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Aberrant gene promoter methylation of E-cadherin, p16 INK4a, p14 ARF, and MGMT in Epstein–Barr virus-associated oral squamous cell carcinomas

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Abstract

The etiology of oral carcinogenesis appears to be multifactorial. There is emerging evidence of the presence of Epstein–Barr virus (EBV) in epithelial oral squamous cell carcinoma (OSCC), but an association of EBV with oral carcinogenesis has not yet been established. Although epigenetic alterations, such as aberrant DNA methylation, are known to contribute to the pathogenesis of oral cancer, the relationship of such alterations with EBV infection is little known. This study aimed to investigate the association between EBV infection and promoter methylation patterns of tumor-associated genes in OSCC tissues. A total of 165 of formalin-fixed paraffin-embedded OSCC tissues were studied (68 of EBV positive and 97 of EBV negative). The promoter methylation patterns were investigated for four tumor-associated genes, E-cadherin, p16 INK4a, p14 ARF, and MGMT, by using methylation-specific polymerase chain reaction (MSP). The frequencies of gene promoter hypermethylation in all cases were 47.3% for E-cadherin, 92.7% for p16 INK4a, 74.5% for p14 ARF, and 35.8% for MGMT. Interestingly, most of the analyzed gene promoters were more frequently hypermethylated in EBV-positive than EBV-negative cases, in particular the E-cadherin (56/22) and MGMT (38/21) gene promoters (p < 0.05). Concomitantly, hypermethylation of multiple gene promoters (≥3) was encountered more frequently in EBV-positive samples. Hypermethylation of the E-cadherin promoter associated with EBV was more frequently observed in moderately and poorly differentiated OSCC tissues. These results indicate that epigenetic changes frequently occur in OSCCs and may partly be induced by EBV infection, therefore, EBV may involve in development and progression of the OSCCs.

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Acknowledgements

This work was supported by the Thailand Research Fund and Khon Kaen University through the Royal Golden Jubilee Ph.D. Program (Grant No. PHD/0041/2557) and by Khon Kaen University (Grant No. 581201 and 592001). We would like to acknowledge Prof. David Blair for English editing the MS via Publication Clinic KKU.

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Authors and Affiliations

  1. Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    Ati Burassakarn, Chamsai Pientong, Jureeporn Chuerduangphui & Tipaya Ekalaksananan

  2. Department of Microbiology, Faculty of Sciences, Mahasarakham University, Mahasarakham, Thailand

    Nuchsupha Sunthamala

  3. Department of Otorhinolaryngology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    Patravoot Vatanasapt

  4. Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    Natcha Patarapadungkit

  5. Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    Bunkerd Kongyingyoes

  6. HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand

    Ati Burassakarn, Chamsai Pientong, Nuchsupha Sunthamala, Jureeporn Chuerduangphui, Patravoot Vatanasapt, Natcha Patarapadungkit & Tipaya Ekalaksananan

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  1. Ati Burassakarn
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Correspondence to Tipaya Ekalaksananan.

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Ethical approval was given by the Khon Kaen University Ethics Committee (No. HE 581211). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study, giving their authorization to access their clinical information and tumor samples for research purpose.

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Burassakarn, A., Pientong, C., Sunthamala, N. et al. Aberrant gene promoter methylation of E-cadherin, p16 INK4a, p14 ARF, and MGMT in Epstein–Barr virus-associated oral squamous cell carcinomas. Med Oncol 34, 128 (2017). https://doi.org/10.1007/s12032-017-0983-5

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