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.
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
Cell Rep. 2024 Apr 23;43(4):114104. doi: 10.1016/j.celrep.2024.114104. Epub 2024 Apr 10.
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 mutation and cancer driver mutant TRP53. Concomitant expression of NRF2 and TRP53 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 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 mutant mouse model developed here will be instrumental in elucidating the mechanistic basis leading to NRF2-activated ESCC.
临床证据表明，NRF2（NFE2L2）的体细胞突变引起的 NRF2 高水平激活在食管鳞状细胞癌（ESCC）中经常检测到，而 NRF2 的负调节剂 KEAP1 的体细胞突变引起的则不然。在这里，我们希望使用源自癌症的 NRF2 突变和癌症驱动突变 TRP53 来生成 NRF2 激活的 ESCC 小鼠模型。NRF2 和 TRP53 的共表达导致 NRF2 激活的 ESCC 样病变的形成。相比之下，虽然鳞状细胞特异性的 KEAP1 缺失诱导了类似的 NRF2 过度激活，但 KEAP1 的缺失加上 TRP53 的表达不会引发 ESCC 样病变的形成。相反，随着时间的推移，KEAP1 缺失的细胞从食管上皮中消失。这些发现表明，虽然细胞 NRF2 水平相似地被诱导，但 NRF2 功能获得和 KEAP1 功能丧失引发了鳞状细胞的不同命运。这里开发的 NRF2 突变小鼠模型将有助于阐明导致 NRF2 激活的 ESCC 的机制基础。
