{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:10:32Z","timestamp":1788948632559,"version":"build-2803163510"},"reference-count":43,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372720"],"award-info":[{"award-number":["82372720"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"abstract":"Abstract<\/jats:title>\n \n Germline variations contribute to esophageal squamous cell carcinoma (ESCC) susceptibility. We identified a germline deletion (exons 7\u20138) in\n HIF3A<\/jats:italic>\n in an ESCC family and investigated its functional impact using CRISPR\/Cas9\u2010engineered cells and\n Hif3a<\/jats:italic>\n \u2010eKO1 mice (heterozygous for exons 7\u20138 deletion). Multi\u2010omics analysis of\n Hif3a<\/jats:italic>\n \u2010eKO1 and WT mice revealed dysregulated pathways in normal esophagus and during 4NQO\u2010induced carcinogenesis, with key biomarkers validated by immunohistochemistry.\n Hif3a<\/jats:italic>\n deficiency enhanced ESCC cell proliferation and invasion\n in vitro<\/jats:italic>\n and accelerated 4NQO\u2010induced tumorigenesis\n in vivo<\/jats:italic>\n , with\n Hif3a<\/jats:italic>\n \u2010eKO1 mice developing more and larger neoplastic lesions. Multi\u2010omics analysis revealed downregulation of cytokeratin\u2010related genes (notably Krt17) and \u03b3\u03b4 T cells in normal esophagus of\n Hif3a<\/jats:italic>\n \u2010eKO1 compared with WT. Consistently reduced Krt17 expression in\n Hif3a<\/jats:italic>\n \u2010eKO1 was confirmed by both esophageal immunohistochemistry and cellular Western blot analyses. During 4NQO\u2010induced carcinogenesis,\n Hif3a<\/jats:italic>\n deficiency upregulated DNA damage response markers, including Kr\u00fcppel\u2010like factor 4 (Klf4) and ATR serine\/threonine kinase (Atr). Notably, epithelial cells with abundant \u03b3H\n 2<\/jats:sub>\n AX foci lacked Krt17 expression, while Krt17\u2010positive cells showed minimal \u03b3H\n 2<\/jats:sub>\n AX foci. Heterozygous germline\n Hif3a<\/jats:italic>\n deletion (exons 7\u20138) may promote ESCC by disrupting esophageal barrier function\u2014impairing Krt17\u2010mediated epithelial integrity and reducing \u03b3\u03b4 T cells\u2014while exacerbating genomic instability. These findings reveal ESCC predisposition mechanisms and therapeutic targets. \u00a9 2026 The Pathological Society of Great Britain and Ireland.\n <\/jats:p>","DOI":"10.1002\/path.70106","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T09:55:22Z","timestamp":1788947722000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heterozygous germline deletion in\n \n Hif3a<\/i>\n <\/scp>\n exacerbates esophageal squamous cell carcinoma development"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7195-3845","authenticated-orcid":false,"given":"Yanli","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Pathology The First Affiliated Hospital of Shantou University Medical College Shantou PR China"},{"name":"Department of Pathology Shantou University Medical College Shantou PR 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