Interactions between polymorphisms in the 3'untranslated region of the cyclin dependent kinase 6 gene and the human papillomavirus infection, and risk of cervical precancerous lesions

Ye,Xingguang; Jing,Lipeng; Zhong,Xingming; Xiao,Di; Ou,Meiling; Guo,Congcong; Yang,Guang; Jing,Chunxia; Wei,Xiangcai

doi:10.3892/br.2017.898

Interactions between polymorphisms in the 3'untranslated region of the cyclin dependent kinase 6 gene and the human papillomavirus infection, and risk of cervical precancerous lesions

Authors:
- Xingguang Ye
- Lipeng Jing
- Xingming Zhong
- Di Xiao
- Meiling Ou
- Congcong Guo
- Guang Yang
- Chunxia Jing
- Xiangcai Wei
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Affiliations: Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China, Family Planning Research Institute of Guangdong, Guangzhou, Guangdong 510062, P.R. China, Department of Parasitology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
Published online on: May 3, 2017 https://doi.org/10.3892/br.2017.898
Pages: 640-648
Copyright: © Ye et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The human papillomavirus (HPV) infection is essential for the development of cervical cancer and its precursor lesions. However, only certain persistently infected individuals develop cervical cancer. Cyclin-dependent kinase 6 (CDK6) is a critical regulatory cancer‑associated gene in the cell cycle and in tumorigenesis. Single nucleotide polymorphisms (SNPs) in microRNA sites in the 3'‑untranslated region (UTR) of target genes may result in target gene expression level changes and susceptibility to diseases, including cancer. Therefore, the aim of the present study was to determine whether SNPs in the 3'UTR of the CDK6 gene may affect susceptibility to cervical precancerous lesions in a Chinese population. Five polymorphisms in the 3'UTR of the CDK6 gene were evaluated in 164 cervical precancerous lesion cases and 296 control subjects. Differences in environmental factors between cases and controls were evaluated using the χ2 test or unpaired t‑test. Logistic regression was used to examine the association between the five polymorphisms and cervical precancerous lesions. The model‑free multifactor dimensionality reduction (MDR) method was performed to evaluate the interaction effect of environment variables and gene polymorphisms. Interactions on the additive scale are calculated by using the relative excess risk due to interaction (RERI). After controlling for potential confounders, a significantly decreased risk of cervical precancerous lesions for the GA genotype, rs8179, and the AT genotype, rs42033 [GA vs. GA: odds ratio (OR)adjusted=0.17, 95% confidence interval (CI), 0.05‑0.57; AT vs. AA: ORadjusted=0.18, 95% CI, 0.05‑0.59, respectively] was identified. Furthermore, following MDR analysis, a significant three‑locus interaction model was identified, which involved the HPV infection, the number of pregnancies and rs8179. Additionally, a significant antagonistic interaction between the HPV infection and rs8179 was identified on an additive scale. Haplotype AGTA was associated with a decreased risk of developing cervical precancerous lesions (ORadjusted=0.21; 95% CI, 0.06‑0.75). Thus, the present results indicated that the rs8179 and rs42033 polymorphisms confer genetic susceptibility to cervical precancerous lesions. Furthermore, the interaction between the rs8179 polymorphism in CDK6 and the HPV infection and haplotype AGTA may be associated with cervical precancerous lesions.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
3	Ambros RA and Kurman RJ: Current concepts in the relationship of human papillomavirus infection to the pathogenesis and classification of precancerous squamous lesions of the uterine cervix. Semin Diagn Pathol. 7:158–172. 1990.PubMed/NCBI
4	Xiao D, Huang W, Ou M, Guo C, Ye X, Liu Y, Wang M, Zhang B, Zhang N, Huang S, et al: Interaction between susceptibility loci in cGAS-STING pathway, MHC gene and HPV infection on the risk of cervical precancerous lesions in Chinese population. Oncotarget. 7:84228–84238. 2016.PubMed/NCBI
