Tohoku J. Exp. Med., 2022 November, 258(3)

Decreased Expression of NRF2 Target Genes after Alcohol Exposure in the Background Esophageal Mucosa of Patients with Esophageal Squamous Cell Carcinoma

Shusuke Toda,¹ Waku Hatta,¹ Kiyotaka Asanuma,¹ Naoki Asano,¹ Yoshitaka Ono,¹ Hiroko Abe,¹ Yohei Ogata,¹ Masahiro Saito,¹ Takeshi Kanno,¹ Xiaoyi Jin,¹ Kaname Uno,¹ Tomoyuki Koike,¹ Akira Imatani,¹ Shin Hamada,¹ Tomohiro Nakamura,² Naoki Nakaya³ and Atsushi Masamune¹

¹Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
²Department of Health Record Informatics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
³Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan

Patients with esophageal squamous cell carcinoma (ESCC) might have a specific mechanism for the carcinogenesis by alcohol consumption in the background esophageal mucosa, and nuclear factor erythroid 2-related factor 2 (NRF2), which plays a protective role against esophageal carcinogenesis, and barrier dysfunction might be associated with this phenomenon. This study aimed to confirm this hypothesis. Twenty patients with superficial ESCCs (ESCC patients) and 20 age- and sex-matched patients without ESCC (non-ESCC patients) were enrolled. Biopsy samples were obtained from non-neoplastic esophageal mucosa: one for histological evaluation, one for quantitative real-time polymerase chain reaction (PCR), and two for the mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) and, thereafter, for PCR. The TEER after acetaldehyde or both acetaldehyde and ethanol exposure did not differ significantly between ESCC and non-ESCC patients. Unlike non-ESCC patients, mRNA levels of NRF2 target genes and claudin4 in ESCC patients tended to decrease after the exposure, with a significant difference between no exposure and both acetaldehyde and ethanol exposure in NRF2 target genes (p < 0.05). Furthermore, in ESCC patients, the decreased tendency of mRNA levels of NRF2 target genes after the exposure was more pronounced in high-risk states, such as aldehyde dehydrogenase 2 (ALDH2) Lys alleles (Glu/Lys + Lys/Lys), Lugol-voiding lesion grade C, and drinking history. In conclusion, the protective role of NRF2 against carcinogenesis from alcohol exposure might be disrupted in the background esophageal mucosa of ESCC patients, which might lead to a high incidence of metachronous ESCC.

Keywords —— acetaldehyde; esophageal mucosa; esophageal squamous cell carcinoma; ethanol; NRF2 target genes

© 2022 Tohoku University Medical Press

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Tohoku J. Exp. Med 2022, 258, 195-206.

Correspondence: Waku Hatta, M.D., Ph.D., Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: waku-style@festa.ocn.ne.jp