Association of estradiol and HPV/HPV16 infection with the occurrence of cervical squamous cell carcinoma

Ding,Ling; Liu,Chunliang; Zhou,Qin; Feng,Meijuan; Wang,Jintao

doi:10.3892/ol.2019.10005

Association of estradiol and HPV/HPV16 infection with the occurrence of cervical squamous cell carcinoma

Authors:
- Ling Ding
- Chunliang Liu
- Qin Zhou
- Meijuan Feng
- Jintao Wang
View Affiliations

Affiliations: Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
Published online on: February 1, 2019 https://doi.org/10.3892/ol.2019.10005
Pages: 3548-3554

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The associations between human papillomavirus (HPV) infection or hormonal exposure and cervical cancer risk are well established. However, to the best of our knowledge, the association between high endogenous estradiol levels in conjunction with HPV/HPV16 infection and the risk of cervical squamous cell carcinoma remains unknown. To investigate this, the current study conducted a matched case‑control study in Shanxi Province, China, in which clinical samples were obtained from 74 females with newly diagnosed uterine cervix squamous cell carcinoma and 74 matched healthy females who were selected from 582 healthy females according to age, place of residence, marital status and menopausal status. From all participants, DNA was extracted from cells obtained from a cervical smear and serum was separated from venous blood withdrawn during days 5‑8 of the menstrual cycle. HPV/HPV16 DNA and estradiol expression levels in the serum were measured by general polymerase chain reaction and enzyme‑linked immunosorbent assay, respectively. Significant differences were identified in the positive HPV and HPV16 DNA expression rates between patients and controls, with odds ratios (95% confidence interval) of 3.74 (1.84‑7.59) and 4.04 (1.97‑8.28), respectively. Expression levels of estradiol in patients were significantly higher compared with the controls (P<0.001), however, this was only identified when the HPV16 E2 or E6 oncogene status was negative. Considering 40 ng/ml as the cut‑off estradiol level, 78.38% of patients exhibited high estradiol levels, which was significantly higher than the percentage of controls (P<0.001). An additive interaction pattern was revealed between estradiol expression levels and HPV/HPV16 infection. The results suggest that among the various types of HPV, HPV16 may be most likely to cause uterine cervix squamous cell carcinoma and an abnormally high level of endogenous estradiol may further increase this risk. Therefore, estradiol therapy may represent a new treatment strategy for cases of cervical cancer associated with HPV infection.

