Research Article

Association of HPV Cervical Dysplasia Progression with DNA Methylation of Genes, Connected to Cellular Stress and Oncogenesis

Koprinarova Miglena1 , Kovachev Stefan 2, Dimitrov Ivan3, Andreeva Petya3, Nikolova Dragomira4, Hammoudeh Zora4, Slavova Kremena5, Slavov Viktor5, Todorova Albena6, Dimova Ivanka4,*
1Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria
2Gynecology Unit, Military Medical Academy Sofia, Bulgaria
3Medical Complex for Obstetrics and Gynecology “Dr. Shterev”, Sofia, Bulgaria
4Department of Medical Genetics, Medical University Sofia, Bulgaria
5Genetic Medical Diagnostic Laboratory “Genika”, Sofia, Bulgaria
6Department of Medical Chemistry and Biochemistry, Medical University Sofia, Bulgaria

*Corresponding author:

Ivanka Dimova, Department of Medical Genetics, Medical University Sofia, Bulgaria, Email:


HPV, Cervical dysplasia, DNA methylation, Tumor-suppressor genes, Oxidative stress, oncogenesis

Cervical cancer is tightly connected to HPV infection, but it is not yet elucidated why some of infected cases progress to cancer, but others not. Our aim was to study the role of DNA methylation in this process. We measured hypermethylated DNA fraction in promoters of 22 genes, connected to cellular stress and oncogenesis by real-time PCR arrays in two groups: HPV positive PAP I/II and HPV positive PAP III/IV. Hypermethylated DNA fraction (Fhm) represents the proportion of hypermethylated CpG sites (CpG site with >60% methylated reads) over the total CpG sites in a sequence. The most hypermethylated genes (Fhm >15%) from our study were BRCA1, Tp53 and Gpx3. We were interested in analyzing the DNA methylation changes in different grades of HPV-positive cervical lesions. Six genes showed an increase of more than 50% in the fraction of hypermethylated DNA between PAP I/II and PAP III/IV groups-Rara (2.1 times), Gadd45G (1.67 times), SCARA3 (1.63 times) and Mlh1, Xpc and CDKN1a (all with an increase of 1.5 times).

We suggest an association between HPV dysplasia progression and hypermethylation (inactivation) of important tumor-suppressor genes and genes, connected to oxidative stress protection.

Cervical Carcinoma (CC) is the second most common malignancy in women worldwide [1,2]. The major etiological and initiating agent for the CC is the infection with human papillomavirus carcinogenic types (HPV), found in 99.7% of cases of CC [3]. Infection with high-risk human papillomaviruses (HR-HPV), however, leads to invasive growth only in a small percentage of cases [4]. Accordingly, the viral oncogene expression is not sufficient for neoplastic transformation of cervical epithelial cells. Obviously some other accompanying events are needed for the occurrence of cancer. It is believed that the combination of genetic and epigenetic factors are necessary for carcinogenesis. As a result, these factors can alter the cell cycle control in the infected cells, which lead to cell immortalization and malignant/ invasive phenotype [5,6].

It is believed that HR-HPV, by genome integration, are able to induce increased proliferative status to complete their replicative cycle in otherwise slow-replicative epithelial cells. This is achieved through the activity of two viral oncoproteins-E6 and E7, whose targets are regulatory proteins, including the two major tumor suppressor proteins of the host cell-p53 and retinoblastoma (pRb) [4]. The E6 oncoprotein binds to p53, leading to its degradation and E7 inactivates pRb by hypophosphorylation [1]. Thus viral oncogenes induce instability and enable infected cells to acquire and accumulate genomic changes leading to their neoplastic transformation [7–9]. It has been shown that E6 and E7 interact also with the proteins associated with the processes of cell adhesion, apoptosis, DNA repair and cell cycle regulation [7,10]. The most recent studies show epigenetic changes resulting from infection with HR-HPV [11,12].

A classic example of epigenetic transcriptional regulation is the covalent post-replicative methylation of DNA at the 5′ position of the cytosine ring of CpG dinucleotides. DNA methylation is a highly dynamic process in development and disease. It is strongly associated with gene silencing and decreased gene expression [9]. The functional significance of DNA methylation alterations became apparent with their recognition as critical contributors to the pathogenesis of cancer, acting by silencing of tumor suppressor genes [10].

There is not much information about epigenetic changes accompanying the initiation and progression of CC. Research is still in its infancy and the accumulation of data is not only of scientific but also of practical interest in order to establish markers for early diagnosis and prognosis.

