Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function
Jun Takahashi,
Takafumi Suzuki,
Miu Sato,
Shuji Nitta,
Nahoko Yaguchi,
Tatsuki Muta,
Kouhei Tsuchida,
Hiromi Suda,
Masanobu Morita,
Shin Hamada,
Atsushi Masamune,
Satoru Takahashi,
Takashi Kamei,
Masayuki Yamamoto
Affiliations
Jun Takahashi
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan; Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
Takafumi Suzuki
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan; Corresponding author
Miu Sato
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan
Shuji Nitta
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan
Nahoko Yaguchi
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan
Tatsuki Muta
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan
Kouhei Tsuchida
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan
Hiromi Suda
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan
Masanobu Morita
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan
Shin Hamada
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
Atsushi Masamune
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
Satoru Takahashi
Laboratory Animal Resource Center in Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan
Takashi Kamei
Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
Masayuki Yamamoto
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan; Corresponding author
Summary: Clinical evidence has revealed that high-level activation of NRF2 caused by somatic mutations in NRF2 (NFE2L2) is frequently detected in esophageal squamous cell carcinoma (ESCC), whereas that caused by somatic mutations in KEAP1, a negative regulator of NRF2, is not. Here, we aspire to generate a mouse model of NRF2-activated ESCC using the cancer-derived NRF2L30F mutation and cancer driver mutant TRP53R172H. Concomitant expression of NRF2L30F and TRP53R172H results in formation of NRF2-activated ESCC-like lesions. In contrast, while squamous-cell-specific deletion of KEAP1 induces similar NRF2 hyperactivation, the loss of KEAP1 combined with expression of TRP53R172H does not elicit the formation of ESCC-like lesions. Instead, KEAP1-deleted cells disappear from the esophageal epithelium over time. These findings demonstrate that, while cellular NRF2 levels are similarly induced, NRF2 gain of function and KEAP1 loss of function elicits distinct fates of squamous cells. The NRF2L30F mutant mouse model developed here will be instrumental in elucidating the mechanistic basis leading to NRF2-activated ESCC.