View Figures

View References

1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
2	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
3	Skinner RS, Wheeler CM, Romanowski B, Castellsagué X, Lazcano-Ponce E, Del Rosario-Raymundo RM, Vallejos C, Minkina G, Pereira Da Silva D, McNeil S, et al: Progression of HPV infection to detectable cervical lesions or clearance in adult women: Analysis of the control arm of the VIVIANE study. Int J Cancer. 138:2428–2438. 2016. View Article : Google Scholar : PubMed/NCBI
4	Madeleine MM, Anttila T, Schwartz SM, Saikku P, Leinonen M, Carter JJ, Wurscher M, Johnson LG, Galloway DA and Daling JR: Risk of cervical cancer associated with Chlamydia trachomatis antibodies by histology, HPV type and HPV cofactors. Int J Cancer. 120:650–655. 2007. View Article : Google Scholar : PubMed/NCBI
5	Choi YJ and Park JS: Clinical significance of human papillomavirus genotyping. J Gynecol Oncol. 7:e212016. View Article : Google Scholar
6	Egawa N, Egawa K, Griffin H and Doorbar J: Human papillomaviruses: epithelial tropisms, and the development of neoplasia. Viruses. 7:3863–3890. 2015. View Article : Google Scholar : PubMed/NCBI
7	Bellanger S, Tan CL, Xue YZ, Teissier S and Thierry F: Tumor suppressor or oncogene? A critical role of the human papillomavirus (HPV) E2 protein in cervical cancer progression. Am J Cancer Res. 1:373–389. 2011.PubMed/NCBI
8	Doorbar J, Egawa N, Griffin H, Kranjec C and Murakami I: Human papillomavirus molecular biology and disease association. Rev Med Virol. 25 (Suppl 1):S2–S23. 2015. View Article : Google Scholar
9	Wang JT, Ding L, Gao ES and Cheng YY: Analysis on the expression of human papillomavirus type 16 E2 and E6 oncogenes and disruption of E2 in cervical cancer. Zhonghua Liu Xing Bing Xue Za Zhi. 28:968–971. 2007.(In Chinese). PubMed/NCBI
10	Missaoui N, Trabelsi A, Landolsi H, Jaidaine L, Mokni M, Korbi S and Hmissa S: Cervical adenocarcinoma and squamous cell carcinoma incidence trends among Tunisian women. Asian Pac J Cancer Prev. 11:777–780. 2010.PubMed/NCBI
11	Wang SS, Sherman ME, Hildesheim A, Lacey JV Jr and Devesa S: Cervical adenocarcinoma and squamous cell carcinoma incidence trends among white women and black women in the United States for 1976–2000. Cancer. 100:1035–1044. 2004. View Article : Google Scholar : PubMed/NCBI
12	Auborn KJ, Woodworth C, DiPaolo JA and Bradlow HL: The interaction between HPV infection and estrogen metabolism in cervical carcinogenesis. Int J Cancer. 49:867–869. 1991. View Article : Google Scholar : PubMed/NCBI
13	Newfield L, Bradlow HL, Sepkovic DW and Auborn K: Estrogen metabolism and the malignant potential of human papillomavirus immortalized keratinocytes. Proc Soc Exp Biol Med. 217:322–326. 1998. View Article : Google Scholar : PubMed/NCBI
14	Moodley M, Moodley J, Chetty R and Herrington CS: The role of steroid contraceptive hormones in the pathogenesis of invasive cervical cancer: A review. Int J Gynecol Cancer. 13:103–110. 2003. View Article : Google Scholar : PubMed/NCBI
15	Salazar EL, Sojo-Aranda I, Lopez R and Salcedo M: The evidence for an etiological relationship between oral contraceptive use and dysplastic change in cervical tissue. Gynecol Endocrinol. 15:23–28. 2001. View Article : Google Scholar : PubMed/NCBI
16	Muñoz N, Franceschi S, Bosetti C, Moreno V, Herrero R, Smith JS, Shah KV, Meijer CJ and Bosch FX;: International Agency for Research on Cancer (IARC) Multicentric Cervical Cancer Study Group: Role of parity and human papillomavirus in cervical cancer: The IARC multicentric case-control study. Lancet. 359:1093–1101. 2002. View Article : Google Scholar : PubMed/NCBI
17	Plapinger L and Bern HA: Adenosis-like lesions and other cervicovaginal abnormalities in mice treated perinatally with estrogen. J Natl Cancer Inst. 63:507–518. 1979.PubMed/NCBI
18	McLachlan JA, Newbold RR and Bullock BC: Long-term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res. 40:3988–3999. 1980.PubMed/NCBI
