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E(2) inhibits IL-8 release by ERbeta in CF bronchial epithelial cells through up-regulation of secretory leucoprotease inhibitor, inhibition of nuclear factor (NF)-kappaB, and IL-8 gene expression. These data implicate a novel anti-inflammatory mechanism for E(2) in females with CF, which predisposes to infection and colonization. This could, in part, account for the observed gender dichotomy in CF.

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The K + channel KCNQ1 has been proposed as a tumor suppressor in colorectal cancer (CRC). We investigated the molecular mechanisms regulating KCNQ1:β-catenin bidirectional interactions and their effects on CRC differentiation, proliferation, and invasion. Molecular and pharmacologic approaches were used to determine the influence of KCNQ1 expression on the Wnt/β-catenin signaling and epithelial-to-mesenchymal transition (EMT) in human CRC cell lines of varying stages of differentiation. The expression of KCNQ1 was lost with increasing mesenchymal phenotype in poorly differentiated CRC cell lines as a consequence of repression of the KCNQ1 promoter by β-catenin:T-cell factor (TCF)-4. In welldifferentiated epithelial CRC cell lines, KCNQ1 was localized to the plasma membrane in a complex with β-catenin and E-cadherin. The colocalization of KCNQ1 with adherens junction proteins was lost with increasing EMT phenotype. ShRNA knock-down of KCNQ1 caused a relocalization of β-catenin from the plasma membrane and a loss of epithelial phenotype in CRC spheroids. Overexpression of KCNQ1 trapped β-catenin at the plasma membrane, induced a patent lumen in CRC spheroids, and slowed CRC cell invasion. The KCNQ1 ion channel inhibitor chromanol 293B caused membrane depolarization, redistribution of β-catenin into the cytosol, and a reduced transepithelial electrical resistance, and stimulated CRC cell proliferation. Analysis of human primary CRC tumor patient databases showed a positive correlation between KCNQ1:KCNE3 channel complex expression and disease-free survival. We conclude that the KCNQ1 ion channel is a target gene and regulator of the Wnt/β-catenin pathway, and its repression leads to CRC cell proliferation, EMT, and tumorigenesis.T he development of colorectal cancer (CRC) is determined by multiple factors including ion transport (1, 2). During the last 10 years, evidence for the role of K + channels in the development and growth of tumors has greatly expanded. Voltage-gated K + channels (Kv) are involved in the proliferation of many cell types, including intestinal cells. Although the recent literature clearly demonstrates that Kv channels are among the targets of interest in the fight against cancer (3-5), the specific role of each Kv channel in tumorigenesis and the molecular mechanisms involved are unknown. This is notably the case of the KCNQ1 K + channel. The KCNQ1 gene has recently been identified as a tumor suppressor in mouse and human CRC tissues (6). KCNQ1 deficiency in mice caused rectal adenomatous hyperplasia and progression to adenocarcinoma. A loss of imprinting of KCNQ1 has been described in CRC (7). However, the functional and molecular events linking KCNQ1 and CRC progression remain unclear. One obvious pathway, which may interact with KCNQ1, is Wnt/ β-catenin signaling, which plays a key role in driving early embryogenesis, as well as intestinal homeostasis and stem cell renewal in the intestinal mucosa epithelia (8). Deregulation of the β-catenin signaling axis is present in more than 80% of CRC...