Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function

被引：8

作者：

Takahashi, Jun ^{[1
,2
]}

Suzuki, Takafumi ^{[1
]}

Sato, Miu ^{[1
]}

Nitta, Shuji ^{[1
]}

Yaguchi, Nahoko ^{[1
]}

Muta, Tatsuki ^{[1
]}

Tsuchida, Kouhei ^{[1
]}

Suda, Hiromi ^{[1
]}

Morita, Masanobu ^{[1
]}

Hamada, Shin ^{[3
]}

Masamune, Atsushi ^{[3
]}

Takahashi, Satoru ^{[4
]}

Kamei, Takashi ^{[2
]}

Yamamoto, Masayuki ^{[1
]}

机构：

[1] Tohoku Univ, Dept Biochem & Mol Biol, Tohoku Med Megabank Org, 2-1 Seiryo machi,Aoba ku, Sendai, Japan

[2] Tohoku Univ, Dept Surg, Grad Sch Med, Sendai, Japan

[3] Tohoku Univ, Grad Sch Med, Div Gastroenterol, Sendai, Japan

[4] Univ Tsukuba, Lab Anim Resource Ctr Transborder Med Res Ctr, Tsukuba, Japan

来源：

CELL REPORTS | 2024年 / 43卷 / 04期

关键词：

E3; LIGASE; OXIDATIVE STRESS; LUNG-CANCER; DEGRADATION; ACTIVATION; MUTATIONS; GROWTH; GENE; RECOGNITION; RESISTANCE;

D O I：

10.1016/j.celrep.2024.114104

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 NRF2 L30F mutation and cancer driver mutant TRP53 R172H . Concomitant expression of NRF2 L30F and TRP53 R172H 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 TRP53 R172H 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 NRF2 L30F mutant mouse model developed here will be instrumental in elucidating the mechanistic basis leading to NRF2-activated ESCC.

引用

页数：21

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