Carcinogenesis Advance Access published online on August 1, 2003
Carcinogenesis, doi:10.1093/carcin/bgg121
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-0061, Japan
* Corresponding author. E-mail: tsaito{at}sapmed.ac.jp.
Received 9 June 2003
; revised 30 June 2003
; accepted 1 July 2003
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 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, 2 showed cell-cell localization, 25 weak expression and 2 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.
endometrial carcinoma, cell adhesion, intercellular communication, gap junction, clonal dispersion
Suppression of gap junctional intercellular communication via 5' CpG island methylation in promoter region of E-cadherin gene in endometrial cancer cells
2 School of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan
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