2. Academic Validation
  3. E3 Ubiquitin Ligase NEDD4L Negatively Regulates Skin Tumorigenesis by Inhibiting IL-6/GP130 Signaling Pathway

E3 Ubiquitin Ligase NEDD4L Negatively Regulates Skin Tumorigenesis by Inhibiting IL-6/GP130 Signaling Pathway

  • J Invest Dermatol. 2024 Apr 4:S0022-202X(24)00272-0. doi: 10.1016/j.jid.2024.03.030.
Huan Liu 1,  Ning Wang 2,  Run Yang 3,  Jing Luan 1,  Meng Cao 1,  Cui Zhai 1,  Shan Wang 1,  Mengqian Wei 1,  Duorong Wang 3,  Jiayue Qiao 3,  Yuqian Liu 4,  Wenting She 4,  Na Guo 5,  Bo Liao 6,  Xingchun Gou 7
Affiliations

Affiliations

  • 1 Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China; Shaanxi Provincial Key Laboratory of Brain Diseases, Xi'an Medical University, Xi'an, China.
  • 2 Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.
  • 3 School of Clinical Medicine, Xi'an Medical University, Xi'an, China.
  • 4 College of pharmacy, Xi'an Medical University, Xi'an, China.
  • 5 Department of Immunology, Xi'an Medical University, Xi'an, China.
  • 6 Department of Orthopedics, Tangdu Hospital, Air Force Military Medical University, Xi'an, China. Electronic address: liaobo@fmmu.edu.cn.
  • 7 Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China; Shaanxi Provincial Key Laboratory of Brain Diseases, Xi'an Medical University, Xi'an, China. Electronic address: go@xiyi.edu.cn.
PMID: 38580105 DOI: 10.1016/j.jid.2024.03.030
Abstract

IL-6 signaling plays a crucial role in the survival and metastasis of skin Cancer. NEDD4L acts as a suppressor of IL-6 signaling by targeting GP130 degradation. However, the effects of the NEDD4L-regulated IL-6/GP130 signaling pathway on skin Cancer remain unclear. In this study, protein expression levels of NEDD4L and GP130 were measured in tumor tissues from patients with cutaneous squamous cell carcinoma. Skin tumors were induced in wild-type and Nedd4l-knockout mice, and activation of the IL-6/GP130/signal transducer and activator of transcription 3 signaling pathway was detected. The results indicated a negative correlation between the protein expression levels of NEDD4L and GP130 in cutaneous squamous cell carcinoma tissues from patients. Nedd4l deficiency significantly promoted 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin tumorigenesis and benign-to-malignant conversion by activating the IL-6/GP130/signal transducer and activator of transcription 3 signaling pathway, which was abrogated by supplementation with the GP130 inhibitor SC144. Furthermore, our findings suggested that NEDD4L can interact with GP130 and promote its ubiquitination in skin tumors. In conclusion, our results indicate that NEDD4L could act as a tumor suppressor in skin Cancer, and inhibition of GP130 could be a potential therapeutic method for treating this disease.

Keywords

GP130; NEDD4L; SC144; Skin cancer; Ubiquitination.

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