NRF2 signaling plays an essential role in cancer progression through the NRF2-GPX2-NOTCH3 axis in head and neck squamous cell carcinoma
Xiaoye Jin,
Xiayuan Lou,
Haoxiang Qi,
Chao Zheng,
Bo Li,
Xuerong Siwu,
Ren Liu,
Qiaoli Lv,
An Zhao,
Jian Ruan,
Ming Jiang
Affiliations
Xiaoye Jin
Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Xiayuan Lou
Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Haoxiang Qi
School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University
Chao Zheng
Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Bo Li
Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Xuerong Siwu
Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Ren Liu
Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Qiaoli Lv
Institute of Cancer Research, Jiangxi Cancer Hospital
An Zhao
Institute of Cancer Research, Zhejiang Cancer Hospital
Jian Ruan
Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University and Key Laboratory of Cancer Prevention and Intervention, Ministry of Education
Ming Jiang
Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Abstract 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.
