2. Academic Validation
  3. LncRNA EUDAL shapes tumor cell response to hypoxia-induced constitutive EGFR activation and promotes chemoresistance in oral cancer

LncRNA EUDAL shapes tumor cell response to hypoxia-induced constitutive EGFR activation and promotes chemoresistance in oral cancer

  • Int J Oral Sci. 2025 Sep 12;17(1):64. doi: 10.1038/s41368-025-00396-2.
Shengkai Chen # 1 2 3,  Zhenlin Dai # 4,  Jianbo Shi # 1 2 3,  Mengyu Rui 1 2 3,  Zhiyuan Zhang 5 6 7,  Qin Xu 8 9 10
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
  • 2 Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
  • 3 National Clinical Research Center for Oral Disease, Shanghai, China.
  • 4 Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 5 Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China. zhiyuan.zhang@sh9hospital.org.cn.
  • 6 Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China. zhiyuan.zhang@sh9hospital.org.cn.
  • 7 National Clinical Research Center for Oral Disease, Shanghai, China. zhiyuan.zhang@sh9hospital.org.cn.
  • 8 Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China. xuqin_2004@hotmail.com.
  • 9 Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China. xuqin_2004@hotmail.com.
  • 10 National Clinical Research Center for Oral Disease, Shanghai, China. xuqin_2004@hotmail.com.
  • # Contributed equally.
PMID: 40940319 DOI: 10.1038/s41368-025-00396-2
Abstract

Hypoxia and aberrant activation of epidermal growth factor receptor (EGFR) are considered important features of various malignancies. However, whether hypoxia can directly trigger EGFR activation and its clinical implications remain unclear. In this study, we demonstrated that in oral Cancer, a typical hypoxic tumor, hypoxia can induce chronic but constitutive phosphorylation of wild-type EGFR in the absence of ligands. Oral Cancer cell lines exhibit different EGFR phosphorylation responses to hypoxia. In hypoxic HN4 and HN6 cells, ubiquitination-mediated endocytosis, lysosomal sorting, and degradation lead to low levels of EGFR phosphorylation. However, in CAL-27 and HN30 cells, a novel HIF-1α-induced long noncoding RNA (lncRNA), EUDAL, can compete with the E3 Ligase/adaptor complex c-Cbl/Grb2 for binding to EGFR, stabilizing phosphorylated EGFR (pEGFR) and resulting in sustained activation of EGFR and its downstream STAT3/BNIP3 signaling. STAT3/BNIP3-mediated Autophagy leads to antitumor drug resistance. A high EUDAL/EGFR/STAT3/Autophagy pathway activation predicts poor response to chemotherapy in oral Cancer patients. Collectively, hypoxia can induce noncanonical ligand-independent EGFR phosphorylation. High EUDAL expression facilitates sustained EGFR phosphorylation in hypoxic tumor cells and leads to autophagy-related drug resistance.

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