5	Nieves-Ramirez ME, Partida-Rodriguez O, Alegre-Crespo PE, Tapia-Lugo Mdel C and Perez-Rodriguez ME: Characterization of single-nucleotide polymorphisms in the tumor necrosis factor alpha promoter region and in lymphotoxin α in squamous intraepithelial lesions, precursors of cervical cancer. Transl Oncol. 4:336–344. 2011. View Article : Google Scholar : PubMed/NCBI
6	Bodily J and Laimins LA: Persistence of human papillomavirus infection: Keys to malignant progression. Trends Microbiol. 19:33–39. 2011. View Article : Google Scholar : PubMed/NCBI
7	Castle PE, Schiffman M, Wheeler CM and Solomon D: Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstet Gynecol. 113:18–25. 2009. View Article : Google Scholar : PubMed/NCBI
8	Kobayashi A, Weinberg V, Darragh T and Smith-McCune K: Evolving immunosuppressive microenvironment during human cervical carcinogenesis. Mucosal Immunol. 1:412–420. 2008. View Article : Google Scholar : PubMed/NCBI
9	Zhang J, Wang L, Li B, Huo M, Mu M, Liu J and Han J: miR-145 downregulates the expression of cyclin-dependent kinase 6 in human cervical carcinoma cells. Exp Ther Med. 8:591–594. 2014.PubMed/NCBI
10	Li Y, Wang F, Xu J, Ye F, Shen Y, Zhou J, Lu W, Wan X, Ma D and Xie X: Progressive miRNA expression profiles in cervical carcinogenesis and identification of HPV-related target genes for miR-29. J Pathol. 224:484–495. 2011. View Article : Google Scholar : PubMed/NCBI
11	Wang X, Meyers C, Guo M and Zheng ZM: Upregulation of p18Ink4c expression by oncogenic HPV E6 via p53-miR-34a pathway. Int J Cancer. 129:1362–1372. 2011. View Article : Google Scholar : PubMed/NCBI
12	Sridhar J, Akula N and Pattabiraman N: Selectivity and potency of cyclin-dependent kinase inhibitors. AAPS J. 8:E204–E221. 2006. View Article : Google Scholar : PubMed/NCBI
13	Tadano T, Kakuta Y, Hamada S, Shimodaira Y, Kuroha M, Kawakami Y, Kimura T, Shiga H, Endo K, Masamune A, et al: MicroRNA-320 family is downregulated in colorectal adenoma and affects tumor proliferation by targeting CDK6. World J Gastrointest Oncol. 8:532–542. 2016. View Article : Google Scholar : PubMed/NCBI
14	Lee AR, Park J, Jung KJ, Jee SH and Kim-Yoon S: Genetic variation rs7930 in the miR-4273-5p target site is associated with a risk of colorectal cancer. Onco Targets Ther. 9:6885–6895. 2016. View Article : Google Scholar : PubMed/NCBI
15	Zheng N, Yang P, Wang Z and Zhou Q: OncomicroRNAs-mediated tumorigenesis: Implication in cancer diagnosis and targeted therapy. Curr Cancer Drug Targets. 17:40–47. 2017. View Article : Google Scholar : PubMed/NCBI
16	Nayar R and Wilbur DC: The Pap test and Bethesda 2014. Cancer Cytopathol. 123:271–281. 2015. View Article : Google Scholar : PubMed/NCBI
17	Yi X, Li J, Yu S, Zhang A, Xu J, Yi J, Zou J, Nie X, Huang J and Wang J: A new PCR-based mass spectrometry system for high-risk HPV, part I: Methods. Am J Clin Pathol. 136:913–919. 2011. View Article : Google Scholar : PubMed/NCBI
18	Qu S, Huang J, Zhao J, Zhao X, Deng H, Yang H, Chen W, Liu L, Zhang L and Gao S: A comparison of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and surface plasmon resonance for genotyping of high-risk human papillomaviruses. Intervirology. 54:326–332. 2011. View Article : Google Scholar : PubMed/NCBI
19	Jurinke C, van den Boom D, Cantor CR and Köster H: Automated genotyping using the DNA MassArray technology. Methods Mol Biol. 187:179–192. 2002.PubMed/NCBI
20	Hahn LW, Ritchie MD and Moore JH: Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics. 19:376–382. 2003. View Article : Google Scholar : PubMed/NCBI
21	Heidema AG, Feskens EJ, Doevendans PA, Ruven HJ, van Houwelingen HC, Mariman EC and Boer JM: Analysis of multiple SNPs in genetic association studies: Comparison of three multi-locus methods to prioritize and select SNPs. Genet Epidemiol. 31:910–921. 2007. View Article : Google Scholar : PubMed/NCBI
22	Tunesi S, Ferrante D, Mirabelli D, Andorno S, Betti M, Fiorito G, Guarrera S, Casalone E, Neri M, Ugolini D, et al: Gene-asbestos interaction in malignant pleural mesothelioma susceptibility. Carcinogenesis. 36:1129–1135. 2015. View Article : Google Scholar : PubMed/NCBI
23	Andersson T, Alfredsson L, Källberg H, Zdravkovic S and Ahlbom A: Calculating measures of biological interaction. Eur J Epidemiol. 20:575–579. 2005. View Article : Google Scholar : PubMed/NCBI
