1887

Abstract

Nodal may play an important role in the development of cancers. The present study was designed to determine the effects of Nodal induced by respiratory syncytial virus (RSV) infection on the occurrence and development of lung cancer and the underlying mechanisms.

After verification of RSV infection by observation of cytopathic effect and indirect immunofluorescence, real-time PCR, Western blot and methylation assays were used to verify the influence of RSV on Nodal expression. Then, a Nodal overexpressed vector was constructed and the effects of Nodal on the proliferation and apoptosis of bronchial epithelial cells (BECs) and epithelial-mesenchymal transition (EMT) were assayed by flow cytometry and Western blot, respectively. Moreover, Lefty and pSmad2/3 were assayed by Western blot and Cyclin D1, CDK4, c-myc and Bcl-2 induced by Nodal overepression or RSV infection were also assayed by real-time PCR.

The results showed that Nodal over expression and demethylation of the promoter were observed in BECs after RSV infection. Activation of Nodal promoted proliferation, colony formation and EMT and inhibited apoptosis of BECs. Nodal also promoted malignant change by promoting expression of cyclin D1 and related-dependent kinase and inhibiting apoptosis. Besides, RSV infection inhibited Lefty expression and promoted the activation of pSmad2/3. RSV also promoted Cyclin D1, CDK4, c-myc and Bcl-2 expression through the activation of pSmad2/3.

Our data showed that persistence of RSV promoted the proliferation, epithelial-mesenchymal transition and expression of oncogenes through Nodal signaling, which may be associated with the occurrence and development of lung cancers.

Keyword(s): EMT , lung cancer , nodal , proliferation and RSV
Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.000581
2017-10-01
2020-01-22
Loading full text...

Full text loading...

/deliver/fulltext/jmm/66/10/1499.html?itemId=/content/journal/jmm/10.1099/jmm.0.000581&mimeType=html&fmt=ahah

