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KCl Cotransporter-3 Down-regulates E-Cadherin/ß-Catenin Complex to Promote Epithelial-Mesenchymal Transition

¹ Institute of Basic Medical Sciences, and Departments of ² Pharmacology, ³ Obstetrics and Gynecology, and ⁴ Physiology, College of Medicine and ⁵ Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, Taiwan; ⁶ Graduate Institute of Molecular and Cell Biology, College of Life Sciences, Tzu Chi University, Hualien, Taiwan; and ⁷ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom

Requests for reprints: Meng-Ru Shen, Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan. Phone: 886-6-2353535, ext. 5505; Fax: 886-6-2766185; E-mail: mrshen{at}mail.ncku.edu.tw.

The potassium chloride cotransporter (KCC) is a major determinant of osmotic homeostasis and plays an emerging role in tumor biology. Here, we investigate if KCC is involved in the regulation of epithelial-mesenchymal transition (EMT), a critical cellular event of malignancy. E-cadherin and ß-catenin colocalize in the cell-cell junctions, which becomes more obvious in a time-dependent manner by blockade of KCC activity in cervical cancer SiHa and CaSki cells. Real-time reverse transcription-PCR on the samples collected from the laser microdissection indicates that KCC3 is the most abundant KCC isoform in cervical carcinoma. The characteristics of EMT appear in KCC3-overexpressed, but not in KCC1- or KCC4-overexpressed cervical cancer cells, including the elongated cell shape, increased scattering, down-regulated epithelial markers (E-cadherin and ß-catenin), and up-regulated mesenchymal marker (vimentin). Some cellular functions are enhanced by KCC3 overexpression, such as increased invasiveness and proliferation, and weakened cell-cell association. KCC3 overexpression decreases mRNA level of E-cadherin. The promoter activity assays of various regulatory sequences confirm that KCC3 expression is a potent negative regulator for human E-cadherin gene expression. The proteosome inhibitor restores the decreased protein abundance of ß-catenin by KCC3 overexpression. In the surgical specimens of cervical carcinoma, the decreased E-cadherin amount was accompanied by the increased KCC3 abundance. Vimentin begins to appear at the invasive front and becomes significantly expressed in the tumor nest. In conclusion, KCC3 down-regulates E-cadherin/ß-catenin complex formation by inhibiting transcription of E-cadherin gene and accelerating proteosome-dependent degradation of ß-catenin protein. The disruption of E-cadherin/ß-catenin complex formation promotes EMT, thereby stimulating tumor progression. [Cancer Res 2007;67(22):11064–73]

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				M.-Y. Lee, C.-Y. Chou, M.-J. Tang, and M.-R. Shen Epithelial-Mesenchymal Transition in Cervical Cancer: Correlation with Tumor Progression, Epidermal Growth Factor Receptor Overexpression, and Snail Up-Regulation Clin. Cancer Res., August 1, 2008; 14(15): 4743 - 4750. [Abstract] [Full Text] [PDF]