{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T04:50:58Z","timestamp":1749185458890,"version":"3.40.5"},"reference-count":39,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T00:00:00Z","timestamp":1672704000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP18ck0106252"],"award-info":[{"award-number":["JP18ck0106252"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19H03789","19K07469","22H0284"],"award-info":[{"award-number":["19H03789","19K07469","22H0284"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>A distinct subset of lung adenocarcinomas (LADs), arising from a series of peripheral lung cells defined as the terminal respiratory unit (TRU), is characterised by thyroid transcription factor 1 (TTF\u20101) expression. The clinical relevance of transcription factors (TFs) other than TTF\u20101 remains unknown in LAD and was explored in the present study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Seventy\u2010one LAD samples were subjected to high\u2010throughput transcriptome screening of LAD using cap analysis gene expression (CAGE) sequencing data; CAGE provides genome\u2010wide expression levels of the transcription start sites (TSSs). In total, 1083 invasive LAD samples were subjected to immunohistochemical examination for paired box 9 (PAX9) and TTF\u20101 expression levels. <jats:italic>PAX9<\/jats:italic> is an endoderm development\u2010associated TF that most strongly and inversely correlates with the expression of <jats:italic>TTF\u20101<\/jats:italic> TSS subsets. Immunohistochemically, PAX9 expression was restricted to the nuclei of ciliated epithelial and basal cells in the bronchi and bronchioles and the nuclei of epithelial cells of the bronchial glands; moreover, PAX9 expression was observed in 304 LADs (28%). PAX9\u2010positive LADs were significantly associated with heavy smoking, non\u2010lepidic subtype, <jats:italic>EGFR<\/jats:italic> wild\u2010type tumours and PD\u2010L1 expression (all <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.0001). All these characteristics were opposite to those of TRU\u2010type LADs with TTF\u20101 expression. PAX9 expression was an independent prognostic factor for decreased overall survival (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.022).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results revealed that PAX9 expression defines an aggressive subset of LADs preferentially occurring in smokers that may arise from bronchial or bronchiolar cells.<\/jats:p><\/jats:sec>","DOI":"10.1111\/his.14853","type":"journal-article","created":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T06:26:25Z","timestamp":1671258385000},"page":"672-683","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Expression of paired box 9 defines an aggressive subset of lung adenocarcinoma preferentially occurring in smokers"],"prefix":"10.1111","volume":"82","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8544-9370","authenticated-orcid":false,"given":"Takuo","family":"Hayashi","sequence":"first","affiliation":[{"name":"Department of Human Pathology Juntendo University Graduate School of Medicine  Bunkyo\u2010ku, Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monami","family":"Kishi","sequence":"additional","affiliation":[{"name":"Department of Human Pathology Juntendo University Graduate School of Medicine  Bunkyo\u2010ku, Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuya","family":"Takamochi","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery Juntendo University Graduate School of Medicine  Bunkyo\u2010ku, Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaki","family":"Hosoya","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Juntendo University Graduate School of Medicine  Bunkyo\u2010ku, Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinji","family":"Kohsaka","sequence":"additional","affiliation":[{"name":"Division of Cellular Signaling National Cancer Center Research Institute  Chuo\u2010ku, Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satsuki","family":"Kishikawa","sequence":"additional","affiliation":[{"name":"Department of Human Pathology Juntendo University Graduate School of Medicine  Bunkyo\u2010ku, Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayako","family":"Ura","sequence":"additional","affiliation":[{"name":"Department of Human Pathology Juntendo University Graduate School of Medicine  Bunkyo\u2010ku, Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kei","family":"Sano","sequence":"additional","affiliation":[{"name":"Department of Human Pathology Juntendo University Graduate School of Medicine  Bunkyo\u2010ku, Tokyo"},{"name":"Department of Medicine for Orthopaedics and Motor Organ Juntendo University Graduate School of Medicine  Bunkyo\u2010ku, Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noriko","family":"Sasahara","sequence":"additional","affiliation":[{"name":"Department of Human Pathology Juntendo University Graduate School of Medicine  Bunkyo\u2010ku, Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiyuki","family":"Suehara","sequence":"additional","affiliation":[{"name":"Department of Medicine for Orthopaedics and Motor Organ Juntendo University Graduate School of Medicine  Bunkyo\u2010ku, Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumiyuki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Juntendo University Graduate School of Medicine  Bunkyo\u2010ku, Tokyo 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