References

  1. Lin FC, Huang JY, Tsai SC, Nfor ON, Chou MC et al. The association between human papillomavirus infection and female lung cancer: a population-based cohort study. Medicine 2016;95:e3856 [CrossRef][PubMed]
    [Google Scholar]
  2. Giuliani L, Jaxmar T, Casadio C, Gariglio M, Manna A et al. Detection of oncogenic viruses SV40, BKV, JCV, HCMV, HPV and p53 codon 72 polymorphism in lung carcinoma. Lung Cancer 2007;57:273–281 [CrossRef][PubMed]
    [Google Scholar]
  3. Jafarian AH, Omidi-Ashrafi A, Mohamadian-Roshan N, Karimi-Shahri M, Ghazvini K et al. Association of Epstein Barr virus deoxyribonucleic acid with lung carcinoma. Indian J Pathol Microbiol 2013;56:359–364 [CrossRef][PubMed]
    [Google Scholar]
  4. Brouchet L, Valmary S, Dahan M, Didier A, Galateau-Salle F et al. Detection of oncogenic virus genomes and gene products in lung carcinoma. Br J Cancer 2005;92:743–746 [CrossRef][PubMed]
    [Google Scholar]
  5. Zomer-Kooijker K, van der Ent CK, Ermers MJ, Uiterwaal CS, Rovers MM et al. Increased risk of wheeze and decreased lung function after respiratory syncytial virus infection. PLoS One 2014;9:e87162 [CrossRef][PubMed]
    [Google Scholar]
  6. Sikkel MB, Quint JK, Mallia P, Wedzicha JA, Johnston SL. Respiratory syncytial virus persistence in chronic obstructive pulmonary disease. Pediatr Infect Dis J 2008;27:S63–S70 [CrossRef][PubMed]
    [Google Scholar]
  7. Piedimonte G, Perez MK. Alternative mechanisms for respiratory syncytial virus (RSV) infection and persistence: could RSV be transmitted through the placenta and persist into developing fetal lungs?. Curr Opin Pharmacol 2014;16:82–88 [CrossRef][PubMed]
    [Google Scholar]
  8. Spann KM, Baturcam E, Schagen J, Jones C, Straub CP et al. Viral and host factors determine innate immune responses in airway epithelial cells from children with wheeze and atopy. Thorax 2014;69:918–925 [CrossRef][PubMed]
    [Google Scholar]
  9. Pickles RJ. Human airway epithelial cell cultures for modeling respiratory syncytial virus infection. Curr Top Microbiol Immunol 2013;372:371–387 [CrossRef][PubMed]
    [Google Scholar]
  10. Tan Y, Yang T, Liu S, Liu H, Xiang Y et al. Infection with respiratory syncytial virus alters peptidergic innervation in the lower airways of guinea-pigs. Exp Physiol 2008;93:1284–1291 [CrossRef][PubMed]
    [Google Scholar]
  11. Tan YR, Peng D, Chen CM, Qin XQ. Nonstructural protein-1 of respiratory syncytial virus regulates HOX gene expression through interacting with histone. Mol Biol Rep 2013;40:675–679 [CrossRef][PubMed]
    [Google Scholar]
  12. Qin L, Peng D, Hu C, Xiang Y, Zhou Y et al. Differentiation of Th subsets inhibited by nonstructural proteins of respiratory syncytial virus is mediated by ubiquitination. PLoS One 2014;9:e101469 [CrossRef][PubMed]
    [Google Scholar]
  13. Heijink IH, Postma DS, Noordhoek JA, Broekema M, Kapus A. House dust mite-promoted epithelial-to-mesenchymal transition in human bronchial epithelium. Am J Respir Cell Mol Biol 2010;42:69–79 [CrossRef][PubMed]
    [Google Scholar]
  14. Krohn A, Ahrens T, Yalcin A, Plönes T, Wehrle J et al. Tumor cell heterogeneity in small cell lung cancer (SCLC): phenotypical and functional differences associated with epithelial-mesenchymal transition (EMT) and DNA methylation changes. PLoS One 2014;9:e100249 [CrossRef][PubMed]
    [Google Scholar]
  15. Aykul S, Ni W, Mutatu W, Martinez-Hackert E. Human cerberus prevents nodal-receptor binding, inhibits nodal signaling, and suppresses nodal-mediated phenotypes. PLoS One 2015;10:e0114954 [CrossRef][PubMed]
    [Google Scholar]
  16. Fu G, Peng C. Nodal enhances the activity of FoxO3a and its synergistic interaction with smads to regulate cyclin G2 transcription in ovarian cancer cells. Oncogene 2011;30:3953–3966 [CrossRef][PubMed]
    [Google Scholar]
  17. Vo BT, Khan SA. Expression of nodal and nodal receptors in prostate stem cells and prostate cancer cells: autocrine effects on cell proliferation and migration. Prostate 2011;71:1084–1096 [CrossRef][PubMed]
    [Google Scholar]
  18. Wang L, Wu G, Qin X, Ma Q, Zhou Y et al. Expression of nodal on bronchial epithelial cells influenced by lung microbes through dna methylation modulates the differentiation of T-helper cells. Cell Physiol Biochem 2015;37:2012–2022 [CrossRef][PubMed]
    [Google Scholar]
  19. Johnson JR, Nishioka M, Chakir J, Risse PA, Almaghlouth I et al. IL-22 contributes to TGF-β1-mediated epithelial-mesenchymal transition in asthmatic bronchial epithelial cells. Respir Res 2013;14:118 [CrossRef][PubMed]
    [Google Scholar]
  20. Klauzinska M, Castro NP, Rangel MC, Spike BT, Gray PC et al. The multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition. Semin Cancer Biol 2014;29:51–58 [CrossRef][PubMed]
    [Google Scholar]
  21. Tsuchida K, Nakatani M, Uezumi A, Murakami T, Cui X. Signal transduction pathway through activin receptors as a therapeutic target of musculoskeletal diseases and cancer. Endocr J 2008;55:11–21 [CrossRef][PubMed]
    [Google Scholar]
  22. Juan H, Hamada H. Roles of nodal-lefty regulatory loops in embryonic patterning of vertebrates. Genes Cells 2001;6:923–930 [CrossRef][PubMed]
    [Google Scholar]
  23. Fan X, Yu K, Wu J, Shao J, Zhu L et al. Correlation between squamous cell carcinoma of the lung and human papillomavirus infection and the relationship to expression of p53 and p16. Tumour Biol 2015;36:3043–3049 [CrossRef][PubMed]
    [Google Scholar]
  24. Casimiro MC, Velasco-Velázquez M, Aguirre-Alvarado C, Pestell RG. Overview of cyclins D1 function in cancer and the CDK inhibitor landscape: past and present. Expert Opin Investig Drugs 2014;23:295–304 [CrossRef][PubMed]
    [Google Scholar]
  25. Wilken R, Veena MS, Wang MB, Srivatsan ES. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol Cancer 2011;10:12 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.000581
Loading
/content/journal/jmm/10.1099/jmm.0.000581
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error