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Down-regulation of UL16-binding protein 3 mediated by interferon-gamma impairs immune killing in nasopharyngeal carcinoma.

ABSTRACT: BACKGROUND:Nasopharyngeal carcinoma (NPC) is a malignant tumor characterized by a large number of tumor-infiltrating lymphocytes and high expression of programmed death ligand-1 (PD-L1). Interferon-gamma (IFN-?) has proven to be the strongest inducers of PD-L1. This study aims at investigating the effect of IFN-? on the expression of natural killer group 2, member D ligands (NKG2DLs), a series of immune-activating proteins, and their further effect on immune killing in NPC. METHODS:RNA-seq data from the Gene Expression Omnibus database was downloaded and analyzed for the correlation between IFN-? and NKG2DLs. IHC staining of clinical biopsy samples was performed to support the correlation between IFN-? and ULBP3. Different NPC cell lines were treated with IFN-? (100 U/ml) and the expression of PD-L1 and ULBP3 were detected at different time points. The 5-8F cell lines with PD-L1 over-expression and ULBP3 knockout were established and the T-cell cytotoxicity assay was performed to investigate the effect of ULPB3 on cytotoxicity. RESULTS:Correlation analysis and IHC staining showed that the expression of ULBP3 had a significant negative correlation with IFN-? in NPC patients. The vitro assays revealed that ULBP3 can be time-dependently down-regulated by IFN-?. The cytotoxicity of CD8+ T-cells that were co-cultured with ULBP3 knockout 5-8F cells was significantly impaired compared to wild type 5-8F cells. CONCLUSIONS:IFN-? can significantly down-regulate the expression of ULBP3 in NPC. And the down-regulation of ULBP3 and the up-regulation of PD-L1 are both mediated by IFN-? and may collectively play a role in the inhibition of immune killing in NPC.

SUBMITTER: Guo L

PROVIDER: S-EPMC7653630 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Down-regulation of UL16-binding protein 3 mediated by interferon-gamma impairs immune killing in nasopharyngeal carcinoma.

Guo Lingling L Chen Yu Y Wang Jing J Chen Chuanben C

American journal of translational research 20201015 10

<h4>Background</h4>Nasopharyngeal carcinoma (NPC) is a malignant tumor characterized by a large number of tumor-infiltrating lymphocytes and high expression of programmed death ligand-1 (PD-L1). Interferon-gamma (IFN-γ) has proven to be the strongest inducers of PD-L1. This study aims at investigating the effect of IFN-γ on the expression of natural killer group 2, member D ligands (NKG2DLs), a series of immune-activating proteins, and their further effect on immune killing in NPC.<h4>Methods</h ...[more]

PMID: 33194048

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Project description:BACKGROUND:Transcription factor Sp1 is multifaceted, with the ability to function as an oncogene or a tumor suppressor, depending on the cellular context. We previously reported that Sp1 is required for the transcriptional activation of the key oncogenes in nasopharyngeal carcinoma (NPC), including B-lymphoma mouse Moloney leukemia virus insertion region 1 (Bmi1) and centromere protein H (CENPH), but the role of Sp1 and its underlying mechanisms in NPC remained largely unexplored. The objective of this study was to investigate the cellular function of Sp1 and to verify the clinical significance of Sp1 as a potential therapeutic target in NPC. METHODS:The levels of Sp1 in the normal primary nasopharyngeal epithelial cells (NPECs) and NPC cell lines were analyzed by Quantitative Real-time RT-PCR (qRT-PCR) and Western blot. The location and expression of Sp1 in the NPC tissues were detected by immunohistochemistry staining (IHC). The effect of Sp1 knockdown on the cell proliferation, clonogenicity, anchorage-independent growth and the stem-cell like phenotype in NPC cells were evaluated by MTT, flow cytometry, clonogenicity analysis and sphere formation assay. RESULTS:The mRNA and protein levels of Sp1 were elevated in NPC cell lines than in the normal primary NPECs. Higher expression of Sp1 was found in NPC tissues with advanced clinical stage (P=0.00036). Either inhibition of Sp1 activity by mithramycin A, the FDA-approved chemotherapeutic anticancer drug or Sp1 silencing by two distinct siRNA against Sp1 suppressed the growth of NPC cells. Mechanism analysis revealed that Sp1 silencing may suppress cell proliferation, clonogenicity, anchorage-independent growth and the stem-cell like phenotype through inducing the expression of p27 and p21, and impairing the expressions of the critical stem cell transcription factors (SCTFs), including Bmi1, c-Myc and KLF4 in NPC cells. CONCLUSIONS:Sp1 was enriched in advanced NPC tissues and silencing of Sp1 significantly inhibited cell proliferation, clonogenicity, anchorage-independent growth and the stem-cell like phenotype of NPC cells, suggesting Sp1 may serve as an appealing drug target for NPC.

Dataset Information

Down-regulation of UL16-binding protein 3 mediated by interferon-gamma impairs immune killing in nasopharyngeal carcinoma.

Publications

Down-regulation of UL16-binding protein 3 mediated by interferon-gamma impairs immune killing in nasopharyngeal carcinoma.

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