For rapid identification of potential targets for aberrant methylation in gynecological cancers as markers for cancer management, thus, in the present study with the technologies at hand, the pooled DNA approach and methylation-signature PCR arrays were employed to determine the methylation status of 22 gene loci among the different PAP groups of HPV positive cervical samples.

3.1 Subjects

We have collected HPV-positive cervical swabs samples from gynecological patients. The patients were subdivided according to PAP group: with PAP I/II (n=8) and with PAP III/IV (n=9). The participants were recruited at the Clinics of Gynecology, Military Academy Hospital, Sofia. All of them declared their written informed consent and were familiar with the aims, methods and risks of participating in the study in accordance with the Helsinki Declaration and rules of Good Clinical Practice, as the study was approved by the Ethics Committee of the Medical University, Sofia. The cervical swabs of patients were investigated by liquid based cytology and genotyping for high risk HPV. The results were interpreted according to reactive cell changes (i.e., inflammation) and presence of abnormal epithelial cells.

3.2 DNA methylation analysis of 22 stress and toxicity genes

Whole genome DNA was extracted using DNeasy Blood & Tissue Kit, Qiagen. The DNA samples were combined into two DNA pools: (i) PAP I/II HPV-positive patients (n=8), and (ii) PAP III/IV HPV-positive patients (n=9). DNA in each pool was adjusted to a final concentration of 25 ng/µl. Each DNA pool was analyzed for the promoter methylation status of 22 genes included in The Human Stress & Toxicity PathwayFinder EpiTect Methyl II Signature PCR Array (Table 1). The method is based on detection of remaining input DNA after cleavage with a methylation-sensitive and/or a methylation-dependent restriction enzyme. These enzymes will digest unmethylated and methylated DNA, respectively. Following digestion, the remaining DNA in each individual enzyme reaction is quantified by real-time PCR using primers that flank a promoter (gene) region of interest. The relative fractions of hypermethylated and unmethylated DNA are subsequently determined by comparing the amount in each digest with that of a mock (no enzymes added) digest using a ΔCt method. Unmethylated represents the fraction of input genomic DNA containing no methylated CpG sites in the amplified region of a gene. Hypermethylated DNA represents fraction of input genomic DNA containing CpG sites with more than 60% methylated residues in the targeted region of a gene. Data quality control parameters were strictly accomplished according to the protocol of the manufacturer.

Processes mediated by the genes


Oxidative Stress

Bnip3, Cyp1a1, Gpx3, Prdx2, Ptgs2 (Cox2),

DNA Damage

Atm, Brca1, Ccnd1, Gadd45a, Gadd45g, Mlh1, Msh2, Tp53, Xpc

Unfolded Protein Response

Insig1, Ube2g2


Cstb, Rara

Heat Shock Protein


Growth Arrest & Senescence

Atm, Cdkn1a (P21cip1/Waf1), Gadd45a,  (Plab), Msh2, Tp53


Prdx2, Ptgs2 (Cox2)


Bnip3, Cdkn1a (P21cip1/Waf1), Prdx2

Proliferation and Carcinogenesis

Brca1, Ccnd1, Cdkn1a (P21cip1/Waf1), Cyp1a1, Prdx2, Ptgs2 (Cox2), Tp53

Table 1. List of 22 analyzed genes and the processes they mediate

4.1 Changes in Fhm of genes, connected to cellular stress’ response, in different grade cervical dysplasia

We analyzed successfully the fraction of hypermethylated DNA (Fhm) in the promoters of 19 genes, using The Human Stress & Toxicity PathwayFinder EpiTect Methyl II Signature PCR Array. Hypermethylated DNA fraction represents the proportion of hypermethylated CpG sites over the total CpG sites in a sequence. A hypermethylated CpG site is defined as the CpG site with >60% methylated reads. The percentage of hypermethylated DNA fraction is presented in Table 2. We analyzed the changes in Fhm of genes, connected to cellular response to stress, between the two groups of cervical dysplasia, both HPV-positive–PAP I/II (Group 1) and PAP III/IV (Group 2). There was an overall increase in Fhm of these genes in Group 2 compared to Group 1 (Figure 1)–the highest was the increase in Fhm of Gadd45G (1.67 times) and SCARA3 (1.63 times), followed by BNIP3 (1.44 times).

