Mechanistic links between HPV16/18 E6 and lung cancer


Downloads: 592
Keith Jeng 1, Marisa Chang 1, Steve Pili 1, Christian Ellis 2, Kebba Dhanda 2, Xing Lee 3,  Per Fielding 1*
Author Affiliations
∗Correspondence author e-mail: behnamzamanzad5@gmail.com: 1Division of Thoracic Surgery, Columbia University. 2Biochemistry Department, Institute for Molecular Virology, University of Minnesota, 3Department of Pathology, China Medical University Hospital, Taiwan

 

Abstract

Lung cancer has emerged as a global public health issue. Recent studies have consistently linked the presence of HPV16/18 E6 to the development of lung cancer as oncoproteins. HPV16/18 E6 and E7 have been shown to regulate the expression of various target genes and proteins including p53/pRb, VEGF, HIF-1α, cIAP-2, and hTERT, and contribute to cell proliferation, angiogenesis, and cell immortalization. We hypothesized that HPV16/18 E6 links to development of lung cancer through activation of HIF-1α/ VEGF signaling. Lung cancer patients eligible for surgical treatment were tested for the presence of HPV16/18 E6 in excised tumor tissue. HPV16/18 E6 detection and genotyping was performed using facility of a polymerase chain reaction and immunohistochemistry. Of the 292 tumor samples tested, 98 samples showed presence of HPV16/18 E6, and significantly, high in nonsmoker patients. Furthermore, overexpression of HPV16/18 E6 associated with increased level of HIF-1α and VEGF, that demonstrated by using reporter gene assays. We conclude that HPV16/18 E6 is strongly associated with lung cancer and might represent novel therapeutic targets to manage lung cancer.

Key words: Lung cancer; HPV16/18 E6; HIF-1α; VEGF; Immunohistochemistry

Copyright © 2014 by The American Society for BioMedicine and BM-Publisher, Inc.

Article citationReferencesFull-Text/PDFBecome reviewer
The citation data is computed by the following citation measuring services:

