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Abstract
A case-control study was used to explore the association between the methylation status in the promoter regions of the cGAS, MAVS, and TRAF3 genes and the diseases of cervical precancerous lesions (CPL) and cervical cancer (CC) in a Southern Chinese population, and to further explore their interaction effects with high-risk human papillomavirus (hrHPV) infection and environmental factors in these diseases. The study protocol was approved by the ethics committee of The First Affiliated Hospital of Jinan University, and this study was performed in 97 healthy controls, 75 patients with CPL and 33 patients with CC, while each participant has read and signed the informed consent forms before enrolment. The promoter methylation status genes were detected from the bisulfite-treated DNA by the bisulfite sequencing PCR (BSP) technique, which was carried out using MethPrimer. The cGAS, MAVS, and TRAF3 promoter methylation levels in CPL (CPLcGAS = 35.40%, CPLMAVS = 24.26%, and CPLTRAF3 = 96.76%) were significantly higher than those in the control (ControlcGAS = 31.87%, ControlMAVS = 21.16%, and ControlTRAF3 = 96.26%, PcGAS< 0.001, PMAVS< 0.001, and PTRAF3 = 0.001); however, there was no significant differences between the CC and control. In the logistic regression model with adjusted covariates, compared with the individuals whose cGAS methylation levels were less than or equal to 31.87%, the women with the levels more than 31.87% increased the risk of CPL by 2.49 times (ORa = 2.49, 95% CI = 1.31-4.75, Pa = 0.006). The women with MAVS methylation levels above 21.16% were 1.97 times more likely to have CPL than the those with the levels less than 21.16% (ORa = 1.97, 95% CI = 1.06–3.69, Pa = 0.033). A synergistic interaction was found between hrHPV and gene promoter methylation levels of cGAS and MAVS in CPL; however, no potential interaction was observed in CC. The promoter methylation levels in cGAS, MAVS, and TRAF3 genes are higher in CPL than in control, indicating that hypermethylation might be an early event in the progression of cervical intraepithelial neoplasia (CIN). The interaction between the promoter methylation levels in cGAS and MAVS genes and hrHPV infection might play a role in the development of CPL.
Highlights
Abnormal DNA methylation in the gene promoter region is a well-recognized epigenetic hallmark in the premalignant and malignant stages of cancers, and it has been observed in different kinds of genes, such as tumor suppressor genes and DNA repair genes (Merlo et al, 1995; Esteller et al, 1999a; Esteller et al, 2000; Guo et al, 2009; Zou et al, 2009; Esteller et al, 1999b)
We investigated the promoter methylation status of cyclic GMPAMP synthase (cGAS), mitochondrial antiviral-signaling (MAVS), and tumor necrosis factor receptor-associated factor 3 (TRAF3) in cervical precancerous lesions (CPL) and CC, and we further explored the association between potential biological interactions and the risk of CPL and CC in the Southern Chinese population
There were no relationships between High-risk human papillomavirus (hrHPV) and gene promoter methylation levels in the different groups (Table S3); we further explored the biological interactions of hrHPV and methylation levels and the estimated risk of CPL and CC
Summary
Abnormal DNA methylation in the gene promoter region is a well-recognized epigenetic hallmark in the premalignant and malignant stages of cancers, and it has been observed in different kinds of genes, such as tumor suppressor genes and DNA repair genes (Merlo et al, 1995; Esteller et al, 1999a; Esteller et al, 2000; Guo et al, 2009; Zou et al, 2009; Esteller et al, 1999b). Several studies have reported that promoter methylation status of multiple genes is associated with cervical precancerous lesions (CPL) and cervical cancer (CC) development, such as CDH13, CDKN2B, TIM3, and RASSF1A (Dong et al, 2001; Missaoui et al, 2011a; Li et al, 2015a). DNA methylation of promoter regions is associated with the cervical disease, but very few studies have been reported for gene promoter methylation related to antiviral innate immunity pathways, the research evaluating DNA methylation and epidemiologic factors for CPL and CC is very limited in Chinese women. Viral infection of the host can trigger innate immune responses, and previous studies have revealed that cyclic GMPAMP synthase (cGAS)/STING and RIG-I/MAVS pathways play important roles in host innate immunity against HPV-induced precursor lesions and invasive cancer of the uterine cervix (Karim et al, 2013; Lau et al, 2015; Xiao et al, 2016). We investigated the promoter methylation status of cGAS, MAVS, and TRAF3 in CPL and CC, and we further explored the association between potential biological interactions and the risk of CPL and CC in the Southern Chinese population
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