non\u2010small cell lung cancer"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3852-9781","authenticated-orcid":false,"given":"Bing","family":"Zhao","sequence":"first","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education Fudan University  Shanghai China"},{"name":"Department of Biochemistry and Molecular 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