24	Muthuri SG, Doherty S, Zhang W, Maciewicz RA, Muir KR and Doherty M: Gene-environment interaction between body mass index and transforming growth factor beta 1 (TGFβ1) gene in knee and hip osteoarthritis. Arthritis Res Ther. 15:R522013. View Article : Google Scholar : PubMed/NCBI
25	Knol MJ, van der Tweel I, Grobbee DE, Numans ME and Geerlings MI: Estimating interaction on an additive scale between continuous determinants in a logistic regression model. Int J Epidemiol. 36:1111–1118. 2007. View Article : Google Scholar : PubMed/NCBI
26	Knol MJ, VanderWeele TJ, Groenwold RH, Klungel OH, Rovers MM and Grobbee DE: Estimating measures of interaction on an additive scale for preventive exposures. Eur J Epidemiol. 26:433–438. 2011. View Article : Google Scholar : PubMed/NCBI
27	Dai X, Li L, Liu X, Hu W, Yang Y and Bai Z: Cooperation of DLC1 and CDK6 affects breast cancer clinical outcome. G3 (Bethesda). 5:81–91. 2014. View Article : Google Scholar : PubMed/NCBI
28	Xia B, Yang S, Liu T and Lou G: miR-211 suppresses epithelial ovarian cancer proliferation and cell-cycle progression by targeting Cyclin D1 and CDK6. Mol Cancer. 14:572015. View Article : Google Scholar : PubMed/NCBI
29	Li LP, Wu WJ, Sun DY, Xie ZY, Ma YC and Zhao YG: miR-449a and CDK6 in gastric carcinoma. Oncol Lett. 8:1533–1538. 2014.PubMed/NCBI
30	Lu X, Fang Y, Wang Z, Xie J, Zhan Q, Deng X, Chen H, Jin J, Peng C, Li H and Shen B: Downregulation of gas5 increases pancreatic cancer cell proliferation by regulating CDK6. Cell Tissue Res. 354:891–896. 2013. View Article : Google Scholar : PubMed/NCBI
31	Arvanitis DA and Spandidos DA: Deregulation of the G1/S phase transition in cancer and squamous intraepithelial lesions of the uterine cervix: A case control study. Oncol Rep. 20:751–760. 2008.PubMed/NCBI
32	Choi YJ and Anders L: Signaling through cyclin D-dependent kinases. Oncogene. 33:1890–1903. 2014. View Article : Google Scholar : PubMed/NCBI
33	Costello JF, Plass C, Arap W, Chapman VM, Held WA, Berger MS, Su Huang HJ and Cavenee WK: Cyclin-dependent kinase 6 (CDK6) amplification in human gliomas identified using two-dimensional separation of genomic DNA. Cancer Res. 57:1250–1254. 1997.PubMed/NCBI
34	Zhou X, Chen X, Hu L, Han S, Qiang F, Wu Y, Pan L, Shen H, Li Y and Hu Z: Polymorphisms involved in the miR-218-LAMB3 pathway and susceptibility of cervical cancer, a case-control study in Chinese women. Gynecol Oncol. 117:287–290. 2010. View Article : Google Scholar : PubMed/NCBI
35	Reshmi G, Surya R, Jissa VT, Babu PS, Preethi NR, Santhi WS, Jayaprakash PG and Pillai MR: C-T variant in a miRNA target site of BCL2 is associated with increased risk of human papilloma virus related cervical cancer-an in silico approach. Genomics. 98:189–193. 2011. View Article : Google Scholar : PubMed/NCBI
36	Shi TY, Cheng X, Yu KD, Sun MH, Shao ZM, Wang MY, Zhu ML, He J, Li QX, Chen XJ, et al: Functional variants in TNFAIP8 associated with cervical cancer susceptibility and clinical outcomes. Carcinogenesis. 34:770–778. 2013. View Article : Google Scholar : PubMed/NCBI
37	Giuliano AR, Sedjo RL, Roe DJ, Harri R, Baldwi S, Papenfuss MR, Abrahamsen M and Inserra P: Clearance of oncogenic human papillomavirus (HPV) infection: Effect of smoking (United States). Cancer Causes Control. 13:839–846. 2002. View Article : Google Scholar : PubMed/NCBI
38	Syrjänen K, Shabalova I, Petrovichev N, Kozachenko V, Zakharova T, Pajanidi J, Podistov J, Chemeris G, Sozaeva L, Lipova E, et al: Age at menarche is not an independent risk factor for high-risk human papillomavirus infections and cervical intraepithelial neoplasia. Int J STD AIDS. 19:16–25. 2008. View Article : Google Scholar : PubMed/NCBI
39	Moscicki AB, Winkler B, Irwin CE Jr and Schachter J: Differences in biologic maturation, sexual behavior, and sexually transmitted disease between adolescents with and without cervical intraepithelial neoplasia. J Pediatr. 115:487–493. 1989. View Article : Google Scholar : PubMed/NCBI
40	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, ; 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