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A dysfunctional mitochondrial aldehyde dehydrogenase 2 (Aldh2) delays the clearance of acetaldehyde, a genotoxic alcohol metabolite, and increases SCC risks. TP53 plays key roles in squamous carcinogenesis. However, the mechanism of alcohol-mediated squamous field cancerization has not been clearly elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We developed a novel genetically engineered mouse strain\n                      <jats:italic>KTPA<\/jats:italic>\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      (\n                      <jats:italic>Krt5Cre<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>ERT2<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>; Trp53<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>loxp\/loxp<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>; Aldh2<\/jats:italic>\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      ) featuring\n                      <jats:italic>Aldh2<\/jats:italic>\n                      -loss concurrent with epithelial-specific\n                      <jats:italic>Trp53<\/jats:italic>\n                      deletion. These mice were given 10%-EtOH, and we evaluated the development of squamous cell carcinogenesis histologically and genetically.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Widespread multifocal rete ridges (RRs), characterized by downward growth of proliferative preneoplastic cells, were found only in\n                      <jats:italic>Aldh2<\/jats:italic>\n                      <jats:sup>\n                        +\n                        <jats:italic>\/<\/jats:italic>\n                        \u2013\n                      <\/jats:sup>\n                      and\n                      <jats:italic>Aldh2<\/jats:italic>\n                      <jats:sup>\n                        \u2013\n                        <jats:italic>\/<\/jats:italic>\n                        \u2013\n                      <\/jats:sup>\n                      mice with keratin5-specific Trp53 deletion (\n                      <jats:italic>KTPA<\/jats:italic>\n                      <jats:sup>\n                        +\n                        <jats:italic>\/\u2013<\/jats:italic>\n                      <\/jats:sup>\n                      and\n                      <jats:italic>KTPA<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2013\/\u2013<\/jats:italic>\n                      <\/jats:sup>\n                      mice, respectively), and alcohol drinking apparently increased RR formation rate. SCC occurred only in\n                      <jats:italic>KTPA<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2013\/\u2013<\/jats:italic>\n                      <\/jats:sup>\n                      (\n                      <jats:italic>Aldh2<\/jats:italic>\n                      loss\n                      <jats:italic>\/TP53<\/jats:italic>\n                      loss) mice with alcohol drinking (15\/18: 83%). Total alcohol consumption volume was significantly higher in\n                      <jats:italic>KTPA<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2013\/\u2013<\/jats:italic>\n                      <\/jats:sup>\n                      (\n                      <jats:italic>Aldh2<\/jats:italic>\n                      loss\n                      <jats:italic>\/TP53<\/jats:italic>\n                      loss) mice with SCCs than those without SCCs. Further, target sequence revealed the occurrence of genetic abnormalities including\n                      <jats:italic>Trp53<\/jats:italic>\n                      mutations in the esophageal epithelium of\n                      <jats:italic>Aldh2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2013\/\u2013<\/jats:italic>\n                      <\/jats:sup>\n                      mice with alcohol drinking, suggesting direct mutagenic effects of alcohol drinking to the esophageal epithelium.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study provides for the first time the evidence that alcohol drinking,\n                      <jats:italic>Aldh2<\/jats:italic>\n                      dysfunction and\n                      <jats:italic>Trp53<\/jats:italic>\n                      loss cooperate in squamous field cancerization. Alcohol consumption volume affects the SCCs development, even in the same genotype.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00535-024-02210-y","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T22:30:19Z","timestamp":1738794619000},"page":"546-560","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Aldh2 and the tumor suppressor Trp53 play important roles in alcohol-induced squamous field cancerization"],"prefix":"10.1007","volume":"60","author":[{"given":"Yuki","family":"Kondo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1776-4309","authenticated-orcid":false,"given":"Shinya","family":"Ohashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chikatoshi","family":"Katada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukie","family":"Nakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Tamaoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Kikuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenshiro","family":"Hirohashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Mitani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeki","family":"Kataoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trang H. 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