DNA methyltransferase 1 expression and promoter methylation of E-cadherin in mucoepidermoid carcinoma

Authors

  • Yi-Shing Shieh D.D.S., Ph.D.,

    1. School of Dentistry, National Defense Medical Center, Taipei, Taiwan
    2. Department of Oral Diagnosis and Pathology, Tri-Service General Hospital, Taipei, Taiwan
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  • Shine-Gwo Shiah Ph.D.,

    1. President Laboratory, National Health Research Institutes, Taipei, Taiwan
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  • Hao-Hsuan Jeng M.S.,

    1. School of Dentistry, National Defense Medical Center, Taipei, Taiwan
    2. President Laboratory, National Health Research Institutes, Taipei, Taiwan
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  • Herng-Sheng Lee M.D., Ph.D.,

    1. Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan
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  • Cheng-Wen Wu M.D., Ph.D.,

    1. President Laboratory, National Health Research Institutes, Taipei, Taiwan
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  • Long-Chang Chang D.D.S., Ph.D.

    Corresponding author
    1. School of Dentistry, National Defense Medical Center, Taipei, Taiwan
    2. Department of Oral Diagnosis and Pathology, Tri-Service General Hospital, Taipei, Taiwan
    • School of Dentistry, National Defense Medical Center, P.O. Box 90048-503, Taipei, Taiwan
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    • Fax: (011) 886-2-87919276 or (011) 886-2-87923149

    • Long-Chang Chang, D.D.S., Ph.D., School of Dentistry, National Defense Medical Center, P.O. Box 90048-503, Taipei, Taiwan. Fax: 011 (886) 287919276 or 011 (886) 287923149; E-mail: ndmcyss@nhri.org.tw


Abstract

BACKGROUND

Loss of E-cadherin expression is found frequently in many types of human malignancies, including mucoepidermoid carcinoma (MEC). CpG methylation in the promoter region has proven important in the regulation of gene expression implicated in malignant transformation. DNA methyltransferases (DNMTs) are the major enzymes involved in establishing genomic methylation patterns. The current study was designed to test the hypothesis that CpG methylation of the promoter region of the E-cadherin gene may inactivate its expression and to examine DNMT 1 (DNMT1) protein expression in MEC.

METHODS

Genomic DNA was obtained from paraffin embedded sections by laser microdissection in 46 MEC specimens. Methylation status of the E-cadherin promoter was examined by utilizing the methylation-specific polymerase chain reaction assay. To examine E-cadherin and DNMT1 proteins expression levels, the MEC specimens and adjacent epithelial tissues were studied immunohistochemically. Chi-square analysis was used to evaluate the correlation of protein expression and E-cadherin methylation status with clinicopathologic parameters. Comparisons of the survival rate between patients with DNMT1-positive and DNMT1-negative patients were made using Kaplan–Meier analysis.

RESULTS

The data showed that all normal tissues expressed E-cadherin, and no promoter methylation was detected. Of the MEC samples analyzed, methylation allele was found in 33 of 46 samples (72%), and reduced E-cadherin expression was found in 21 of 46 samples (45%). DNMT1-positive expression was observed in 29 of 46 MEC samples (63%). A significant correlation was found between E-cadherin expression and the methylation status of E-cadherin promoter (P = 0.021). In addition, increased DNMT1 expression was correlated with histologic grade, clinical stage, and a poor prognosis in patients with MEC.

CONCLUSIONS

Hypermethylation of CpG sites at the 5′ promoter of E-cadherin was a common event associated with E-cadherin expression levels in MEC, suggesting an epigenetically mediated loss of E-cadherin function in these tumors. Increased DNMT1 protein expression may play a critical role in the carcinogenesis and disease progression of MEC. Cancer 2005. © 2005 American Cancer Society.

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