19	Liu Y, Tian LB, Yang HY and Zhang HP: Effects of estradiol and progesterone on the growth of HeLa cervical cancer cells. Eur Rev Med Pharmacol Sci. 21:3959–3965. 2017.PubMed/NCBI
20	Brake T and Lambert PF: Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model. Proc Natl Acad Sci USA. 102:2490–2495. 2005. View Article : Google Scholar : PubMed/NCBI
21	den Boon JA, Pyeon D, Wang SS, Horswill M, Schiffman M, Sherman M, Zuna RE, Wang Z, Hewitt SM, Pearson R, et al: Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling. Proc Natl Acad Sci USA. 112:E3255–E3264. 2015. View Article : Google Scholar : PubMed/NCBI
22	Zhang SK, Kang LN, Chang IJ, Zhao FH, Hu SY, Chen W, Shi JF, Zhang X, Pan QJ, Li SM, et al: The natural history of cervical cancer in Chinese women: results from an 11-year follow-up study in china using a multistate model. Cancer Epidemiol Biomarkers Prev. 23:1298–1305. 2014. View Article : Google Scholar : PubMed/NCBI
23	Sambrook J and Russell DW: Purification of nucleic acids by extraction with phenol:chloroform. CSH Protoc. 2006(pii): pdb.prot4455. 2006.
24	Yoshikawa H, Kawana T, Kitagawa K, Mizuno M, Yoshikura H and Iwamoto A: Detection and typing of multiple genital human papillomaviruses by DNA amplification with consensus primers. Jpn J Cancer Res. 82:524–531. 1991. View Article : Google Scholar : PubMed/NCBI
25	Badaracco G, Venuti A, Sedati A and Marcante ML: HPV16 and HPV18 in genital tumors: Significantly different levels of viral integration and correlation to tumor invasiveness. J Med Virol. 67:574–582. 2002. View Article : Google Scholar : PubMed/NCBI
26	Knol MJ and VanderWeele TJ: Recommendations for presenting analyses of effect modification and interaction. Int J Epidemiol. 41:514–520. 2012. View Article : Google Scholar : PubMed/NCBI
27	Rothman KJ, Greenland S and Lash TL: Chapter 5 Concepts of Interaction. In: Modern epidemiology. Lippincott Williams & Wilkins. 2008.
28	Goodman MT, Shvetsov YB, McDuffie K, Wilkens LR, Zhu X, Ning L, Killeen J, Kamemoto L and Hernandez BY: Acquisition of anal human papillomavirus (HPV) infection in women: The Hawaii HPV Cohort study. J Infect Dis. 197:957–966. 2008. View Article : Google Scholar : PubMed/NCBI
29	Shvetsov YB, Hernandez BY, McDuffie K, Wilkens LR, Zhu X, Ning L, Killeen J, Kamemoto L and Goodman MT: Duration and clearance of anal human papillomavirus (HPV) infection among women: The Hawaii HPV cohort study. Clin Infect Dis. 48:536–546. 2009. View Article : Google Scholar : PubMed/NCBI
30	Chen HC, Schiffman M, Lin CY, Pan MH, You SL, Chuang LC, Hsieh CY, Liaw KL, Hsing AW, Chen CJ, et al: Persistence of type-specific human papillomavirus infection and increased long-term risk of cervical cancer. J Natl Cancer Inst. 103:1387–1396. 2011. View Article : Google Scholar : PubMed/NCBI
31	Byun JM, Jeong DH, Kim YN, Jung EJ, Lee KB, Sung MS and Kim KT: Persistent HPV-16 infection leads to recurrence of high-grade cervical intraepithelial neoplasia. Medicine (Baltimore). 97:e136062018. View Article : Google Scholar : PubMed/NCBI
32	Dai M, Bao YP, Li N, Clifford GM, Vaccarella S, Snijders PJ, Huang RD, Sun LX, Meijer CJ, Qiao YL and Franceschi S: Human papillomavirus infection in Shanxi Province, People's Republic of China: A population-based study. Br J Cancer. 95:96–101. 2006. View Article : Google Scholar : PubMed/NCBI
33	Guo J, Zhao F, Liu R and Mu Y: Prevalence and type distribution of human papillomavirus infection in women from Datong, China. Scand J Infect Dis. 42:72–75. 2010. View Article : Google Scholar : PubMed/NCBI
34	Briolat J, Dalstein V, Saunier M, Joseph K, Caudroy S, Prétet JL, Birembaut P and Clavel C: HPV prevalence, viral load and physical state of HPV-16 in cervical smears of patients with different grades of CIN. Int J Cancer. 121:2198–2204. 2010. View Article : Google Scholar
