Top

Published in:

01-05-2021 | Epstein-Barr Virus | Original Article

EBV-miR-BART12 inhibits cell migration and proliferation by targeting Snail expression in EBV-associated gastric cancer

Authors: Jun Li, Yan Zhang, Juanjuan Liu, Qianzhu Shi, Wen Liu, Bing Luo

Published in: Archives of Virology | Issue 5/2021

Abstract

Epstein-Barr virus (EBV) was the first oncovirus found to encode microRNAs. In EBV-associated gastric cancer (EBVaGC), EBV-encoded BamHI-A rightward transcript microRNAs (BARTs) are highly expressed. However, the role of BARTs in EBVaGC remains obscure. In this study, we found that EBV-miR-BART12 (miR-BART12) inhibits cell proliferation and migration. Zinc finger protein SNAI1 (Snail) is an important epithelial-mesenchymal transition (EMT) inducer, and overexpression of Snail is closely associated with cancer metastasis. Here, we report that Snail expression in EBVaGC cells is lower than in EBV-negative gastric cancer (EBVnGC) cells. A dual luciferase reporter assay showed that miR-BART12 targets Snail directly by interacting with its 3ʹ-UTR. A CHX chase assay revealed that miR-BART12 accelerates the degradation of Snail. Furthermore, we found that miR-BART12 can regulate the expression of EMT-related genes. Flow cytometry analysis showed that transfection with miR-BART12 induced G2/M phase arrest and promoted cell apoptosis. In summary, the results of our study have suggested a new mechanism by which BARTs can repress cell proliferation and migration in gastric cancer.

Young LS, Rickinson AB (2004) Epstein–Barr virus: 40 years on. Nat Rev Cancer 4(10):757–768. https://doi.org/10.1038/nrc1452CrossRefPubMed

Kutok JL, Wang F (2006) Spectrum of Epstein–Barr virus-associated diseases. Annu Rev Pathol 1:375–404. https://doi.org/10.1146/annurev.pathol.1.110304.100209CrossRefPubMed

Carbone A, Gloghini A, Dotti G (2008) EBV-associated lymphoproliferative disorders: classification and treatment. Oncologist 13(5):577–585. https://doi.org/10.1634/theoncologist.2008-0036CrossRefPubMed

Shinozaki-Ushiku A, Kunita A, Fukayama M (2015) Update on Epstein–Barr virus and gastric cancer (review). Int J Oncol 46(4):1421–1434. https://doi.org/10.3892/ijo.2015.2856CrossRefPubMed

Pfeffer S, Zavolan M, Grasser FA, Chien M, Russo JJ, Ju J, John B, Enright AJ, Marks D, Sander C, Tuschl T (2004) Identification of virus-encoded microRNAs. Science 304(5671):734–736. https://doi.org/10.1126/science.1096781CrossRefPubMed

Dong M, Chen JN, Huang JT, Gong LP, Shao CK (2019) The roles of EBV-encoded microRNAs in EBV-associated tumors. Crit Rev Oncol Hematol 135:30–38. https://doi.org/10.1016/j.critrevonc.2019.01.014CrossRefPubMed

Alberga A, Boulay JL, Kempe E, Dennefeld C, Haenlin M (1991) The snail gene required for mesoderm formation in Drosophila is expressed dynamically in derivatives of all three germ layers. Development 111(4):983–992PubMed

Nieto MA (2002) The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3(3):155–166. https://doi.org/10.1038/nrm757CrossRefPubMed

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013CrossRefPubMed

10.

Barrallo-Gimeno A, Nieto MA (2005) The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132(14):3151–3161. https://doi.org/10.1242/dev.01907CrossRefPubMed

11.

Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890. https://doi.org/10.1016/j.cell.2009.11.007CrossRefPubMed

12.

Lee K, Nelson CM (2012) New insights into the regulation of epithelial-mesenchymal transition and tissue fibrosis. Int Rev Cell Mol Biol 294:171–221. https://doi.org/10.1016/b978-0-12-394305-7.00004-5CrossRefPubMed

13.

Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y (2009) Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 15(3):195–206. https://doi.org/10.1016/j.ccr.2009.01.023CrossRefPubMed

14.

Wang Y, Shi J, Chai K, Ying X, Zhou BP (2013) The role of Snail in EMT and tumorigenesis. Curr Cancer Drug Targets 13(9):963–972. https://doi.org/10.2174/15680096113136660102CrossRefPubMedPubMedCentral

15.

Shi Q, Zhang Y, Liu W, Xiao H, Qi Y, Li J, Luo B (2020) Latent membrane protein 2A inhibits expression level of Smad2 through regulating miR-155-5p in EBV-associated gastric cancer cell lines. J Med Virol 92(1):96–106. https://doi.org/10.1002/jmv.25579CrossRefPubMed

16.

Liu J, Zhang Y, Liu W, Zhang Q, Xiao H, Song H, Luo B (2020) MiR-BART1-5p targets core 2beta-1,6-acetylglucosaminyltransferase GCNT3 to inhibit cell proliferation and migration in EBV-associated gastric cancer. Virology 541:63–74. https://doi.org/10.1016/j.virol.2019.12.004CrossRefPubMed

17.

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359-386. https://doi.org/10.1002/ijc.29210CrossRefPubMed

18.

Bass AJ, Thorsson V et al (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517):202–209. https://doi.org/10.1038/nature13480CrossRef

19.

Marquitz AR, Mathur A, Nam CS, Raab-Traub N (2011) The Epstein–Barr virus BART microRNAs target the pro-apoptotic protein Bim. Virology 412(2):392–400. https://doi.org/10.1016/j.virol.2011.01.028CrossRefPubMed

20.

Kim DN, Chae HS, Oh ST, Kang JH, Park CH, Park WS, Takada K, Lee JM, Lee WK, Lee SK (2007) Expression of viral microRNAs in Epstein–Barr virus-associated gastric carcinoma. J Virol 81(2):1033–1036. https://doi.org/10.1128/jvi.02271-06CrossRefPubMed

21.

Morales-Sanchez A, Fuentes-Panana EM (2017) Epstein–Barr virus-associated gastric cancer and potential mechanisms of oncogenesis. Curr Cancer Drug Targets 17(6):534–554. https://doi.org/10.2174/1568009616666160926124923CrossRefPubMed

22.

Olmeda D, Moreno-Bueno G, Flores JM, Fabra A, Portillo F, Cano A (2007) SNAI1 is required for tumor growth and lymph node metastasis of human breast carcinoma MDA-MB-231 cells. Cancer Res 67(24):11721–11731. https://doi.org/10.1158/0008-5472.can-07-2318CrossRefPubMed

23.

Horikawa T, Yoshizaki T, Kondo S, Furukawa M, Kaizaki Y, Pagano JS (2011) Epstein–Barr virus latent membrane protein 1 induces Snail and epithelial-mesenchymal transition in metastatic nasopharyngeal carcinoma. Br J Cancer 104(7):1160–1167. https://doi.org/10.1038/bjc.2011.38CrossRefPubMedPubMedCentral

24.

Gaur N, Gandhi J, Robertson ES, Verma SC, Kaul R (2015) Epstein–Barr virus latent antigens EBNA3C and EBNA1 modulate epithelial to mesenchymal transition of cancer cells associated with tumor metastasis. Tumour Biol 36(4):3051–3060. https://doi.org/10.1007/s13277-014-2941-6CrossRefPubMed

25.

Yu T, Wang LN, Li W, Zuo QF, Li MM, Zou QM, Xiao B (2018) Downregulation of miR-491-5p promotes gastric cancer metastasis by regulating SNAIL and FGFR4. Cancer Sci 109(5):1393–1403. https://doi.org/10.1111/cas.13583CrossRefPubMedPubMedCentral

26.

Kang D, Skalsky RL, Cullen BR (2015) EBV BART microRNAs target multiple pro-apoptotic cellular genes to promote epithelial cell survival. PLoS Pathog 11(6):e1004979. https://doi.org/10.1371/journal.ppat.1004979CrossRefPubMedPubMedCentral

27.

