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Study on the regulatory mechanism of latent membrane protein 2A on GCNT3 expression in nasopharyngeal carcinoma

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Abstract

O-Glycan synthesis enzyme glucosaminyl (N-acetyl) transferase 3 (GCNT3) is closely related to the occurrence and development of various cancers. However, the regulatory mechanism and function of GCNT3 in nasopharyngeal carcinoma (NPC) are still poorly understood. This study aims to explore the regulatory mechanism of EBV-encoded latent membrane protein 2A (LMP2A) on GCNT3 and the biological role of GCNT3 in NPC. The results show that LMP2A can activate GCNT3 through the mTORC1 pathway, and there is a positive feedback between the mTORC1 and GCNT3. GCNT3 regulates EMT progression by forming a complex with ZEB1 to promote cell migration. GCNT3 can also promote cell proliferation. These findings indicate that targeting the LMP2A-mTORC1-GCNT3 axis may represent a novel therapeutic target in NPC.

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References

  1. Badoual C (2022) Update from the 5th edition of the World Health Organization classification of head and neck tumors: oropharynx and nasopharynx. Head Neck Pathol 16(1):19–30

    Article  PubMed  PubMed Central  Google Scholar 

  2. Young LS, Dawson CW (2014) Epstein-Barr virus and nasopharyngeal carcinoma. Chin J Cancer 33(12):581–590

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Gao R, Wang L, Liu Q, Zhang LF, Ye YF, Xie SH et al (2017) Evaluation of seven recombinant VCA-IgA ELISA kits for the diagnosis of nasopharyngeal carcinoma in China: a case-control trial. BMJ Open 7(6):e013211

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wu TC, Mann RB, Epstein JI, MacMahon E, Lee WA, Charache P et al (1991) Abundant expression of EBER1 small nuclear RNA in nasopharyngeal carcinoma. A morphologically distinctive target for detection of Epstein-Barr virus in formalin-fixed paraffin-embedded carcinoma specimens. Am J Pathol 138(6):1461–1469

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Banko AV, Lazarevic IB, Folic MM, Djukic VB, Cirkovic AM, Karalic DZ et al (2016) Characterization of the variability of Epstein-Barr virus genes in nasopharyngeal biopsies: potential predictors for carcinoma progression. PLoS ONE 11(4):e0153498

    Article  PubMed  PubMed Central  Google Scholar 

  6. Brooks L, Yao QY, Rickinson AB, Young LS (1992) Epstein-Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J Virol 66(5):2689–2697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Heussinger N, Büttner M, Ott G, Brachtel E, Pilch BZ, Kremmer E et al (2004) Expression of the Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) in EBV-associated nasopharyngeal carcinoma. J Pathol 203(2):696–699

    Article  CAS  PubMed  Google Scholar 

  8. Kong QL, Hu LJ, Cao JY, Huang YJ, Xu LH, Liang Y et al (2010) Epstein-Barr virus-encoded LMP2A induces an epithelial-mesenchymal transition and increases the number of side population stem-like cancer cells in nasopharyngeal carcinoma. PLoS Pathog 6(6):e1000940

    Article  PubMed  PubMed Central  Google Scholar 

  9. Tsang CK, Qi H, Liu LF, Zheng XF (2007) Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today 12(3–4):112–124

    Article  CAS  PubMed  Google Scholar 

  10. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H et al (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14(14):1296–1302

    Article  CAS  PubMed  Google Scholar 

  11. Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A et al (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6(11):1122–1128

    Article  CAS  PubMed  Google Scholar 

  12. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H et al (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110(2):163–175

    Article  CAS  PubMed  Google Scholar 

  13. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S et al (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110(2):177–189

    Article  CAS  PubMed  Google Scholar 

  14. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H et al (2003) GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11(4):895–904

    Article  CAS  PubMed  Google Scholar 

  15. Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168(6):960–976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zou Z, Tao T, Li H, Zhu X (2020) mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell Biosci 10:31

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lin Z, Wan X, Jiang R, Deng L, Gao Y, Tang J et al (2014) Epstein-Barr virus-encoded latent membrane protein 2A promotes the epithelial-mesenchymal transition in nasopharyngeal carcinoma via metastatic tumor antigen 1 and mechanistic target of rapamycin signaling induction. J Virol 88(20):11872–11885

    Article  PubMed  PubMed Central  Google Scholar 

  18. Li RW, Li C, Elsasser TH, Liu G, Garrett WM, Gasbarre LC (2009) Mucin biosynthesis in the bovine goblet cell induced by Cooperia oncophora infection. Vet Parasitol 165(3–4):281–289

    Article  CAS  PubMed  Google Scholar 

  19. Li Q, Ran P, Zhang X, Guo X, Yuan Y, Dong T et al (2018) Downregulation of N-Acetylglucosaminyltransferase GCNT3 by miR-302b-3p decreases non-small cell lung cancer (NSCLC) cell proliferation, migration and invasion. Cell Physiol Biochem 50(3):987–1004

