Abstract
Nasopharyngeal carcinoma (NPC) is one of the most common tumors of head and neck in the Southeast Asia. PD-L1-dependent immune escape plays a critical role involved in NPC development. BPIFB1 has previously reported to take tumor-suppressive actions on NPC cell proliferation and migration. Nonetheless, the function of BPIFB1 in immune escape remains largely elusive. Expression pattern on mRNA and protein levels of target genes in NPC patients’ samples and cell lines were examined by qRT-PCR, western blot, and immunohistochemistry staining, respectively. The assessment of CD8+ T-cell apoptosis and expression was determined by flow cytometry. Molecular interactions were verified using chromatin immunoprecipitation (ChIP) and luciferase reporter assay. BPIFB1 was downregulated in NPC tumor tissues, exhibiting a negative correlation of PD-L1. Overexpression of BPIFB1 significantly inhibited the expression of PD-L1, suppressing the apoptosis and enhancing the expression of CD8+ T cells. Mechanistically, BPIFB1 was found to repress the expression of STAT1, which was identified to be an upstream activator of PD-L1. Furthermore, the EBV-encoded miR-BART4 overexpressed in NPC cells could directly target and inhibit BPIFB1. This study provided a comprehensive understanding of the molecular mechanism for the upstream and downstream pathway of BPIFB1 related with immune escape, indicating a novel approach for the treatment of NPC.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
All data generated or analyzed during this study are included in this published article.
References
Bingle CD, Seal RL, Craven CJ (2011) Systematic nomenclature for the PLUNC/PSP/BSP30/SMGB proteins as a subfamily of the BPI fold-containing superfamily. Biochem Soc Trans 39:977–983. https://doi.org/10.1042/BST0390977
Chang ET, Ye W, Zeng YX, Adami HO (2021) The evolving epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 30:1035–1047. https://doi.org/10.1158/1055-9965.EPI-20-1702
Chen CJ et al (2014) Epidemiology of virus infection and human cancer. Recent Results Cancer Res 193:11–32. https://doi.org/10.1007/978-3-642-38965-8_2
Ferris RL et al (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375:1856–1867. https://doi.org/10.1056/NEJMoa1602252
Harrington KJ et al (2017) Nivolumab versus standard, single-agent therapy of investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncol 18:1104–1115. https://doi.org/10.1016/S1470-2045(17)30421-7
Jiang X et al (2022) BPIFB1 inhibits vasculogenic mimicry via downregulation of GLUT1-mediated H3K27 acetylation in nasopharyngeal carcinoma. Oncogene 41:233–245. https://doi.org/10.1038/s41388-021-02079-8
Li J et al (2020) Molecular biology of BPIFB1 and its advances in disease. Ann Transl Med 8:651. https://doi.org/10.21037/atm-20-3462
Liao Q et al (2014) LPLUNC1 suppresses IL-6-induced nasopharyngeal carcinoma cell proliferation via inhibiting the Stat3 activation. Oncogene 33:2098–2109. https://doi.org/10.1038/onc.2013.161
Lopes LF et al (2013) Epstein-Barr virus (EBV) microRNAs: involvement in cancer pathogenesis and immunopathology. Int Rev Immunol 32:271–281. https://doi.org/10.3109/08830185.2012.748053
Mendell JT, Olson EN (2012) MicroRNAs in stress signaling and human disease. Cell 148:1172–1187. https://doi.org/10.1016/j.cell.2012.02.005
Moon JW et al (2017) IFNgamma induces PD-L1 overexpression by JAK2/STAT1/IRF-1 signaling in EBV-positive gastric carcinoma. Sci Rep 7:17810. https://doi.org/10.1038/s41598-017-18132-0
Richardo T et al (2020) Epstein-Barr virus mediated signaling in nasopharyngeal carcinoma carcinogenesis. Cancers (basel). https://doi.org/10.3390/cancers12092441
Sasidharan Nair V, Toor SM, Ali BR, Elkord E (2018) Dual inhibition of STAT1 and STAT3 activation downregulates expression of PD-L1 in human breast cancer cells. Expert Opin Ther Targets 22:547–557. https://doi.org/10.1080/14728222.2018.1471137
Shinozaki-Ushiku A et al (2015) Profiling of virus-encoded microRNAs in Epstein-Barr virus-associated gastric carcinoma and their roles in gastric carcinogenesis. J Virol 89:5581–5591. https://doi.org/10.1128/JVI.03639-14
Sun K et al (2020) EBV-positive gastric cancer: current knowledge and future perspectives. Front Oncol 10:583463. https://doi.org/10.3389/fonc.2020.583463
