Journal Article

Suppression of gap junctional intercellular communication via 5′ CpG island methylation in promoter region of E-cadherin gene in endometrial cancer cells

Makoto Nishimura, Tsuyoshi Saito, Hiroshi Yamasaki and Ryuichi Kudo

in Carcinogenesis

Volume 24, issue 10, pages 1615-1623
Published in print October 2003 | ISSN: 0143-3334
Published online October 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg121
Suppression of gap junctional intercellular communication via 5′ CpG island methylation in promoter region of E-cadherin gene in endometrial cancer cells

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Previously, we demonstrated that connexins (Cxs) showed aberrant localization and expression in most endometrial hyperplasia and carcinoma samples, indicating that during endometrial carcinogenesis, loss of gap junctional intercellular communication (GJIC) may occur at relatively early stages. In the present study, we focused on the correlations between GJIC and the expression of the E-cadherin and its 5′ CpG island methylation in endometrial cancer cells and tissues to investigate their roles in the carcinogenesis and tumor progression of endometrial cancer. In this study, three of the 10 cell lines investigated, Ishikawa, RL-952 and KLE, in which both Cxs and E-cadherin mRNA were expressed, exhibited GJIC by scrape-loading/dye transfer. On the other hand, the other seven cell lines, in which either or both Cxs and E-cadherin mRNA were negative or weakly expressed, did not show GJIC. HEC-50, HEC-1B and HEC-108, in which Cxs were positively expressed but E-cadherin was negatively expressed, showed cytoplasmic localization of Cxs by immunohistochemistry. All five lines, which showed the weak expression of E-cadherin, had E-cadherin 5′ CpG island methylation. By immunohistochemistry of 56 endometrial carcinomas, 13 of 27 methylated samples showed weak expression of Cx26 and the other 14 showed diffuse localization in cytoplasm. On the other hand, of 29 unmethylated samples, two showed cell–cell localization, 25 weak expression and two diffuse localization. Furthermore, E-cadherin expression was revealed to be drastically down-regulated by E-cadherin antisense oligonucleotides that post-transcriptionally down-regulated E-cadherin expression and in the cell, the localization of Cxs were changed from the cell–cell borders to the cytoplasm, and GJIC also decreased. The results indicated that 5′ CpG island methylation, which caused loss of E-cadherin expression, indirectly caused the suppression of GJIC by aberrant localization of Cxs in endometrial carcinoma cells.

Keywords: Cxs, connexins; GJIC, gap junctional intercellular communication; LY, lucifer yellow; MSP, methylation-specific PCR

Journal Article.  6707 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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