    Article  CAS  PubMed  Google Scholar 

  20. Fernández LP, Sánchez-Martínez R, Vargas T, Herranz J, Martín-Hernández R, Mendiola M et al (2018) The role of glycosyltransferase enzyme GCNT3 in colon and ovarian cancer prognosis and chemoresistance. Sci Rep 8(1):8485

    Article  PubMed  PubMed Central  Google Scholar 

  21. Liu J, Zhang Y, Yu C, Li J, Liu W, Luo B (2021) Epstein-Barr virus-encoded latent membrane protein 2A downregulates GCNT3 via the TGF-β1/Smad-mTORC1 signaling axis. J Virol 95(10):10

    Article  Google Scholar 

  22. Rao CV, Janakiram NB, Madka V, Kumar G, Scott EJ, Pathuri G et al (2016) Small-molecule inhibition of GCNT3 disrupts mucin biosynthesis and malignant cellular behaviors in pancreatic cancer. Can Res 76(7):1965–1974

    Article  CAS  Google Scholar 

  23. González-Vallinas M, Vargas T, Moreno-Rubio J, Molina S, Herranz J, Cejas P et al (2015) Clinical relevance of the differential expression of the glycosyltransferase gene GCNT3 in colon cancer. Eur J Cancer 51(1):1–8

    Article  PubMed  Google Scholar 

  24. González-Vallinas M, Molina S, Vicente G, Zarza V, Martín-Hernández R, García-Risco MR et al (2014) Expression of microRNA-15b and the glycosyltransferase GCNT3 correlates with antitumor efficacy of Rosemary diterpenes in colon and pancreatic cancer. PLoS ONE 9(6):e98556

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lee AW, Poon YF, Foo W, Law SC, Cheung FK, Chan DK et al (1992) Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976–1985: overall survival and patterns of failure. Int J Radiat Oncol Biol Phys 23(2):261–270

    Article  CAS  PubMed  Google Scholar 

  26. Babaei G, Aziz SG, Jaghi NZZ (2021) EMT, cancer stem cells and autophagy; the three main axes of metastasis. Biomed Pharmacother 133:110909

    Article  CAS  PubMed  Google Scholar 

  27. Jia W, Zhu J, Martin TA, Jiang A, Sanders AJ, Jiang WG (2015) Epithelial-mesenchymal transition (EMT) markers in human pituitary adenomas indicate a clinical course. Anticancer Res 35(5):2635–2643

    PubMed  Google Scholar 

  28. Wells A, Yates C, Shepard CR (2008) E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metas 25(6):621–628

    Article  CAS  Google Scholar 

  29. Zhang P, Sun Y, Ma L (2015) ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle 14(4):481–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Huang Q, Miller MR, Schappet J, Henry MD (2015) The glycosyltransferase LARGE2 is repressed by snail and ZEB1 in prostate cancer. Cancer Biol Ther 16(1):125–136

    Article  CAS  PubMed  Google Scholar 

  31. Rakhmanova V, Jin M, Shin J (2018) Inhibition of mast cell function and proliferation by mTOR activator MHY1485. Immune Netw 18(3):e18

    Article  PubMed  PubMed Central  Google Scholar 

  32. Arriola Apelo SI, Lamming DW (2016) Rapamycin: an InhibiTOR of aging emerges from the soil of Easter Island. J Gerontol Ser A 71(7):841–849

    Article  Google Scholar 

  33. Chen J, Hu CF, Hou JH, Shao Q, Yan LX, Zhu XF et al (2010) Epstein-Barr virus encoded latent membrane protein 1 regulates mTOR signaling pathway genes which predict poor prognosis of nasopharyngeal carcinoma. J Transl Med 8:30

    Article  PubMed  PubMed Central  Google Scholar 

  34. Xiang T, Lin YX, Ma W, Zhang HJ, Chen KM, He GP et al (2018) Vasculogenic mimicry formation in EBV-associated epithelial malignancies. Nat Commun 9(1):5009

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wang LW, Jiang S, Gewurz BE (2017) Epstein-Barr virus LMP1-mediated oncogenicity. J Virol 91(21):e01718–e01816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

Funding was provided by Natural Science Foundation of Shandong Province (Grant Nos.: ZR2020MC020, ZR2021MC068, ZR2020MH302).

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YC, DS, YZ, WL and BL designed research; YC performed research; YC and WL analyzed data; YC prepared original draft; WL and BL reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Wen Liu or Bing Luo.

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Edited by Joachim J. Bugert.

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Chen, Y., Zhang, Y., Duo, S. et al. Study on the regulatory mechanism of latent membrane protein 2A on GCNT3 expression in nasopharyngeal carcinoma. Virus Genes (2024). https://doi.org/10.1007/s11262-024-02071-w

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