Epstein‑Barr virus‑encoded microRNA BART7 downregulates major histocompatibility complex class I chain‑related peptide A and reduces the cytotoxicity of natural killer cells to nasopharyngeal carcinoma

Wong,Thian‑Sze; Chen,Siqi; Zhang,Min‑Juan; Chan,Jimmy  Yu‑Wai; Gao,Wei

doi:10.3892/ol.2018.9041

Epstein‑Barr virus‑encoded microRNA BART7 downregulates major histocompatibility complex class I chain‑related peptide A and reduces the cytotoxicity of natural killer cells to nasopharyngeal carcinoma

Authors:
- Thian‑Sze Wong
- Siqi Chen
- Min‑Juan Zhang
- Jimmy Yu‑Wai Chan
- Wei Gao
View Affiliations

Affiliations: Department of Surgery, The University of Hong Kong, Hong Kong SAR, P.R. China
Published online on: June 28, 2018 https://doi.org/10.3892/ol.2018.9041
Pages: 2887-2892
Copyright: © Wong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Evasion from natural killer (NK) cell surveillance enables cancer to proliferate and spread at the early stages. NK cells mediate specific cytolysis by activation of the triggering receptors on their cell surface, of which the communication between natural killer group 2, member D (NKG2D) and major histocompatibility complex class I chain‑related peptide A (MICA) is a key regulatory axis. It has been indicated that cancer cells can reduce the surface expression of MICA, which thereby reduces the cytotoxicity of NK cells. In nasopharyngeal carcinoma (NPC), however, the underlying mechanism remains unclear. The present study indicated that MICA expression in NPC was regulated by TGFβ1. Furthermore, the human MICA gene was demonstrated to contain the c‑Myc binding site in the promoter region. Notably, the results suggested that TGFβ1 upregulated MICA expression by promoting c‑Myc expression. Additionally, the findings demosntrated that TGFβ1 expression in NPC was negatively controlled by Epstein‑Barr virus‑encoded microRNA BART7 (ebv‑miR‑BART7). In ebv‑miR‑BART7‑expressing NPC, the TGFβ1/c‑Myc/MICA regulatory axis was significantly inhibited. Notably, functional analysis indicated that NPC cells expressing ebv‑miR‑BART7 were less sensitive to the cytolysis mediated by NK cells. In conclusion, the present results revealed that ebv‑miR‑BART7‑expressing NPC may impair NK cells recognition and activity, which suggests that targeting ebv‑miR‑BART7 may be a useful therapeutic strategy in NPC immunotherapy.

