Jin Xiaoye, Lou Xiayuan, Qi Haoxiang, Zheng Chao, Li Bo, Siwu Xuerong, Liu Ren, Lv Qiaoli, Zhao An, Ruan Jian, Jiang Ming
Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China.
Oncogenesis. 2024 Sep 27;13(1):35. doi: 10.1038/s41389-024-00536-z.
The activation of nuclear factor erythroid 2-related factor 2 (NRF2) has been observed in various cancers. Yet its exact contribution to the development of head and neck squamous cell carcinoma (HNSCC) remains undetermined. We previously found that NRF2 signaling is critical for the differentiation of squamous basal progenitor cells, while disruption of NRF2 causes basal cell hyperplasia. In this study, we revealed a correlation between elevated NRF2 activity and poor outcomes in HNSCC patients. We demonstrated that NRF2 facilitates tumor proliferation, migration, and invasion, as evidenced by both in vitro and in vivo studies. Significantly, NRF2 augments the expression of the antioxidant enzyme GPX2, thereby enhancing the proliferative, migratory, and invasive properties of HNSCC cells. Activation of GPX2 is critical for sustaining cancer stem cells (CSCs) by up-regulating NOTCH3, a key driver of cancer progression. These results elucidate that NRF2 regulates HNSCC progression through the NRF2-GPX2-NOTCH3 axis. Our findings proposed that pharmacological targeting of the NRF2-GPX2-NOTCH3 axis could be a potential therapeutic approach against HNSCC.
在多种癌症中均观察到核因子红细胞2相关因子2（NRF2）的激活。然而，其对头颈部鳞状细胞癌（HNSCC）发展的确切作用仍未明确。我们之前发现NRF2信号传导对鳞状基底祖细胞的分化至关重要，而NRF2的破坏会导致基底细胞增生。在本研究中，我们揭示了HNSCC患者中NRF2活性升高与不良预后之间的相关性。我们证明NRF2促进肿瘤增殖、迁移和侵袭，体外和体内研究均证实了这一点。值得注意的是，NRF2增强抗氧化酶GPX2的表达，从而增强HNSCC细胞的增殖、迁移和侵袭特性。GPX2的激活对于通过上调NOTCH3（癌症进展的关键驱动因素）来维持癌症干细胞（CSC）至关重要。这些结果阐明了NRF2通过NRF2 - GPX2 - NOTCH3轴调节HNSCC进展。我们的研究结果表明，对NRF2 - GPX2 - NOTCH3轴进行药物靶向可能是一种针对HNSCC的潜在治疗方法。