Figure 1. Fhm of genes, connected to cellular stress’ response, in the two groups of cervical lesions (Group 2/Group 1)































































Table 2. Hypermethylated DNA fraction (Fhm) for the analyzed genes in the groups

4.2 Changes in Fhm of genes, connected to carcinogenesis, in different grade cervical dysplasia

We performed the same analysis for Fhm changes in genes, connected to carcinogenesis, in different grade cervical lesions–Figure 2. Increase was detected for Fhm of Rara (2.1 times) and Mlh1, Xpc and CDKN1a (all with an increase of 1.5 times) in Group 2 compared to Group 1.

Figure 2. Fhm of genes, connected to carcinogenesis, in the two groups of cervical lesions (Group 2/Group 1)

Cervical cancer is one of the most important causes of death in women worldwide [13]. Many studies use a variety of clinical and histopathological features as prognostic factors in this type of cancer. Uni- and/or multi-variant analyses showed that significant predictors of recurrent disease may be tumor stage, metastases in the pelvic lymph nodes, tumor size, vascular invasion and depth of tumor growth [14,15]. Persistent infection with one of about 15 genotypes of carcinogenic Human Papillomavirus (HPV) causes almost all cases of cervical cancer. Precancerous lesions resulting from persistent infections are established usually within 5-10 years, and in less than 10% of cases of infected patients. Invasive cancer occurs over many years, even decades, at a fraction of women with HPV infection, with peak or plateau of risk in 35-55 years of age. What causes carcinogenesis in addition to the HPV infection remains unclear. Obviously new molecular and biochemical approaches are needed for early diagnosis and treatment of high-risk patients to improve survival and avoid unnecessary treatment in patients with low risk.

Hypermethylation of CpG islands has been best characterized epigenetic change associated with transcriptional silencing of genes, thus providing a DNA-based surrogate marker for levels of gene expression. Genes with CpG islands in the promoter region are usually unmethylated in normal tissues. In neoplasia hypermethylation is considered one of the most important mechanisms leading to silencing in the expression of tumor suppressor genes, such as the genes responsible for the control of normal cell differentiation and/or cell growth inhibition [16]. Currently, hypermerthylated biomarkers have been used for the diagnosis and monitoring of cancer [17–19]. Two classic examples are hypermethylation of MGMT in the prediction of response to therapy with temozolomide in glioblastomas [20] and DNA hypermethylation of GSTP1 in the early detection of prostate cancer [21].

It was suggested in the last years that HPV infection can cause abnormal DNA methylation in the human genome [22–25]. It has been shown that HPV increased the expression of DNA Methyltransferase (DNMT) and Histone Deacetylase (HDAC). Leonard et al showed that transfection of HPV16 and 18 induces the expression of DNMT1 and DNMT3B with subsequent changes in the methylation status of multiple genes from the genome [25]. To see whether DNA methylation changes in our candidate genes may be associated with the progression of cervical dysplasia, we examined DNA methylation differences between different HPV-positive PAP groups. It was found that the average methylated DNA fraction of housekeeping genes, highly expressed, moderately expressed and poorly expressed active genesis, respectively, 5.4, 6.6, 7.7 and 11.3% [26]. In our study, the average hypermethylated DNA fraction in both groups of HPV-positive cervical samples was greatly increased-between 5.19 and 30.98% in group PAP I/II, and between 5.45 and 32.31% in group PAP III/IV. The greatest increase was for gene DNAJC15, also known as MCJ (Methylation-Controlled J protein)-a mitochondrial protein that regulates the mitochondrial metabolic status of macrophages and their response to inflammatory stimuli. The control of MCJ transcription constitutes a mechanism to regulate cellular responses to environmental changes and may allow normal tissues to adapt dynamically to a changing environment. It was shown that MCJ gene is a transcriptional target of IFNγ contributing to the regulation of the inflammatory output [27]. The authors hypothesize that the effect of IFNγ on the regulation of MCJ expression results in a more efficient elimination of the bacteria from the infected tissue without a concomitant increase in the inflammatory damage. We assume that MCJ repression by DNA methylation could be an adaptive mechanism to HPV infection in cervical tissue.

