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Abstract
Poor prognosis of head and neck squamous cell carcinomas (HNSCCs) results from resistance to chemotherapy and radiotherapy. To uncover the drivers of HNSCC resistance, including stemness and hypoxia, in this study, we compared the gene expression between CD44+ and CD44- HNSCC cells and assessed the correlation of CD44 and hypoxia-inducible factor 1α (HIF-1α) expression with mouse features and outcomes of patients with HNSCC. We combined the knockdown or activation of HIF-1α with in vitro and in vivo assays to evaluate effects on stemness and resistance of HNSCC cells. Analysis of clinical data showed that activation of HIF-1α in CD44+ patients with HNSCC was correlated with worse prognosis. Functional assays showed that HIF-1α promoted stemness, resistance, and epithelial-mesenchymal transition in HNSCC CD44+ cells. HIF-1α activated NOTCH1 signaling in HNSCC stem-like cells characterized by CD44 expression. Moreover, inhibition of these signaling proteins using shRNA or Evofosfamide (Evo) development for cancer treatment, reversed chemoresistance in vitro and in vivo. Taken together, our results indicated that targeting HIF-1α attenuated NOTCH1-induced stemness, which regulates responses to chemotherapy or radiotherapy and malignancy in CD44+ HNSCCs. HIF-1α/NOTCH1 signaling may represent a target for HNSCC treatment.

Affiliations

Joo-Yun Byun #  1 , Kun Huang #  2 , Jong Suk Lee #  1 , Wenjie Huang  3 , Li Hu  2 , Xuyu Zheng  2 , Xin Tang  2 , Fengzeng Li  2 , Dong-Gyu Jo  4 , Xinmao Song  5 , Chuang Huang  6
1 School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
2 Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
3 Key Laboratory of Diagnostic Medicine designated by the Ministry of Education, Chongqing Medical University, Chongqing, China.
4 School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea. jodg@skku.edu.
5 Department of Radiation Oncology, Eye, Ear, Nose and Throat Hospital of Fudan University, Shanghai, China. muqinger@sina.com.
6 Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China. huangchuang@126.com.
# Contributed equally.