Tsao SW, Tsang CM, Lo KW (2017) Epstein-Barr virus infection and nasopharyngeal carcinoma. Philos Trans R Soc Lond B Biol Sci. https://doi.org/10.1098/rstb.2016.0270
Wang M et al (2019) The function and therapeutic potential of Epstein-Barr virus-encoded microRNAs in cancer. Mol Ther Nucleic Acids 17:657–668. https://doi.org/10.1016/j.omtn.2019.07.002
Wei F et al (2017) Trend analysis of cancer incidence and mortality in China. Sci China Life Sci 60:1271–1275. https://doi.org/10.1007/s11427-017-9172-6
Wei F et al (2018a) BPIFB1 (LPLUNC1) inhibits migration and invasion of nasopharyngeal carcinoma by interacting with VTN and VIM. Br J Cancer 118:233–247. https://doi.org/10.1038/bjc.2017.385
Wei F et al (2018b) BPIFB1 (LPLUNC1) inhibits radioresistance in nasopharyngeal carcinoma by inhibiting VTN expression. Cell Death Dis 9:432. https://doi.org/10.1038/s41419-018-0409-0
Wong KCW et al (2021) Nasopharyngeal carcinoma: an evolving paradigm. Nat Rev Clin Oncol 18:679–695. https://doi.org/10.1038/s41571-021-00524-x
Wu Q, Han T, Sheng X, Zhang N, Wang P (2018) Downregulation of EB virus miR-BART4 inhibits proliferation and aggressiveness while promoting radiosensitivity of nasopharyngeal carcinoma. Biomed Pharmacother 108:741–751. https://doi.org/10.1016/j.biopha.2018.08.146
Xiao WW et al (2011) Local control, survival, and late toxicities of locally advanced nasopharyngeal carcinoma treated by simultaneous modulated accelerated radiotherapy combined with cisplatin concurrent chemotherapy: long-term results of a phase 2 study. Cancer 117:1874–1883. https://doi.org/10.1002/cncr.25754
Xu Y, Tao Z, Jiang Y, Liu T, Xiang Y (2019) Overexpression of BPIFB1 promotes apoptosis and inhibits proliferation via the MEK/ERK signal pathway in nasopharyngeal carcinoma. Int J Clin Exp Pathol 12:356–364
Yan Q et al (2015) EBV-miR-BART10-3p facilitates epithelial-mesenchymal transition and promotes metastasis of nasopharyngeal carcinoma by targeting BTRC. Oncotarget 6:41766–41782. https://doi.org/10.18632/oncotarget.6155
Yang Y et al (2013) LPLUNC1 inhibits nasopharyngeal carcinoma cell growth via down-regulation of the MAP kinase and cyclin D1/E2F pathways. PLoS ONE 8:e62869. https://doi.org/10.1371/journal.pone.0062869
Zhang L, Chen QY, Liu H, Tang LQ, Mai HQ (2013) Emerging treatment options for nasopharyngeal carcinoma. Drug Des Devel Ther 7:37–52. https://doi.org/10.2147/DDDT.S30753
Zhang Y et al (2015) Prognostic significance of programmed cell death 1 (PD-1) or PD-1 ligand 1 (PD-L1) Expression in epithelial-originated cancer: a meta-analysis. Medicine (baltimore) 94:e515. https://doi.org/10.1097/MD.0000000000000515
Zhao T, Li Y, Zhang J, Zhang B (2020) PD-L1 expression increased by IFN-gamma via JAK2-STAT1 signaling and predicts a poor survival in colorectal cancer. Oncol Lett 20:1127–1134. https://doi.org/10.3892/ol.2020.11647
Zhou Y et al (2017) PD-L1 predicts poor prognosis for nasopharyngeal carcinoma irrespective of PD-1 and EBV-DNA load. Sci Rep 7:43627. https://doi.org/10.1038/srep43627
Acknowledgements
We would like to give our sincere gratitude to the reviewers for their constructive comments.
Funding
This work was supported by the Project of Changsha Natural Science Foundation (No. kq2202023).
Author information
Authors and Affiliations
Contributions
Conception and design of study: Guoqun Chen. Acquisition of data: Jiaodi Cai; Li Xiao; Dan Wang; and Zhiming Liao. Analysis and interpretation of data: Jiao Liu and Yadong Zhou. Drafting the manuscript: Jiaodi Cai. Revising the manuscript critically for important intellectual content: Guoqun Chen. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Ethical Approval
This study has obtained approval of the Ethics Committee of the Affiliated Changsha Hospital of Hunan Normal University.
Consent for Publication
The informed consent was obtained from study participants.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Cai, J., Xiao, L., Liu, J. et al. BPIFB1, Serving as a Downstream Effector of EBV-miR-BART4, Blocks Immune Escape of Nasopharyngeal Carcinoma via Inhibiting PD-L1 Expression. Biochem Genet (2024). https://doi.org/10.1007/s10528-024-10719-3
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s10528-024-10719-3