Methylation pattern of CDH1 promoter and its association with CDH1 gene expression in cytological cervical specimens

Holubeková,Veronika; Mendelová,Andrea; Grendár,Marián; Meršaková,Sandra; Kapustová,Ivana; Jašek,Karin; Vaňochová,Andrea; Danko,Jan; Lasabová,Zora

doi:10.3892/ol.2016.5004

Methylation pattern of CDH1 promoter and its association with CDH1 gene expression in cytological cervical specimens

Authors:
- Veronika Holubeková
- Andrea Mendelová
- Marián Grendár
- Sandra Meršaková
- Ivana Kapustová
- Karin Jašek
- Andrea Vaňochová
- Jan Danko
- Zora Lasabová
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Affiliations: Department of Oncology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Biomedical Center Martin, SK‑03601 Martin, Slovakia, Department of Molecular Medicine, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Biomedical Center Martin, SK‑03601 Martin, Slovakia, Bioinformatic Unit, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Biomedical Center Martin, SK‑03601 Martin, Slovakia, Clinic of Gynecology and Obstetrics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Biomedical Center Martin, SK‑03601 Martin, Slovakia, Department of Molecular Biology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Biomedical Center Martin, SK‑03601 Martin, Slovakia
Published online on: August 12, 2016 https://doi.org/10.3892/ol.2016.5004
Pages: 2613-2621
Copyright: © Holubeková et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cervical cancer is the fourth leading cause of cancer mortality in females worldwide. Infection with high‑risk human papillomavirus (HPV) is essential but insufficient to cause cervical cancer, and the clearance of HPV infection is mediated by the immune system. The deficit of molecules responsible for adhesion may play a role in the development of cervical cancer. E‑cadherin is encoded by the cadherin 1 (CDH1) gene, and is involved in cell adhesion by forming adherens junctions. The aim of present study was to investigate the methylation pattern of the CDH1 promoter and to identify the association between CDH1 promoter hypermethylation, CDH1 gene expression and HPV infection in cervical specimens obtained from 93 patients with low‑grade squamous intraepithelial lesions (SILs), high‑grade SILs or squamous cell carcinomas, and from 47 patients with normal cervical cytology (HPV‑negative). The methylation pattern of the CDH1 promoter was investigated by methylation‑specific polymerase chain reaction and quantitative pyrosequencing. CDH1 gene expression was measured by relative quantification. CDH1 methylation was significantly higher in both types of lesions and in cervical cancer than in normal samples, and CDH1 gene expression was significantly reduced during SIL progression (P=0.0162). However, the influence of HPV infection or HPV E6 expression on the methylation pattern of the CDH1 gene or its gene expression levels could not be confirmed. The present results support that the methylation of the CDH1 gene is age‑related in patients with cervical lesions (P=0.01085), and therefore, older patients could be more susceptible to cancer than younger patients. The important methylation of the CDH1 promoter occurred near the transcription factor binding sites on nucleotides ‑13 and +103, which are close to the translational start codon. These results suggest that methylation at these sites may be an important event in the transcriptional regulation of E‑cadherin, and in patients harboring these methylated cytosines, this event may facilitate HPV‑driven carcinogenesis.

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