Aldh2 and the tumor suppressor Trp53 play important roles in alcohol-induced squamous field cancerization

Sep 23, 2026

Background: Field cancerization in the upper aerodigestive tract is linked to excessive alcohol intake. Aldh2 dysfunction delays acetaldehyde clearance, elevating squamous cell carcinoma (SCC) risk, and TP53 is central to squamous carcinogenesis, yet the mechanism of alcohol-driven field cancerization remains unclear. Methods: Genetically engineered mice combining Aldh2 loss with epithelial Trp53 deletion were exposed to ethanol. Results: Multifocal rete ridges and SCC development occurred in KTPA–/– mice (Aldh2 and Trp53 loss) with alcohol drinking, with higher alcohol intake in SCC-bearing animals and detected Trp53 mutations in esophageal epithelium. Conclusion: Alcohol, Aldh2 dysfunction, and Trp53 loss cooperate in squamous field cancerization.

LanguageEnglish

CategoryHealthcare

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Pages15

Reading Time38 min

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J Gastroenterol (2025) 60:546–560 [https://doi.org/10.1007/s00535-024-02210-y](https://doi.org/10.1007/s00535-024-02210-y) ORIGINAL ARTICLE—ALIMENTARY TRACT Aldh2 and the tumor suppressor Trp53 play important roles in alcohol‑induced squamous field cancerization Yuki Kondo1,2 · Shinya Ohashi1,3 · Chikatoshi Katada1 · Yukie Nakai1 · Yoshihiro Yamamoto1 · Masashi Tamaoki1 · Osamu Kikuchi1 · Atsushi Yamada1 · Kenshiro Hirohashi1 · Yosuke Mitani1 · Shigeki Kataoka1 · Tomoki Saito1 · Trang H. Nguyen Vu1 · Tomohiro Kondo1 · Yu Uneno1 · Tomohiko Sunami1 · Akira Yokoyama1 · Junichi Matsubara1 · Tomonari Matsuda4 · Seiji Naganuma5 · Kohei Oryu6 · Samuel Flashner7 · Masataka Shimonosono7 · Hiroshi Nakagawa7 · Manabu Muto1 Received: 30 August 2024 / Accepted: 30 December 2024 / Published online: 6 February 2025 © The Author(s) 2025 Abstract Background Field cancerization defined by multiple development of squamous cell carcinomas (SCCs) in upper aerodigestive tract was explained by excessive alcohol intake. 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. Methods We developed a novel genetically engineered mouse strain KTPA–/–(Krt5CreERT2; Trp53loxp/loxp; Aldh2–/–) Supplementary Information The online version contains supplementary material available at [https://doi.org/10.1007/](https://doi.org/10.1007/)[ ](https://doi.org/10.1007/)[s00535-024-02210-y](s00535-024-02210-y). * Shinya Ohashi [ohashish@kuhp.kyoto-u.ac.jp](ohashish@kuhp.kyoto-u.ac.jp) 1 Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto 606-8507, Japan 2 Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan 3 Preemptive Medicine and Lifestyle Disease Research Center, Kyoto University Hospital, Kyoto, Japan 4 Environment Health Division, Kyoto University Graduate School of Engineering, Kyoto, Japan 5 Faculty of Health Sciences, Department of Medical Laboratory Science, Kochi Gakuen University, Kochi, Japan 6 Faculty of Health Sciences, Department of Nutrition, Kochi Gakuen University, Kochi, Japan 7 Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, USA featuring Aldh2-loss concurrent with epithelial-specific Trp53 deletion. These mice were given 10%-EtOH, and we evaluated the development of squamous cell carcinogenesishistologically and genetically. Results Widespread multifocal rete ridges (RRs), characterized by downward growth of proliferative preneoplastic cells, were found only in Aldh2+/– and Aldh2–/– mice with keratin5-specific Trp53 deletion (KTPA+/– and KTPA–/– mice, respectively), and alcohol drinking apparently increased RR formation rate. SCC occurred only in KTPA–/–(Aldh2 loss/TP53 loss) mice with alcohol drinking (15/18: 83%) . Total alcohol consumption volume was significantly higher in KTPA–/–(Aldh2 loss/TP53 loss) mice with SCCs than those without SCCs. Further, target sequence revealed the occurrence of genetic abnormalities including Trp53 mutations in the esophageal epithelium of Aldh2–/– mice with alcohol drinking, suggesting direct mutagenic effects of alcohol drinking to the esophageal epithelium. Conclusion This study provides for the first time the evidence that alcohol drinking, Aldh2 dysfunction and Trp53 loss cooperate in squamous field cancerization. Alcohol consumption volume affects the SCCs development, even in the same genotype. Keywords Field cancerization · SCC · Alcohol-drinking · Aldh2 · TP53 Abbreviations AA Acetaldehyde Aldh2 Aldehyde-dehdrogenase2 ESCC Esophageal squamous cell carcinoma EtOH Ethanol HGIEN High-

FAQs

What is field cancerization in the context of this study?

Field cancerization refers to the multiple development of squamous cell carcinomas arising within the upper aerodigestive tract. The study links this concept to alcohol intake and its downstream molecular effects.

How do Aldh2 dysfunction and Trp53 loss relate to squamous carcinogenesis here?

Aldh2 dysfunction delays acetaldehyde clearance after alcohol drinking, promoting genotoxic stress. TP53 plays key roles in squamous carcinogenesis, and the study tests their cooperation when both pathways are disrupted.

What evidence supports that alcohol drinking directly contributes to esophageal epithelium mutations?

Target sequence analysis revealed genetic abnormalities, including Trp53 mutations, in the esophageal epithelium of Aldh2–/– mice with alcohol drinking. This suggests mutagenic effects of alcohol drinking on the local epithelium.

Sep 23, 2026

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