Other hypermethylated genes (Fhm >15%) from our study were BRCA1, Tp53 and Gpx3. Tp53 is one of the main targets of HPV oncoproteins. Promoter hypermethylation of the 5' CpG island in the p53 gene promoter was found in 12% of 125 cervical cancer samples [28]. A subset of patients with sporadic invasive cervical cancer shows hypermethylation of the BRCA1 promoter, as do patients with sporadic breast and ovarian cancers [29]. Our results demonstrated that HPV infection is associated with promoter Tp53 and BRCA1 hypermethylation. One unusual finding from our study was the higher Fhm of BRCA1 in Group 1 (29.83%) compared to Group 2 (13.21%). Although in general the promoter methylation is associated with reduced gene expression, the variation in methylation levels across individuals, its environmental or genetic causes, and its association with gene expression remain poorly understood [30]. Al-Moghrabi et al. reported BRCA1 promoter methylation in blood cells of healthy women [31]. It is worthy to investigate BRCA1 gene expression levels in the context of promoter and/or intragenic methylation and in the presence of HPV infection in order to see its methylation-expression correlation. Gpx3 gene product belongs to the glutathione peroxidase family, which functions in the detoxification of hydrogen peroxide. Downregulation of GPX3 due to its promoter hypermethylation has been documented in several different types of cancer, indicating that GPX3 functions as a possible tumor suppressor. It was suggested that its promoter methylation may be a mechanism for inactivation of GPX3, possibly leading to subsequent carcinogenesis and progression of hepato-cellular carcinoma [32]. Treatment of cervical cancer cells with 5-aza-2'-deoxycytidine restored the expression of GPX3 [33].

We were interested in analyzing the DNA methylation changes in different grades of HPV-positive cervical lesions. Six genes showed an increase of more than 50% in the fraction of hypermethylated DNA between PAP I/II and PAP III/IV groups-Rara (2.1 times), Gadd45G (1.67 times), SCARA3 (1.63 times) and Mlh1, Xpc and CDKN1a (all with an increase of 1.5 times). The receptors of retinoic acid (RAR) mediate the antiproliferative and differentiative effects of retinoids [34]. In addition to growth regulation, the product of RAR genes can inhibit transcription of the viral oncogenes (E6 and E7 genes) in high-risk HPV-immortalized cells [35]. The decrease in the expression of negative regulator of viral oncogene may be an additional important step on the way towards malignant progression of HPV-positive cells. It was established that methylation of the 5' region of RAR-β2 gene may contribute to gene silencing and that this methylation may be an important and early event in cervical carcinogenesis [36]. Our study revealed an increase in DNA hypermethylated fraction in the promoter of RARA gene with the progression of cervical dysplasia. These findings may be useful to make retinoids more effective as preventive and therapeutic agents in combination with inhibitors of DNA methylation.

Functional inactivation of MMR genes (mutator phenotype), such as MLH1, by promoter methylation is responsible for the microsatellite instable gastric cancer [37]. Larson et al. [38] reported an attenuated mutator phenotype in cervical carcinoma, which suggests MMR deficiency in cervical carcinogenesis. The absence of Mlh1 immunoreactivity was detected in 4 of 14 (28.6%) cases of non-invasive cervical cancer [39]. It could be speculative for somatic or DNA methylation alterations in Mlh1 gene. Inhibition of Gadd45G function by E6 oncoprotein has been reported to play a crucial role in HPV-induced carcinogenesis [40]. It is a DNA-damage inducible gene and we can speculate that its methylation disturb gene induction and function and participate in cancer cell progression. In addition, we detected an increase in Fhm in three more genes: (i) SCARA3-the protein deplete reactive oxygen species, and thus its inactivation could disturb the protection of cells against oxidative stress; (ii) Xpc–its silencing deplete the nucleotide excision repair; and (iii) CDKN1a-encoding a potent cyclin-dependent kinase inhibitor.

In conclusion, we attempt to unravel an epigenetic mechanism of HPV cervical dysplasia progression. The insights on DNA methylation could provide with new tools for cervical cancer protection and treatment, targeting the methylation processes. We also revealed important aspects of oxidative stress protection by detection of an epigenetic silencing in essential oxidative stress protecting genes.

The authors report no conflicts of interest.

This work was supported by the Council of Medical Science of Medical University Sofia under Grant 25/2015.

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Citation: Miglena K, Stefan K, Ivan D, Petya A, Dragomira N, et al. (2017) Association of HPV Cervical Dysplasia Progression with DNA Methylation of Genes, Connected to Cellular Stress and Oncogenesis. J Oncol Stud 1:001

Published: 30 September 2017

Reviewed By : Dr. Isabel Ferreiro-Neira,


© 2017 Miglena et al.. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.