The emerging role of KCl cotransport in tumor biology

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-1 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.