AJTR Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Am J Translational Res 2010;2(4):345-355

Review Article
The emerging role of KCl cotransport in tumor biology

Yih-Fung Chen, Cheng-Yang Chou, J. Clive Ellory, Meng-Ru Shen

Institute of Basic Medical Sciences, Department of Pharmacology, Department of Obstetrics & Gynecology,
College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; Department of Physiology, Anatomy
and Genetics, University of Oxford, Oxford, OX1 3PT, UK

Received May 26, 2010; accepted June 12, 2010; available online June 18, 2010

Abstract: The electroneutral KCl cotransport carried out by the KCl cotransporter family (KCC) plays a significant
role in the ionic and osmotic homeostasis of epithelial cells. Here we review the emerging importance of KCl
cotransport in epithelial carcinogenesis and tumor malignant behaviors. The malignant transformation of cervical
epithelial cells is associated with the differential expression of volume-sensitive KCC isoforms. The loss-of-
function KCC mutant cervical cancer cells exhibit inhibited cell growth accompanied by decreased activities of the
cell cycle regulators and matrix metalloproteinase. Additionally, insulin-like growth factor-1 (IGF-1) stimulation of
KCl cotransport plays an important role in IGF-1 signaling to promote growth and spread of gynecological
cancers. IGF-1 upregulates KCC3 and KCC4 which are differentially required for cancer cell proliferation and
invasiveness. KCC3 overexpression downregulates E-cadherin/β-catenin complex formation by inhibiting the
transcription of E-cadherin gene and accelerating the proteosome-dependent degradation of β-catenin protein.
That therefore promotes the epithelial-mesenchymal transition of cervical cancer cells, and thereby stimulating
tumor progression. Moreover, epidermal-growth factor (EGF) and IGF-I stimulate the membrane recruitment of
KCC4 at lamellipodia through myosin Va-actin trafficking route. KCC4 functions as a membrane scaffold for the
assembly of signal complexes via the association with the actin-binding protein, ezrin. The molecular studies of
surgical specimens suggest that the expression of KCC3, KCC4, and their stimulators, EGF or IGF-1, exhibit a
close association with the clinical outcome of cancer patients. Therefore, KCC3, KCC4, EGF, and IGF-1 may be a
panel of biomarkers to predict cancer patient outcome.(AJTR1005003).

Key words: KCl cotransport, proliferation, migration, metastasis, cervical cancer, ovarian cancer

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Address all correspondence to:
Dr. Meng-Ru Shen
Department of Pharmacology
College of Medicine, National Cheng Kung University
Tainan 704, Taiwan
Tel: 886-6-2353535 ext 5505; Fax: 886-6-2766185