{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T07:08:51Z","timestamp":1777100931112,"version":"3.51.4"},"reference-count":49,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T00:00:00Z","timestamp":1649721600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16H05175"],"award-info":[{"award-number":["16H05175"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K18483"],"award-info":[{"award-number":["20K18483"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hepatocyte growth factor (HGF) activator inhibitor type\u20101 (HAI\u20101), encoded by the <jats:italic>SPINT1<\/jats:italic>\u00a0gene, is a transmembrane protease inhibitor that regulates membrane\u2010anchored serine proteases, particularly matriptase. Here, we explored the role of HAI\u20101 in tongue squamous cell carcinoma (TSCC) cells. An immunohistochemical study of HAI\u20101 in surgically resected TSCC revealed the cell surface immunoreactivity of HAI\u20101 in the main portion of the tumor. The immunoreactivity decreased in the infiltrative front, and this decrease correlated with enhanced lymphatic invasion as judged by podoplanin immunostaining. In vitro homozygous deletion of <jats:italic>SPINT1<\/jats:italic> (HAI\u20101KO) in TSCC cell lines (HSC3 and SAS) suppressed the cell growth rate but significantly enhanced invasion in vitro. The loss of HAI\u20101 resulted in enhanced pericellular activities of proteases, such as matriptase and urokinase\u2010type plasminogen activator, which induced activation of HGF\/MET signaling in the co\u2010culture with pro\u2010HGF\u2010expressing fibroblasts and plasminogen\u2010dependent plasmin generation, respectively. The enhanced plasminogen\u2010dependent plasmin generation was abrogated partly by matriptase silencing. Culture supernatants of HAI\u20101KO cells had enhanced potency for converting the proform of vascular endothelial growth factor\u2010C (VEGF\u2010C), a lymphangiogenesis factor, into the mature form in a plasminogen\u2010dependent manner. Furthermore, HGF significantly stimulated VEGF\u2010C expression in TSCC cells. Orthotopic xenotransplantation into nude mouse tongue revealed enhanced lymphatic invasion of HAI\u20101KO TSCC cells compared to control cells. Our results suggest that HAI\u20101 insufficiency leads to dysregulated pericellular protease activity, which eventually orchestrates robust activation of protease\u2010dependent growth factors, such as HGF and VEGF\u2010C, in a tumor microenvironment to contribute to TSCC progression.<\/jats:p>","DOI":"10.1111\/cas.15346","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T07:31:23Z","timestamp":1648193483000},"page":"2179-2193","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Insufficiency of hepatocyte growth factor activator inhibitor\u20101 confers lymphatic invasion of tongue carcinoma cells"],"prefix":"10.1111","volume":"113","author":[{"given":"Aya","family":"Izumi","sequence":"first","affiliation":[{"name":"Section of Oncopathology and Regenerative Biology Department of Pathology Faculty of Medicine University of Miyazaki  Miyazaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Section of Oncopathology and Regenerative Biology Department of Pathology Faculty of Medicine University of Miyazaki  Miyazaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makiko","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"Section of Oncopathology and Regenerative Biology Department of Pathology Faculty of Medicine University of Miyazaki  Miyazaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumiki","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Section of Oncopathology and Regenerative Biology Department of Pathology Faculty of Medicine University of Miyazaki  Miyazaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9350-777X","authenticated-orcid":false,"given":"Tsuyoshi","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Section of Oncopathology and Regenerative Biology Department of Pathology Faculty of Medicine University of Miyazaki  Miyazaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takumi","family":"Kiwaki","sequence":"additional","affiliation":[{"name":"Section of Oncopathology and Regenerative Biology Department of Pathology Faculty of Medicine University of Miyazaki  Miyazaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Section of Oncopathology and Regenerative Biology Department of Pathology Faculty of Medicine University of Miyazaki  Miyazaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiro","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery Faculty of Medicine University of Miyazaki  Miyazaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9948-0451","authenticated-orcid":false,"given":"Hiroaki","family":"Kataoka","sequence":"additional","affiliation":[{"name":"Section of Oncopathology and Regenerative Biology Department of Pathology Faculty of Medicine University of Miyazaki  Miyazaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,4,12]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_7_3_1","first-page":"211","article-title":"Epidemiological and histopathological aspects of tongue squamous cell carcinomas \u2010 Retrospective study","volume":"44","author":"Ion Ciuc\u0103 M\u0103r\u0103\u015fescu FI","year":"2018","journal-title":"Curr Health Sci J"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.784924"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/pin.12647"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.10.6370"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20100046"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.26.18237"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1300705"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.051071"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.586"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19113435"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3205"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2014.09.008"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13156"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-0511"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20111020"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0702095104"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002941200"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-11-683110"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-02-001073"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.30426"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-3337"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-3728"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2010.01808.x"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0252197"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.3993"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13732"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1177\/002215549904700509"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.24450"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2015.02.009"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2007.10.005"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2010.03.012"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2257"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2018.00007"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology10020167"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208181"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.13.5687-5698.2005"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.071142"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209966"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.090053"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2011.02162.x"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.796789"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1023039230052"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1023051500010"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12733"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00405-011-1809-2"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.4.672"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2015.11.027"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M313130200"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.15346","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cas.15346","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.15346","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T03:41:41Z","timestamp":1692848501000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.15346"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,12]]},"references-count":49,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["10.1111\/cas.15346"],"URL":"https:\/\/doi.org\/10.1111\/cas.15346","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,12]]},"assertion":[{"value":"2022-01-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}