RNF182 induces p65 ubiquitination to affect PDL1 transcription and suppress immune evasion in lung adenocarcinoma
Open Access
- 22 May 2023
- journal article
- research article
- Published by Wiley in Immunity, Inflammation and Disease
- Vol. 11 (5), e864
- https://doi.org/10.1002/iid3.864
Abstract
BackgroundThe RING finger (RNF) proteins are a large group of ubiquitin ligases whose aberrant expression is often associated with disease progression. This study examines the function of RNF protein 182 (RNF182) in lung adenocarcinoma (LUAD) cells and its impact on p65 and programmed death ligand 1 (PDL1) regulation. MethodsExpression of RNF182, p65, and PDL1 in LUAD tissues and cells was measured using immunohistochemistry, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and/or western blot (WB) assays. LUAD cells were induced to overexpress RNF182 and p65, followed by cell counting kit-8, colony formation, Transwell, and flow cytometry assays to evaluate the cells' malignant phenotype. Coimmunoprecipitation and WB assays were used to verify RNF182's effect on p65 ubiquitination. Chromatin immunoprecipitation-qPCR and luciferase assays were used to analyze p65's transcriptional regulation of PDL1. Coculture of LUAD with CD8(+) cytotoxic T cells was performed to detect lactate dehydrogenase release and interferon-gamma and interleukin-2 concentrations. LUAD cells were implanted in mice to analyze tumorigenicity. ResultsRNF182 was poorly expressed, while p65 and PDL1 were highly expressed in LUAD tissues and cells. RNF182 overexpression suppressed the malignant properties of LUAD cells, and it promoted p65 ubiquitination and protein degradation. p65 activated PDL1 transcription. Overexpression of RNF182 suppressed the PDL1 expression, increased the cytotoxicity in LUAD cells cocultured with CD8(+) T cells, and suppressed the tumorigenesis of cancer cells in vivo. However, these tumor-suppressive effects of RNF182 on LUAD cells were blocked by p65 restoration. ConclusionThis research demonstrates that RNF182 induces p65 ubiquitination to suppress PDL1 transcription and immunosuppression in LUAD.Keywords
This publication has 40 references indexed in Scilit:
- Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escapeMolecular Cancer, 2019
- Phosphorylated RB Promotes Cancer Immunity by Inhibiting NF-κB Activation and PD-L1 ExpressionMolecular Cell, 2018
- CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A reviewJournal of Cellular Physiology, 2018
- A patent review of the ubiquitin ligase system: 2015–2018Expert Opinion on Therapeutic Patents, 2018
- LPS promotes the expression of PD‐L1 in gastric cancer cells through NF‐κB activationJournal of Cellular Biochemistry, 2018
- Co-expression of NF-κB-p65 and phosphorylated NF-κB-p105 is associated with poor prognosis in surgically resectable non-small cell lung cancerJournal of Cellular and Molecular Medicine, 2018
- Cancer statistics, 2018CA: A Cancer Journal for Clinicians, 2018
- Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective StudyPLoS Medicine, 2016
- NF-κB Expression and Outcomes in Solid TumorsMedicine, 2015
- Impaired T-bet-pSTAT1α and perforin-mediated immune responses in the tumoral region of lung adenocarcinomaBritish Journal of Cancer, 2015