Wang Y, Guo Z, Shu Y, Zhou H, Wang H, Zhang W (2017) BART miRNAs: an unimaginable force in the development of nasopharyngeal carcinoma. Eur J Cancer Prev 26(2):144–150. https://doi.org/10.1097/cej.0000000000000221CrossRefPubMedPubMedCentral

28.

Choi H, Lee H, Kim SR, Gho YS, Lee SK (2013) Epstein–Barr virus-encoded microRNA BART15-3p promotes cell apoptosis partially by targeting BRUCE. J Virol 87(14):8135–8144. https://doi.org/10.1128/jvi.03159-12CrossRefPubMedPubMedCentral

29.

Camargo MC, Kim WH, Chiaravalli AM, Kim KM, Corvalan AH, Matsuo K, Yu J, Sung JJ, Herrera-Goepfert R, Meneses-Gonzalez F, Kijima Y, Natsugoe S, Liao LM, Lissowska J, Kim S, Hu N, Gonzalez CA, Yatabe Y, Koriyama C, Hewitt SM, Akiba S, Gulley ML, Taylor PR, Rabkin CS (2014) Improved survival of gastric cancer with tumour Epstein–Barr virus positivity: an international pooled analysis. Gut 63(2):236–243. https://doi.org/10.1136/gutjnl-2013-304531CrossRefPubMed

30.

Matsunou H, Konishi F, Hori H, Ikeda T, Sasaki K, Hirose Y, Yamamichi N (1996) Characteristics of Epstein-Barr virus-associated gastric carcinoma with lymphoid stroma in Japan. Cancer 77(10):1998–2004. https://doi.org/10.1002/(sici)1097-0142(19960515)77:10%3c1998::aid-cncr6%3e3.0.co;2-dCrossRefPubMed

31.

Ozoya OO, Sokol L, Dalia S (2016) EBV-related malignancies, outcomes and novel prevention strategies. Infect Disord Drug Targets 16(1):4–21. https://doi.org/10.2174/1871526516666160407113536CrossRefPubMed

32.

Sokolova O, Naumann M (2017) NF-kappaB signaling in gastric cancer. Toxins (Basel) 9(4):119. https://doi.org/10.3390/toxins9040119CrossRef

33.

Zhang Y, Liu W, Zhang W, Wang W, Song Y, Xiao H, Luo B (2019) Constitutive activation of the canonical NF-kappaB signaling pathway in EBV-associated gastric carcinoma. Virology 532:1–10. https://doi.org/10.1016/j.virol.2019.03.019CrossRefPubMed

34.

Wu Y, Zhou BP (2010) TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion. Br J Cancer 102(4):639–644. https://doi.org/10.1038/sj.bjc.6605530CrossRefPubMedPubMedCentral

Title: EBV-miR-BART12 inhibits cell migration and proliferation by targeting Snail expression in EBV-associated gastric cancer
Authors: Jun Li
Yan Zhang
Juanjuan Liu
Qianzhu Shi
Wen Liu
Bing Luo
Publication date: 01-05-2021
Publisher: Springer Vienna
Keywords: Epstein-Barr Virus
Gastric Cancer
Gastric Cancer
Published in: Archives of Virology / Issue 5/2021
Print ISSN: 0304-8608
Electronic ISSN: 1432-8798
DOI: https://doi.org/10.1007/s00705-021-05001-5

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2021

Isolation and genetic characteristics of a neurotropic teschovirus variant belonging to genotype 1 in northeast China

First detection and genetic characterization of equid herpesvirus 2, 4, and 5 in China

Titer and distribution of little cherry virus 2 in Prunus avium

Transmission of SARS-CoV-2 in northern Ghana: insights from whole-genome sequencing

Low virus diversity and spread in wild Capsicum spp. accessions from Ecuador under natural inoculum pressure

Human pegivirus 1 in Cabo Verde: prevalence and genotypic distribution among HIV-infected individuals

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials