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E3 Ubiquitin Ligase RNF125 Suppresses Immune Escape in Head and Neck Squamous Cell Carcinoma by Regulating PD-L1 Expression

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Abstract

Head and neck squamous cell carcinoma (HNSCC) is a lethal malignancy. Given the essential roles of E3 ligases in cancer immunotherapies, this paper explored the effect of E3 ubiquitin ligase ring finger protein 125 (RNF125) on immune escape in HNSCC. After delivering overexpressed (oe)-RNF125, interferon-gamma, or oe-programmed death-ligand 1 (PD-L1) into HNSCC cells and cell culture with carboxyfluorescein succinimidyl ester-labeled CD8+ T cells, RNF125 and PD-L1 levels were determined via RT-qPCR and Western blot, with HNSCC cell behaviors assessed via colony formation assay, Transwell assays and flow cytometry, and inflammatory factors measured via ELISA. PD-L1 ubiquitination level and PD-L1’s interaction with RNF125 were analyzed via co-immunoprecipitation. The in vivo action of RNF125 on HNSCC was validated via nude mouse tumorigenicity assay. Briefly, RNF125 was weakly expressed in HNSCC cells. RNF125 overexpression inhibited immune escape of HNSCC cells, evidenced by decreased TSCCA cell proliferation, migration, and invasion, increased CD8+ T cell proliferation, and elevated IL-2 and TNF-α levels. RNF125 downregulated PD-L1 in TSCCA cells and facilitated PD-L1 ubiquitinational degradation. PD-L1 overexpression partially abated RNF125-mediated suppression on TSCCA cell immune escape. Moreover, RNF125 suppressed tumorigenesis and tumor growth in vivo. Overall, RNF125 promoted PD-L1 ubiquitinational degradation, hence inhibiting immune escape in HNSCC.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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  1. Department of Head and Neck Radiotherapy (One), Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Tongzipo Road, Yuelu District, Changsha, 410013, Hunan, China

    Cuihong Jiang, Lili He, Shuai Xiao, Wenqiong Wu, Qi Zhao & Feng Liu

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CHJ is guarantor of integrity of the entire study and responsible for study concepts, manuscript review; LLH is responsible for study design, definition of intellectual content, data analysis, manuscript preparation; SX is responsible for literature research, experimental studies; WQW is responsible for clinical studies, manuscript editing; QZ is responsible for data acquisition; FL is responsible for statistical analysis; All authors read and approved the final manuscript.

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Correspondence to Cuihong Jiang.

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The animal-associated experimental procedures were ratified by the ethics committee for animal welfare at Hunan Cancer Hospital (Approval number: 2022-085). Significant efforts were contributed to the reduction of animal number and suffering. The animal experiments have been carried out in accordance with the ARRIVE guidelines.

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Jiang, C., He, L., Xiao, S. et al. E3 Ubiquitin Ligase RNF125 Suppresses Immune Escape in Head and Neck Squamous Cell Carcinoma by Regulating PD-L1 Expression. Mol Biotechnol 65, 891–903 (2023). https://doi.org/10.1007/s12033-022-00587-w

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