Tumor Biology

, Volume 36, Issue 9, pp 7121–7131 | Cite as

Antineoplastic activity of Newcastle disease virus strain D90 in oral squamous cell carcinoma

  • Chun-Xiao Zhang
  • Long-Wei Ye
  • Ying Liu
  • Xiao-Ya Xu
  • Dan-Rui Li
  • Yan-Qing Yang
  • Lu-Lu Sun
  • Jie Yuan
Research Article


Newcastle disease virus (NDV), an avian paramyxovirus, possesses the ability to kill tumor cells. Here, we report the effects of NDV strain D90, which was isolated in China, against oral squamous cell carcinoma (OSCC) cells. In this study, we showed that the cell death induced by D90 was apoptotic. Furthermore, the apoptosis induced by D90 was dependent on the mitochondrial pathway, and the death receptor pathway may be not involved. Bax and Bcl-2 also played a role in the apoptosis induced by D90. Lymph node metastasis is a serious problem for oral cancer; we therefore evaluated the impact of D90 on the migration and invasion of OSCC cells. NDV D90 affected microtubules and microfilaments to inhibit the motility of OSCC prior to apoptosis. The effects of D90 on the migration and invasion rates of OSCC cells were evaluated by migration and invasion assays. Subsequently, the changes in sp1, RECK, MMP-2, and MMP-9 induced by a low concentration of D90 were detected by western blot and gelatin zymography. D90 significantly inhibited the invasion and metastasis of OSCC cells by decreasing the expression of sp1 and increasing the expression of RECK to suppress the expression and activity of MMP-2 and MMP-9.


Newcastle disease virus (NDV) Oral squamous cell carcinoma (OSCC) Apoptosis Migration Invasion 



This study was funded by a grant (2014RFXGJ114) from the Special Foundation for Science and Technology Innovation Research of Harbin, China. We thank Professor Xi Li from the State Key Laboratory of Veterinary Biotechnology of the Harbin Veterinary Research Institute of the Chinese Academy of Agricultural Sciences for donating NDV strain D90 to carry out this study. We also thank Professor Chun Song and Zheng Wei for providing guidance in the study.

Authors’ contributions

Chun-Xiao Zhang and Long-Wei Ye contributed equally to this work.