Cited by (CrossRef)
Google Scholar

  1. Syrjänen K. Detection of human papillomavirus in lung cancer: systematic review and meta-analysis. Anticancer Res. 2012;32:3235–3250.
  2. Ioannidis JP, et al. Uncertainty in heterogeneity estimates in meta-analyses. Br. Med. J. 2007;335:914–916.
  3. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. Ca: A Cancer Journal for Clinicians. 2005;55(2):74–108.
  4. Stremlau A, et al. Human papillomavirus type 16 related DNA in an anaplastic carcinoma of the lung. Cancer. 1985;55:1737–1740.
  5. Jacob SE, Sreevidya S, Chacko E, Pillai MR. Cellular manifestations of human papilloma virus infection in laryngeal tissues. Journal of Surgical Oncology. 2002;79:142–150.
  6. Ferenczy A, Franco E. Persistent human papillomavirus infection and cervical neoplasia. The Lancet Oncology. 2002;3(1):11–16.
  7. Brouchet L, et al. Detection of oncogenic virus genomes and gene products in lung carcinoma. Br. J. Cancer. 2005;92:743–746.
  8. Fei Y, et al. Different human papillomavirus 16/18 infection in Chinese non-small cell lung cancer patients living in Wuhan, China. Jpn. J. Clin. Oncol. 2006;36:274–279.
  9. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers—a different disease. Nature Reviews Cancer. 2007;7(10):778–790.
  10. Yousem SA, et al. Occurrence of human papillomavirus DNA in primary lung neoplasms. Cancer. 1992;69:693–97.
  11. Smith EM, Ritchie JM, Summersgill KF, et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. International Journal of Cancer. 2004;108(5):766–772.
  12. Bejui-Thivolet F, et al. Detection of human papillomavirus DNA in squamous bronchial metaplasia and squamous cell carcinomas of the lung by in situ hybridization using biotinylated probes in paraffin-embedded specimens. Hum. Pathol. 1990;21:111–116.
  13. Bodaghi S, Wood LV, Roby G, Ryder C, Steinberg SM, Zheng ZM. Could human papillomaviruses be spread through blood? Journal of Clinical Microbiology. 2005;43(11):5428–5434.
  14. Cheng YW, et al. The association of human papillomavirus 16/18 E6 oncoprotein and survival in patients with stage I non small cell lung cancer. Oncol. Rep. 2009;21:81–87.
  15. Giroglou T, Florin L, Schäfer F, Streeck RE, Sapp M. Human papillomavirus infection requires cell surface heparan sulfate. Journal of Virology. 2001;75(3):1565–1570.
  16. Rinehart J, Adjei AA, LoRusso PM, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. Journal of Clinical Oncology. 2004;22(22):4456–4462.
  17. Hirayasu T, et al. Human papillomavirus DNA in squamous cell carcinoma of the lung. J. Clin. Pathol. 1996;49:810–817.
  18. Kelly K, Herbst RS, Crowley JJ, et al. Concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in advanced non-small cell lung cancer (NSCLC): a randomized phase II selectional trial SWOG 0342. Journal of Clinical Oncology. 2006;l24(18S):p. 7015.
  19. Klein F, et al. Incidence of human papilloma virus in lung cancer. Lung Cancer. 2009;65:13–18.
  20. Mathur RS, Mathur SP. Vascular endothelial growth factor (VEGF) up-regulates epidermal growth factor receptor (EGF-R) in cervical cancer in vitro: this action is mediated through HPV-E6 in HPV-positive cancers. Gynecologic Oncology. 2005;97(1):206–213.
  21. Brake T, Lambert PF. Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(7):2490–2495.
  22. Ragin CC, et al. 11q13 amplification status and human papillomavirus in relation to p16 expression defines two distinct etiologies of head and neck tumours. Br. J. Cancer. 2006;95:1432–1438.
  23. Crusius K, Auvinen E, Steuer B, Gaissert H, Alonso A. The human papillomavirus type 16 E5-protein modulates ligand-dependent activation of the EGF receptor family in the human epithelial cell line HaCaT. Experimental Cell Research. 1998;241(1):76–83.
  24. zur Hausen H. Cervical carcinoma and human papillomavirus: on the road to preventing a major human cancer. J. Natl Cancer Inst. 2001;93:252–253.
  25. Wu HH, Wu JY, Cheng YW, et al. cIAP2 upregulated by E6 oncoprotein via epidermal growth factor receptor/phosphatidylinositol 3-kinase/AKT pathway confers resistance to cisplatin in human papillomavirus 16/18-infected lung cancer. Clinical Cancer Research. 2010;16(21):5200–5210.
  26. Hajdu SI, et al. Discovery of human papillomavirus in carcinoma of the lung. Ann. Clin. Lab. Sci. 2008;38:3–5.
  27. Pillai MR, Halabi S, McKalip A, et al. The presence of human papillomavirus-16/-18 E6, p53, and bcl-2 protein in cervicovaginal smears from patients with invasive cervical cancer. Cancer Epidemiology Biomarkers and Prevention. 1996;5(5):329–335.
  28. Wang Y, et al. Human papillomavirus type 16 and 18 infection is associated with lung cancer patients from the central part of China. Oncol. Rep. 2008;20:333–339.
  29. Aguayo F, et al. Human papillomavirus-16 is integrated in lung carcinomas: a study in Chile. Br. J. Cancer. 2007;97:85–91.

3. Purchase this article at rate $33.00

For any technique error please contact us 

Who Can Become a Reviewer?
Any expert in the article's research field can become a reviewer with American Journal of Biomedicine. Editors might ask you to look at a specific aspect of an article,...

Find out more

Review Article
DOI: http://dx.doi.org/10.18081/2333-5106/014-08/199-212
American Journal of BioMedicine 2014, Volume 2, Issue 3, pages 199-212
Received 11 April 2014; accepted July 20, 2014, Published August 27, 2014

How to cite this article
Jeng k, Chang M, Pili S, Ellis C, Dhanda K, Lee X, Fielding P. Mechanistic links between HPV16/18 E6 and lung cancer. American Journal of BioMedicine 2014;2(3):199-212.

Case report outline
1. Abstract
2. Keywords
3. Introduction
4. Methods
5. Results
6. Discussion
7. References

Article metric