Volume 9 Issue 2 - June 5, 2009
KCl cotransporter-3 downregulates E-cadherin/β-catenin complex to promote epithelial-mesenchymal transition
Meng-Ru Shen

Department of Pharmacology, College of Medicine, National Cheng Kung University
mrshen@mail.ncku.edu.tw

Cancer Res. 2007; 67(22):11064-73

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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 β-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 RT-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, downregulated epithelial markers (E-cadherin and β-catenin), and upregulated 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 β-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 downregulates E-cadherin/β-catenin complex formation by inhibiting transcription of E-cadherin gene and accelerating proteosome-dependent degradation of β-catenin protein. The disruption of E-cadherin/β-catenin complex formation promotes EMT, thereby stimulating tumor progression.

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