  1. 1.
    Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45:309–16.CrossRefPubMedGoogle Scholar
  2. 2.
    Forastiere A, Koch W, Trotti A, Sidansky D. Head and neck cancer. N Engl J Med. 2001;345:1890.CrossRefPubMedGoogle Scholar
  3. 3.
    Lam HY, Yeap SK, Rasoli M, et al. Safety and clinical usage of Newcastle disease virus in cancer therapy. J Biomed Biotechnol. 2011. doi: 10.1155/2011/718710.Google Scholar
  4. 4.
    Zamarin D, Palese P. Oncolytic Newcastle disease virus for cancer therapy: old challenges and new directions. Future Microbiol. 2012;7(3):347–67.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Romer-Oberdorfer A, Werner O, Veits J, Mebatsion T, Mettenleiter TC. Contribution of the length of the HN protein and the sequence of the F protein cleavage site to Newcastle disease virus pathogenicity. J Gen Virol. 2003;84:3121–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Ravindra PV, Tiwari AK, Sharma B, Chauhan RS. Newcastle disease virus as an oncolytic agent. Indian J Med Res. 2009;130(5):507–13.PubMedGoogle Scholar
  7. 7.
    Molouki A, Hsu YT, et al. The matrix (M) protein of Newcastle disease virus binds to human bax through its BH3 domain. Virol J. 2011;8:385.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Elankumaran S, Rockemann D, Samal SK. Newcastle disease virus exerts oncolysis by both intrinsic and extrinsic caspase-dependent pathways of cell death. J Virol. 2006;80(15):7522–34.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Laurie SA, Bell JC, Atkins HL, et al. A phase 1 clinical study of intravenous administration of PV701, an oncolytic virus, using two-step desensitization. Clin Cancer Res. 2006;12:2555–62.CrossRefPubMedGoogle Scholar
  10. 10.
    Alabsi AM, Ali R, et al. Anti-leukemic activity of Newcastle disease virus strains AF2240 and V4-UPM in murine myelomonocytic leukemia in vivo. Leuk Res. 2012;36(5):634–45.CrossRefPubMedGoogle Scholar
  11. 11.
    Jamal MH, Ch’ng WC, Yusoff K, Shafee N. Reduced Newcastle disease virus-induced oncolysis in a subpopulation of cisplatin-resistant MCF7 cells is associated with survivin stabilization. Cancer Cell Int. 2012;12(1):35.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Meng C, Zhou Z, Jiang K, et al. Newcastle disease virus triggers autophagy in U251 glioma cells to enhance virus replication. Arch Virol. 2012;157(6):1011–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Lazar L, Yaacov B, Shiloach T, et al. The oncolytic activity of Newcastle disease virus NDV-HUJ on chemoresistant primary melanoma cells is dependent on the proapoptotic activity of the inhibitor of apoptosis protein Livin. J Virol. 2010;84(1):639–46.CrossRefPubMedGoogle Scholar
  14. 14.
    Bian J, Wang K, Kong X, et al. Caspase-and p38-MAPK-dependent induction of apoptosis in A549 lung cancer cells by Newcastle disease virus. Arch Virol. 2011;156(8):1335–44.CrossRefPubMedGoogle Scholar
  15. 15.
    Csatary K, Gosztonyi G, Szeberenyi J, et al. MTH-68/H oncolytic vital treatment in human high-grade gliomas. J Neurooncol. 2004;67(1–2):83–93.CrossRefPubMedGoogle Scholar
  16. 16.
    Freeman AL, Zakay-Rones Z, Gomori JM, et al. Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Mol Ther. 2006;13(1):221–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Hotte SJ, Lorence RM, Hirte HW, et al. An optimized clinical regimen for the oncolytic virus PV701. Clin Cancer Res. 2007;13(3):977–85.CrossRefPubMedGoogle Scholar
  18. 18.
    Reichard KW, Lorence RM, Cascino CJ, et al. Newcastle disease virus selectively kills human tumor cells. J Surg Res. 1992;52(5):448–53.CrossRefPubMedGoogle Scholar
  19. 19.
    Alabsi AM, Bakar SA, Ali R, et al. Effects of Newcastle disease virus strains AF2240 and V4-UPM on cytolysis and apoptosis of leukemia cell lines. Int J Mol Sci. 2011;12(12):8645–60.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Zamarin D, Viqil A, Kelly K, Garcia-Sastre A, Fong Y. Genetically engineered Newcastle disease virus for malignant melanoma therapy. Gene Ther. 2009;16(6):796–804.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Viqil A, Park MS, Martinez O, et al. Use of reverse genetics to enhance the oncolytic properties of Newcastle disease virus. Cancer Res. 2007;67(17):8285–92.CrossRefGoogle Scholar
  22. 22.
