Research Article

E6/E7 Oncogenes Mutation of Human Papillomavirus Type 16 Associated with P16 Protein Expression in Cervical Cancer

I Nyoman Bayu Mahendra
Udayana University, Indonesia
I Nyoman Gede Budiana
Udayana University, Indonesia
I Gede Mega Putra
Udayana University, Indonesia
Ryan Saktika Mulyana
Udayana University, Indonesia
I Gde Sastra Winata
Udayana University, Indonesia
Budi Setiawan Harjoto
Udayana University, Indonesia
* Corresponding author
DOI icon 10.24018/ejmed.2023.5.2.1404

Read Counter
698

Downloads
265

Citations

Share

Article Sidebar

Submitted 2022-07-03
Published 2023-04-24

Read counter = 698 times

Table of Contents

Article Main Content

The genetic composition of the E6 and E7 oncogenes is very susceptible to mutation. Mutations occur due to interactions between the viral genome and the host. Changes in one nucleotide oncogenes E6 and E7 can affect the function of these oncogenes so that they can trigger the persistence of Human Papilloma Virus (HPV) infection and cervical cancer progression in several intratypic variants of HPV type 16 and alteration p16 expression in cervical cancer cases. This study was conducted on cervical cancer women first diagnosed from May 2021 to November 2021 who had not received surgery, chemotherapy, or radiation therapy. Willing to participate in the study after signing the informed consent. Cervical tissue samples with a positive test result for HPV 16 were then grouped based on the mutation sequencing of E6 and E7 into a wild-type group and a mutant group. Furthermore, the immunohistochemical examination was carried out to assess the expression of p16 protein in paraffin blocks. The results of this study showed that there was no association between mutations in the E6 and E7 oncogenes of HPV Type 16 with p16 expression (c= 0.048 and p value 0.78). The expression of p16 was stronger in the mutant group with the median percentage of cells from p16 immunohistochemistry staining which was 60.5% (range 3-73%) in the mutant group and 53% (range 2-65%) in the wild type of group. However, the correlation coefficient interval between HPV type 16 and E6 oncogene mutations with p16 protein expression is very weak.

Keywords: cervical cancer E6 E7 HPV oncogene mutation protein expression relationship