35	Luhn P, Walker J, Schiffman M, Zuna RE, Dunn ST, Gold MA, Smith K, Mathews C, Allen RA, Zhang R, et al: The role of co-factors in the progression from human papillomavirus infection to cervical cancer. Gynecol Oncol. 128:265–270. 2013. View Article : Google Scholar : PubMed/NCBI
36	Moreno V, Bosch FX, Munoz N, Meijer CJ, Shah KV, Walboomers JM, Herrero R and Franceschi S;: International Agency for Research on Cancer. Multicentric Cervical Cancer Study Group: Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: The IARC multicentric case-control study. Lancet. 359:1085–1092. 2002. View Article : Google Scholar : PubMed/NCBI
37	Santos Filho MV, Gurgel AP, Lobo CD, Freitas AC, Silva-Neto JC and Silva LA: Prevalence of human papillomavirus (HPV), distribution of HPV types, and risk factors for infection in HPV-positive women. Genet Mol Res. 15:2016. View Article : Google Scholar : PubMed/NCBI
38	Siristatidis C, Sergentanis TN, Kanavidis P, Trivella M, Sotiraki M, Mavromatis I, Psaltopoulou T, Skalkidou A and Petridou ET: Controlled ovarian hyperstimulation for IVF: Impact on ovarian, endometrial and cervical cancer-a systematic review and meta-analysis. Hum Reprod Update. 19:105–123. 2013. View Article : Google Scholar : PubMed/NCBI
39	Lundqvist M, Westin C, Lundkvist O, Simberg N, Strand A, Andersson S and Wilander E: Cytologic screening and human papilloma virus test in women undergoing artificial fertilization. Acta Obstet Gynecol Scand Oct. 81:949–953. 2002. View Article : Google Scholar
40	International Collaboration of Epidemiological Studies of Cervical Cancer, ; Appleby P, Beral V, Berrington de González A, Colin D, Franceschi S, Goodhill A, Green J, Peto J, Plummer M and Sweetland S: Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet. 370:1609–1621. 2007. View Article : Google Scholar : PubMed/NCBI
41	Rinaldi S, Plummer M, Biessy C, Castellsagué X, Overvad K, Krüger Kjær S, Tjønneland A, Clavel-Chapelon F, Chabbert-Buffet N, Mesrine S, et al: Endogenous sex steroids and risk of cervical carcinoma: results from the EPIC study. Cancer Epidemiol Biomarkers Prev. 20:2532–2540. 2011. View Article : Google Scholar : PubMed/NCBI
42	Shields TS, Falk RT, Herrero R, Schiffman M, Weiss NS, Bratti C, Rodriguez AC, Sherman ME, Burk RD and Hildesheim A: A case-control study of endogenous hormones and cervical cancer. Br J Cancer. 90:146–152. 2004. View Article : Google Scholar : PubMed/NCBI
43	Spurgeon ME, den Boon JA, Horswill M, Barthakur S, Forouzan O, Rader JS, Beebe DJ, Roopra A, Ahlquist P and Lambert PF: Human papillomavirus oncogenes reprogram the cervical cancer microenvironment independently of and synergistically with estrogen. Proc Natl Acad Sci USA. 114:E9076–E9085. 2017. View Article : Google Scholar : PubMed/NCBI
44	Kuhl H: Pharmacology of estrogens and progestogens: Influence of different routes of administration. Climacteric. 8 (Suppl 1):S3–S63. 2005. View Article : Google Scholar
45	Adurthi S, Kumar MM, Vinodkumar HS, Mukherjee G, Krishnamurthy H, Acharya KK, Bafna UD, Uma DK, Abhishekh B, Krishna S, et al: Oestrogen receptor-α binds the FOXP3 promoter and modulates regulatory T-cell function in human cervical cancer. Sci Rep. 7:172892017. View Article : Google Scholar : PubMed/NCBI
46	Blachon S and Demeret C: The regulatory E2 proteins of human genital papillomaviruses are pro-apoptotic. Biochimie. 85:813–819. 2003. View Article : Google Scholar : PubMed/NCBI
47	Riley RR, Duensing S, Brake T, Münger K, Lambert PF and Arbeit JM: Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis. Cancer Res. 63:4862–4871. 2003.PubMed/NCBI
48	Shai A, Brake T, Somoza C and Lambert PF: The human papillomavirus E6 oncogene dysregulates the cell cycle and contributes to cervical carcinogenesis through two independent activities. Cancer Res. 67:1626–1635. 2007. View Article : Google Scholar : PubMed/NCBI
49	Arbeit JM, Howley PM and Hanahan D: Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice. Proc Natl Acad Sci USA. 93:2930–2935. 1996. View Article : Google Scholar : PubMed/NCBI