{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:02:35Z","timestamp":1791414155349,"version":"4.3.3"},"reference-count":50,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T00:00:00Z","timestamp":1721865600000},"content-version":"unspecified","delay-in-days":24,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82160129"],"award-info":[{"award-number":["82160129"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital","award":["CY2023-ZD01"],"award-info":[{"award-number":["CY2023-ZD01"]}]},{"name":"Gansu Province Innovation Driven Assistance Project","award":["GXH20230817-14"],"award-info":[{"award-number":["GXH20230817-14"]}]},{"name":"Medical Innovation and Development Project of Lanzhou University","award":["lzuyxcx-2022-160"],"award-info":[{"award-number":["lzuyxcx-2022-160"]}]},{"name":"Medical Innovation and Development Project of Lanzhou University","award":["lzuyxcx-2022-45"],"award-info":[{"award-number":["lzuyxcx-2022-45"]}]},{"name":"Medical Innovation and Development Project of Lanzhou University","award":["lzuyxcx-2022-88"],"award-info":[{"award-number":["lzuyxcx-2022-88"]}]},{"name":"Science and technology project of Chengguan District of Lanzhou City","award":["2020JSCX0073"],"award-info":[{"award-number":["2020JSCX0073"]}]},{"name":"Science and technology project of Chengguan District of Lanzhou City","award":["2020SHFZ0039"],"award-info":[{"award-number":["2020SHFZ0039"]}]},{"name":"Key Talents Project of Gansu Province","award":["2019RCXM020"],"award-info":[{"award-number":["2019RCXM020"]}]},{"name":"Key Project of Science and Technology in Gansu province","award":["22ZD6FA054"],"award-info":[{"award-number":["22ZD6FA054"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,7,12]]},"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The high metastasis rate is one of the main reasons for the poor prognosis of patients with hepatocellular carcinoma (HCC). Coagulation factor Xa (FXa) and its receptor proteinase-activated receptor-2 (PAR-2) proven to promote tumor metastasis in other forms of cancer. Here, we explore the role and mechanism of FXa in the regulation of resistance of anoikis and immune escape of HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In vitro and in vivo experiments were conducted to explore the role of FXa in HCC metastasis and its potential mechanism. The effects of FXa inhibitor rivaroxaban on HCC immunotherapy were evaluated using intrahepatic metastasis animal models and clinical trial (No. ChiCTR20000040540). We investigated the potential of FXa inhibition as a treatment for HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      FXa was highly expressed in HCC and promoted metastasis by activating PAR-2. Mechanistically, FXa-activated PAR-2 endows HCC cells with the ability of anoikis resistance to survive in the circulating blood by inhibiting the extrinsic apoptosis pathway. Furthermore, suspension stimulation-induced phosphorylation of STAT2, which promotes programmed death-ligand 1 (PD-L1) transcription and inhibits the antitumor effects of immune cells by inhibiting the infiltration of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in tumors and the levels of secreted cytokines. In vivo inhibition of FXa with rivaroxaban reduced HCC metastasis by decreasing PD-L1 expression and exhausting tumor-infiltrating lymphocytes. Notably, the combination of rivaroxaban and anti-programmed death-1 monoclonal antibody (anti-PD-1) programmed Death-1 monoclonal antibody (anti-PD-1) induced synergistic antitumor effects in animal models. Most importantly, rivaroxaban improved the objective response rate of patients with HCC to immune checkpoint inhibitors and prolonged overall survival time.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>FXa-activated PAR-2 promotes anoikis resistance and immune escape in HCC, suggesting the potential for combining coagulation inhibitors and PD-1\/PD-L1 immune checkpoint blockade to enhance the therapeutic efficacy of HCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-009565","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T01:41:15Z","timestamp":1721958075000},"page":"e009565","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["FXa-mediated PAR-2 promotes the efficacy of immunotherapy for hepatocellular carcinoma through immune escape and anoikis resistance by inducing PD-L1 transcription"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9728-098X","authenticated-orcid":false,"given":"Xuemei","family":"Li","sequence":"first","affiliation":[{"name":"The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"},{"name":"Gansu Provincial Key Laboratory of Environmental Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Gao","sequence":"additional","affiliation":[{"name":"The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"},{"name":"Gansu Provincial Key Laboratory of Environmental Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bofang","family":"Wang","sequence":"additional","affiliation":[{"name":"The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"},{"name":"Gansu Provincial Key Laboratory of Environmental Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jike","family":"Hu","sequence":"additional","affiliation":[{"name":"The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"},{"name":"Gansu Provincial Key Laboratory of Environmental Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yu","sequence":"additional","affiliation":[{"name":"The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"},{"name":"Gansu Provincial Key Laboratory of Environmental Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baohong","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Li","sequence":"additional","affiliation":[{"name":"The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"},{"name":"Gansu Provincial Key Laboratory of Environmental Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9629-4052","authenticated-orcid":false,"given":"Yunpeng","family":"Wang","sequence":"additional","affiliation":[{"name":"The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China"},{"name":"Gansu Provincial Key Laboratory of Environmental Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 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