References

  1. Jones DL, Alani RM, Münger K. The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2. Genes Dev. 1997;11(16):2101-2111. doi:10.1101/gad.11.16.2101..
    DOI  |   Google Scholar
  2. Prati B, Marangoni B, Boccardo E. Human papillomavirus and genome instability: from productive infection to cancer. Clinics (Sao Paulo). 2018;73(suppl 1):e539s. Published 2018 Sep 6. doi:10.6061/clinics/2018/e539s
    DOI  |   Google Scholar
  3. Kashyap N, Krishnan N, Kaur S, Ghai S. Risk Factors of Cervical Cancer: A Case-Control Study. Asia Pac J Oncol Nurs. 2019;6(3):308-314. doi:10.4103/apjon.apjon_73_18.
    DOI  |   Google Scholar
  4. Gupta SM, Mania-Pramanik J. Molecular mechanisms in progression of HPV-associated cervical carcinogenesis [retracted in: J Biomed Sci. 2019 Jul 04;26(1):50]. J Biomed Sci. 2019;26(1):28. Published 2019 Apr 23. doi:10.1186/s12929-019-0520-2.
    DOI  |   Google Scholar
  5. Pal A, Kundu R. Human Papillomavirus E6 and E7: The Cervical Cancer Hallmarks and Targets for Therapy. Front Microbiol. 2020;10:3116. Published 2020 Jan 21. doi:10.3389/fmicb.2019.03116.
    DOI  |   Google Scholar
  6. Sen P, Ganguly P, Ganguly N. Modulation of DNA methylation by human papillomavirus E6 and E7 oncoproteins in cervical cancer. Oncol Lett. 2018;15(1):11-22. doi:10.3892/ol.2017.7292.
    DOI  |   Google Scholar
  7. Knudsen ES, Witkiewicz AK. The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies. Trends Cancer. 2017;3(1):39-55. doi:10.1016/j.trecan.2016.11.006.
    DOI  |   Google Scholar
  8. Georgakilas AG, Martin OA, Bonner WM. p21: A Two-Faced Genome Guardian. Trends Mol Med. 2017;23(4):310-319. doi:10.1016/j.molmed.2017.02.001.
    DOI  |   Google Scholar
  9. Mesri EA, Feitelson MA, Munger K. Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe. 2014;15(3):266-282. doi:10.1016/j.chom.2014.02.011.
    DOI  |   Google Scholar
  10. Wei L, Griego AM, Chu M, Ozbun MA. Tobacco exposure results in increased E6 and E7 oncogene expression, DNA damage and mutation rates in cells maintaining episomal human papillomavirus 16 genomes. Carcinogenesis. 2014;35(10):2373-2381. doi:10.1093/carcin/bgu156.
    DOI  |   Google Scholar
  11. Wulandari D, Rachmadi L and Sudiro TM. Phylogenetic analysis and predicted functional effect of protein mutations of E6 and E7 HPV16 strains isolated in Indonesia. Med J Indones. 2015;24(1):197–205.
    DOI  |   Google Scholar
  12. Rédei GP. Blast (basic local alignment search tool). Encycl Genet Genomics. Proteomics Informatics. 2008;221–221.Engeland K. Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Differ. 2018;25(1):114-132. doi:10.1038/cdd.2017.172.
    DOI  |   Google Scholar
  13. Ahmed SA, Obaseki DE, Mayun AA, Mohammed A, Rafindadi AH and Abdul MA. The Role of Biomarkers (p16INK4a and Ki-67) in Cervical Cancer Screening: An Appraisal. Ann Trop Pathol. 2017;8: 20–23. doi:10.4103/atp.atp_3_17.
    DOI  |   Google Scholar
  14. Kishore V, Patil AG. Expression of p16INK4A Protein in Cervical Intraepithelial Neoplasia and Invasive Carcinoma of Uterine Cervix. J Clin Diagn Res. 2017;11(9):EC17-EC20. doi:10.7860/JCDR/2017/29394.10644.
    DOI  |   Google Scholar
  15. Jackson R, Togtema M, Lambert PF, Zehbe I. Tumourigenesis driven by the human papillomavirus type 16 Asian-American e6 variant in a three-dimensional keratinocyte model. PLoS One. 2014;9(7):e101540. Published 2014 Jul 1. doi:10.1371/journal.pone.0101540.
    DOI  |   Google Scholar
  16. Moody CA, Laimins LA. Human papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiation. PLoS Pathog. 2009;5(10):e1000605. doi:10.1371/journal.ppat.1000605.
    DOI  |   Google Scholar
  17. Fradet-Turcotte A, Bergeron-Labrecque F, Moody CA, Lehoux M, Laimins LA, Archambault J. Nuclear accumulation of the papillomavirus E1 helicase blocks S-phase progression and triggers an ATM-dependent DNA damage response. J Virol. 2011;85(17):8996-9012. doi:10.1128/JVI.00542-11.
    DOI  |   Google Scholar
  18. Dehlendorff C, Baandrup L, Kjaer SK. Real-World Effectiveness of Human Papillomavirus Vaccination Against Vulvovaginal High-Grade Precancerous Lesions and Cancers. J Natl Cancer Inst. 2021;113(7):869-874. doi:10.1093/jnci/djaa209.
    DOI  |   Google Scholar
  19. Cornet I, Gheit T, Franceschi S. Human papillomavirus type 16 genetic variants: phylogeny and classification based on E6 and LCR. J Virol. 2012;86(12):6855-6861. doi:10.1128/JVI.00483-12.
    DOI  |   Google Scholar
  20. Araujo-Arcos LE, Montaño S, Bello-Rios C, Garibay-Cerdenares OL, Leyva-Vázquez MA, Illades-Aguiar B. Molecular insights into the interaction of HPV-16 E6 variants against MAGI-1 PDZ1 domain. Sci Rep. 2022;12(1):1898. Published 2022 Feb 3. doi:10.1038/s41598-022-05995-1.
    DOI  |   Google Scholar
  21. Nogueira MO, Hošek T, Calçada EO. Monitoring HPV-16 E7 phosphorylation events. Virology. 2017;503:70-75. doi:10.1016/j.virol.2016.12.030.
    DOI  |   Google Scholar
  22. Gheit T. Mucosal and Cutaneous Human Papillomavirus Infections and Cancer Biology. Front Oncol. 2019;9:355. Published 2019 May 8. doi:10.3389/fonc.2019.00355.
    DOI  |   Google Scholar
  23. Chen Z, Li Q, Huang J. E6 and E7 gene polymorphisms in human papillomavirus Type-6 identified in Southwest China. Virol J. 2019;16(1):114. Published 2019 Sep 12. doi:10.1186/s12985-019-1221-x.
    DOI  |   Google Scholar
  24. Lou H, Boland JF, Burk R, Yeager M, Wentzensen N, Schiffman M, Mirabello L, Dean M. HPV16 E7 Nucleotide Variants Found in Cancer-Free Subjects Affect E7 Protein Expression and Transformation. Eur PMC. 2021;1(1). doi: 10.20944/preprints202111.0134.v1.
    DOI  |   Google Scholar
  25. He J, Li T, Wang Y. Genetic variability of human papillomavirus type 39 based on E6, E7 and L1 genes in Southwest China. Virol J. 2021;18(1):72. Published 2021 Apr 8. doi:10.1186/s12985-021-01528-w.
    DOI  |   Google Scholar
  26. Tan H, Bao J, Zhou X. A novel missense-mutation-related feature extraction scheme for 'driver' mutation identification. Bioinformatics. 2012;28(22):2948-2955. doi:10.1093/bioinformatics/bts558.
    DOI  |   Google Scholar
  27. Chu D and Wei L. Nonsynonymous, synonymous and nonsense mutations in human cancer-related genes undergo stronger purifying selections than expectation. BMC Cancer. 2019;19(1):359. doi: 10.1186/s12885-019-5572-x.
    DOI  |   Google Scholar
  28. Benisty H, Weber M, Hernandez-Alias X, Schaefer MH, Serrano L. Mutation bias within oncogene families is related to proliferation-specific codon usage. Proc Natl Acad Sci U S A. 2020;117(48):30848-30856. doi:10.1073/pnas.2016119117.
    DOI  |   Google Scholar
  29. Leemann-Zakaryan RP, Pahlich S, Grossenbacher D, Gehring H. Tyrosine Phosphorylation in the C-Terminal Nuclear Localization and Retention Signal (C-NLS) of the EWS Protein. Sarcoma. 2011;2011:218483. doi:10.1155/2011/218483.
    DOI  |   Google Scholar
  30. Mavinakere MS, Powers JM, Subramanian KS, Roggero VR, Allison LA. Multiple novel signals mediate thyroid hormone receptor nuclear import and export. J Biol Chem. 2012;287(37):31280-31297. doi:10.1074/jbc.M112.397745.
    DOI  |   Google Scholar
  31. Gao R, Wong SM. Basic amino acid mutations in the nuclear localization signal of hibiscus chlorotic ringspot virus p23 inhibit virus long distance movement. PLoS One. 2013;8(9):e74000. Published 2013 Sep 3. doi:10.1371/journal.pone.0074000.
    DOI  |   Google Scholar


Most read articles by the same author(s)

<< < 1 2 3 4 > >>