View Figures

View References

1	Tsao SW, Yip YL, Tsang CM, Pang PS, Lau VM, Zhang G and Lo KW: Etiological factors of nasopharyngeal carcinoma. Oral Oncol. 50:330–338. 2014. View Article : Google Scholar : PubMed/NCBI
2	Young LS and Rickinson AB: Epstein-barr virus: 40 years on. Nat Rev Cancer. 4:757–768. 2004. View Article : Google Scholar : PubMed/NCBI
3	Ressing ME, van Gent M, Gram AM, Hooykaas MJ, Piersma SJ and Wiertz EJ: Immune evasion by epstein-barr virus. Curr Top Microbiol Immunol. 391:355–381. 2015.PubMed/NCBI
4	Trinchieri G: Biology of natural killer cells. Adv Immunol. 47:187–376. 1989. View Article : Google Scholar : PubMed/NCBI
5	Guillerey C, Huntington ND and Smyth MJ: Targeting natural killer cells in cancer immunotherapy. Nat Immunol. 17:1025–1036. 2016. View Article : Google Scholar : PubMed/NCBI
6	Jinushi M, Takehara T, Tatsumi T, Hiramatsu N, Sakamori R, Yamaguchi S and Hayashi N: Impairment of natural killer cell and dendritic cell functions by the soluble form of MHC class I-related chain A in advanced human hepatocellular carcinomas. J Hepatol. 43:1013–1020. 2005. View Article : Google Scholar : PubMed/NCBI
7	Lynn TC, Wang JH, Yang CS and Tu SM: Natural killer cell activity in patients with nasopharyngeal carcinoma. Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi. 19:177–182. 1986.(In Chinese). PubMed/NCBI
8	Tian W, Luo QZ, Li LX, Jin HK, Wang F, Guo SS and Cao Y: Polymorphism of short tandem repeat of exon 5 of MHC class-I chain related gene A and association with nasopharyngeal carcinoma in a southern Chinese population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 22:309–312. 2005.(In Chinese). PubMed/NCBI
9	Tian W, Zeng XM, Li LX, Jin HK, Luo QZ, Wang F, Guo SS and Cao Y: Gender-specific associations between MICA-STR and nasopharyngeal carcinoma in a southern Chinese Han population. Immunogenetics. 58:113–121. 2006. View Article : Google Scholar : PubMed/NCBI
10	Kishikawa T, Otsuka M, Yoshikawa T, Ohno M, Takata A, Shibata C, Kondo Y, Akanuma M, Yoshida H and Koike K: Regulation of the expression of the liver cancer susceptibility gene MICA by microRNAs. Sci Rep. 3:27392013. View Article : Google Scholar : PubMed/NCBI
11	Song H, Kim Y, Park G, Kim YS, Kim S, Lee HK, Chung WY, Park SJ, Han SY, Cho D and Hur D: Transforming growth factor-β1 regulates human renal proximal tubular epithelial cell susceptibility to natural killer cells via modulation of the NKG2 ligands. Int J Mol Med. 36:1180–1188. 2015. View Article : Google Scholar : PubMed/NCBI
12	Gao W, Li ZH, Chen S, Chan JY, Yin M, Zhang MJ and Wong TS: Epstein-Barr virus encoded microRNA BART7 regulates radiation sensitivity of nasopharyngeal carcinoma. Oncotarget. 8:20297–20308. 2017.PubMed/NCBI
13	Moodley K, Angel CE, Glass M and Graham ES: Real-time profiling of NK cell killing of human astrocytes using xCELLigence technology. J Neurosci Methods. 200:173–180. 2011. View Article : Google Scholar : PubMed/NCBI
14	Seliger B, Harders C, Lohmann S, Momburg F, Urlinger S, Tampé R and Huber C: Down-regulation of the MHC class I antigen-processing machinery after oncogenic transformation of murine fibroblasts. Eur J Immunol. 28:122–133. 1998. View Article : Google Scholar : PubMed/NCBI
15	Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL and Spies T: Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 285:727–729. 1999. View Article : Google Scholar : PubMed/NCBI
16	Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR and Spies T: Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat immunol. 2:255–260. 2001. View Article : Google Scholar : PubMed/NCBI
17	Li MO, Wan YY, Sanjabi S, Robertson AK and Flavell RA: Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 24:99–146. 2006. View Article : Google Scholar : PubMed/NCBI
18	White RA, Malkoski SP and Wang XJ: TGFβ signaling in head and neck squamous cell carcinoma. Oncogene. 29:5437–5446. 2010. View Article : Google Scholar : PubMed/NCBI
19	Viel S, Marçais A, Guimaraes FS, Loftus R, Rabilloud J, Grau M, Degouve S, Djebali S, Sanlaville A, Charrier E, et al: TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci Signal. 9:ra192016. View Article : Google Scholar : PubMed/NCBI
20	Rouce RH, Shaim H, Sekine T, Weber G, Ballard B, Ku S, Barese C, Murali V, Wu MF, Liu H, et al: The TGF-β/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia. Leukaemia. 30:800–811. 2016. View Article : Google Scholar
21	Crane CA, Han SJ, Barry JJ, Ahn BJ, Lanier LL and Parsa AT: TGF-beta downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patients. Neuro Oncol. 12:7–13. 2010. View Article : Google Scholar : PubMed/NCBI
22	Lee JC, Lee KM, Kim DW and Heo DS: Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol. 172:7335–7340. 2004. View Article : Google Scholar : PubMed/NCBI
23	Zhu X, Ozturk F, Liu C, Oakley GG and Nawshad A: Transforming growth factor-β activates c-Myc to promote palatal growth. J Cell Biochem. 113:3069–3085. 2012. View Article : Google Scholar : PubMed/NCBI
24	Textor S, Bossler F, Henrich KO, Gartlgruber M, Pollmann J, Fiegler N, Arnold A, Westermann F, Waldburger N, Breuhahn K, et al: The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells. Oncoimmunology. 5:e11166742016. View Article : Google Scholar : PubMed/NCBI
25	Young LS and Dawson CW: Epstein-Barr virus and nasopharyngeal carcinoma. Chin J Cancer. 33:581–590. 2014.PubMed/NCBI
26	Hislop AD, Ressing ME, van Leeuwen D, Pudney VA, Horst D, Koppers-Lalic D, Croft NP, Neefjes JJ, Rickinson AB and Wiertz EJ: A CD8+ T cell immune evasion protein specific to Epstein-Barr virus and its close relatives in Old World primates. J Exp Med. 204:1863–1873. 2007. View Article : Google Scholar : PubMed/NCBI
27	Zuo J, Thomas W, van Leeuwen D, Middeldorp JM, Wiertz EJ, Ressing ME and Rowe M: The DNase of gammaherpesviruses impairs recognition by virus-specific CD8+ T cells through an additional host shutoff function. J Virol. 82:2385–2393. 2008. View Article : Google Scholar : PubMed/NCBI
28	Albanese M, Tagawa T, Bouvet M, Maliqi L, Lutter D, Hoser J, Hastreiter M, Hayes M, Sugden B, Martin L, et al: Epstein-Barr virus microRNAs reduce immune surveillance by virus-specific CD8+ T cells. Proc Natl Acad Sci USA. 113:E6467–E6475. 2016. View Article : Google Scholar : PubMed/NCBI