Association Between E6 and E7 Human Papilloma Virus Type 16 Oncogen Mutations and P21 Protein Expression in Cervical Cancer

I Nyoman Bayu Mahendra; I Nyoman Gede Budiana; Made Suyasa Jaya; I Gede Mega Putra; I Nyoman Hariyasa Sanjaya; Musa Taufiq

doi:10.24018/ejmed.2023.5.1.1390

Research Article

I Nyoman Bayu Mahendra

Udayana University, Indonesia

I Nyoman Gede Budiana

Udayana University, Indonesia

Made Suyasa Jaya

Udayana University, Indonesia

I Gede Mega Putra

Udayana University, Indonesia

I Nyoman Hariyasa Sanjaya

Udayana University, Indonesia

Musa Taufiq

Udayana University, Indonesia

* Corresponding author

10.24018/ejmed.2023.5.1.1390

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Submitted 2022-06-14
Published 2023-02-28

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Abstract

Cervical cancer is a disease characterized by the growth of abnormal cells in the cervical tissue. Cervical cancer is mostly caused by Human Papillomavirus (HPV) types 16 and 18. The role of genetic factors in the development of cervical malignancy is mediated by the presence of a mutation in the HPV 16 oncogene, especially oncogenes E6 and E7. Oncogenic proteins E6 and E7 in HPV initiate dysregulation of cellular proliferation and apoptotic mechanisms by targeting tumor suppressor proteins, such as the p21 protein. The purpose of this study was to assess the association between mutations in the E6 and E7 oncogenes of HPV-HR Type 16 and the pattern of p21 protein expression. This cross-sectional study was conducted at the Obstetrics and Gynecology Polyclinic of Prof. Dr. I.G.N.G. Ngoerah Hospital, from September 2020 to September 2021. The material taken was cervical cancer tissue from cervical cancer patients and then put into a preservative solution and then put in a cooler. DNA isolation was performed, and PCR was performed to determine positive and negative HPV. The amplification of the E6 and E7 genes was carried out before the sequencing and analysis of the E6 and E7 gene mutations was carried out. Then, immunohistochemical staining of p21 was carried out, followed by data analysis using SPSS for windows version 22.0. There were no significant differences in characteristics between the two groups. There was no association between mutations in the E6 and E7 HPV Type 16 oncogenes with p21 protein expression in cervical cancer cases (p-value 0.22).

Keywords: cervical cancer human papilloma virus E6 and E7 oncogenes

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cornet I, Gheit T, Franceschi S, Vignat J, Burk RD, Sylla BS, et al. 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

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

Nogueira MO, Hošek T, Calçada EO, Castiglia F, Massimi P, Banks L, et al. Monitoring HPV-16 E7 phosphorylation events. Virology. 2017;503:70-75. doi:10.1016/j.virol.2016.12.030.
DOI | Google Scholar

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

Chen Z, Li Q, Huang J, Li J, Yang F, Min X, et al. 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

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

He J, Li T, Wang Y, Song Z, Li Q, Liu Y, et al. 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

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

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

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

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Association Between E6 and E7 Human Papilloma Virus Type 16 Oncogen Mutations and P21 Protein Expression in Cervical Cancer . (2023). European Journal of Medical and Health Sciences, 5(1), 85-90. https://doi.org/10.24018/ejmed.2023.5.1.1390

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[1] 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

[2] 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

[3] 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

[4] 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

[5] 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

[6] 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

[7] 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

[8] 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

[9] 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

[10] 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

[11] 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

[12] 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

[13] 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

[14] 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

[15] 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

[16] 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

[17] 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

[18] Cornet I, Gheit T, Franceschi S, Vignat J, Burk RD, Sylla BS, et al. 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

[19] 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

[20] Nogueira MO, Hošek T, Calçada EO, Castiglia F, Massimi P, Banks L, et al. Monitoring HPV-16 E7 phosphorylation events. Virology. 2017;503:70-75. doi:10.1016/j.virol.2016.12.030.
DOI | Google Scholar

[21] 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

[22] Chen Z, Li Q, Huang J, Li J, Yang F, Min X, et al. 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

[23] 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

[24] He J, Li T, Wang Y, Song Z, Li Q, Liu Y, et al. 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

[25] 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

[26] 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

[27] 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

Association Between E6 and E7 Human Papilloma Virus Type 16 Oncogen Mutations and P21 Protein Expression in Cervical Cancer

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