E3 ubiquitin ligase NEDD4L negatively regulates skin tumorigenesis by inhibiting of IL-6/GP130 signaling pathway

Interleukin (IL)-6 signaling plays a crucial role in the survival and metastasis of skin cancer. Neural precursor cell expressed developmentally downregulated 4-Like (NEDD4L) acts as a suppressor of IL-6 signaling by targeting glycoprotein 130 (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 (cSCC). Skin tumors were induced in wild type (WT) and Nedd4l knockout (KO) mice, and activation of the IL-6/GP130/STAT3 signaling pathway was detected. The results indicated a negative correlation between the protein expression levels of NEDD4L and GP130 in cSCC tissues from patients. Nedd4l deficiency significantly promoted DMBA/TPA-induced skin tumorigenesis and benign-to-malignant conversion by activating the IL-6/GP130/STAT3 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.