    Biswas M, Kumar SR, Allen A, et al. Cell-type-specific innate immune response to oncolytic Newcastle disease virus. Viral Immunol. 2012;25(4):268–74.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Molouki A, Yusoff K. NDV-induced apoptosis in absence of Bax; evidence of involvement of apoptotic proteins upstream of mitochondria. Virol J. 2012;9:179.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sui H, Bai Y, Wang K, et al. The anti-tumor effect of Newcastle disease virus HN protein is influenced by differential subcellular targeting. Cancer Immunol Immunother. 2010;59(7):989–99.CrossRefPubMedGoogle Scholar
  25. 25.
    Woolqar JA, Scott J, Vauqhan ED, et al. Survival, metastasis and recurrence of oral cancer in relation to pathological features. Ann R Coll Surg Engl. 1995;77(5):325–31.Google Scholar
  26. 26.
    Kato K, Long NK, Makita H, et al. Effects of green tea polyphenol on methylation status of RECK gene and cancer cell invasion in oral squamous cell carcinoma cells. Br J Cancer. 2008;99(4):647–54.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hsu MC, Chang HC, Hung WC. HER-2/neu represses the metastasis suppressor RECK via ERK and Sp transcription factors to promote cell invasion. J Biol Chem. 2006;281(8):4718–25.CrossRefPubMedGoogle Scholar
  28. 28.
    Puff C, Krudewiq C, Imbschweiler L, Baumqártner W, Alldinqer S. Influence of persistent canine distemper virus infection on expression of RECK, matrix-metalloproteinases and their inhibitors in a canine macrophage/monocytic tumour cell line (DH82). Vet J. 2009;182(1):100–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Tswnq MY, Liu SY, Chen HR, et al. Serine protease inhibitor (SERPIN) B1 promotes oral cancer motility over-expressed in invasive oral squamous cell carcinoma. Oral Oncol. 2009;45(9):771–6.CrossRefGoogle Scholar
  30. 30.
    Kumar R, Tiwari AK, Chaturvedi U, et al. Velogenic Newcastle disease virus as an oncolytic virotherapeutics: in vitro characterization. Appl Biochem Biotechnol. 2012;167(7):2005–22.CrossRefPubMedGoogle Scholar
  31. 31.
    Wu Y, Zhang X, Wang X, et al. Apoptin enhance the oncolytic properties of Newcastle disease virus. Intervirology. 2012;55(4):276–86.CrossRefPubMedGoogle Scholar
  32. 32.
    Li P, Chen CH, Li S, et al. Therapeutic effects of a fusogenic Newcastle disease virus in treating head and neck cancer. Head Neck. 2011;33(10):1394–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Silberhumer GR, Brader P, Wong J, et al. Genetically engineered oncolytic Newcastle disease virus effectively induces sustained remission of malignant pleural mesothelioma. Mol Cancer Ther. 2010;9(10):2761–9.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Song KY, Wong J, Gonzalez L, et al. Antitumor efficacy of viral therapy using genetically engineered Newcastle disease virus [NDV(F3aa)-GFP] for peritoneally disseminated gastric cancer. J Mol Med (Berl). 2010;88(6):589–96.CrossRefGoogle Scholar
  35. 35.
    Fu F, Zhao M, Yang YJ, et al. Antiproliferative effect of Newcastle disease virus strain D90 on human lung cancer line A549. Oncol Res. 2011;19(7):323–33.CrossRefPubMedGoogle Scholar
  36. 36.
    Washburn B, Weiqand MA, Grosse-Wilde A, et al. TNF-related apoptosis-inducing ligand mediates tumoricidal activity of human monocytes stimulated by Newcastle disease virus. J Immunol. 2003;170(4):1814–21.CrossRefPubMedGoogle Scholar
  37. 37.
    Fábián Z, Csatary CM, Szeberényi J, Csatary LK. P53-independent endoplasmic reticulum stress-mediated cytotoxicity of a Newcastle disease virus strain in tumor cell lines. J Virol. 2007;81(6):2817–30.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Marek Ł. The role of the apoptosome in the activation of procaspase-9. Postepy Hig Med Dosw (Online). 2013;67:54–64.CrossRefGoogle Scholar
  39. 39.
    Salvesen GS. Caspases and apoptosis. Biochemistry. 2002;38:9–19.Google Scholar
  40. 40.
    Molouki A, Hsu YT, Jahanshiri F, Rosli R, Yusoff K. Newcastle disease virus infection promotes Bax redistribution to mitochondria and cell death in HeLa cells. Intervirology. 2010;53(2):87–94.CrossRefPubMedGoogle Scholar
  41. 41.
    Ravindra PV, Tiwari AK, Ratta B, et al. Newcastle disease virus-induced cytopathic effect in infected cells is caused by apoptosis. Virus Res. 2009;141(1):13–20.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Chun-Xiao Zhang
    • 1
  • Long-Wei Ye
    • 1
  • Ying Liu
    • 1
  • Xiao-Ya Xu
    • 1
  • Dan-Rui Li
    • 1
  • Yan-Qing Yang
    • 1
  • Lu-Lu Sun
    • 1
  • Jie Yuan
    • 1
  1. 1.Department of Oral Health SciencesThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina

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