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A7086 - Interactions Between Cystic Fibrosis Transmembrane Conductance Regulator and Wnt/b-Catentin Signaling Alter Lung Cancer Stem Cell Properties
Author Block: H. Li1, N. Ma2, Y. Wang2, J. Yang2, Y. Jia2, J. Xue2, X. Liu2, J. Shi2; 1Ningxia Medical University, Yinchuan, China, 2General Hospital, Ningxia Medical University, Yinchuan, China.
Despite advances in cancer therapy, lung cancer remains a leading cause of cancer-related deaths worldwide, due to the development of resistance and eventual relapse. The relapse and resistance to therapies of lung cancers have been attributed to the existence of a subpopulation of lung cancer stem cells (LCSCs) that have the potential of initiating cancer formation. Therefore targeting the LCSCs may offer a novel strategy for treatment of lung cancers. The cystic fibrosis transmembrane conductance regulator (CFTR) plays a crucial role in retaining the homeostasis and function of lung, its expression and function were found to correlate with many types of epithelial cancers including the lung cancer. An impaired CFTR function or loss of CFTR protein might increase the risk of development of lung cancer. Wnt/β-catenin signaling governs the cell fate and proliferation in a variety of cell types, and prominently features in stem cells and cancers. Interestingly, the expression and function of CFTR were impaired in lung by cigarette smoking. Together with the evidence of that both CFTR and Wnt/β-catenin signaling were essential in lung development, in which the abundance of CFTR was inversely correlated with Wnt/β-catenin signaling activities, we thus hypothesized that the interaction of CFTR and Wnt/β-catenin signaling might alter characteristics of LCSCs. By using a strategy of gain/loss function of CFTR or Wnt/β-catenin signaling, the impact of interactions between CFTR and Wnt/β-catenin signaling on properties of LCSCs were interrogated in lung cancer A549 cells using assays of cell migration, invasion and clonogenicity, as well as molecular analysis of the expression of LCSC markers and interaction of proteins by cytometriy, immunoblotting and immunoprecipitation assays. Results showed that an overexpression and knockdown CFTR expression inhibited and enhanced the capacity of cell migration, invasion and clonogenicity, and the frequency of ALDH positive cells in both A549 cells treated with and with nicotine, respectively. Molecular analysis demonstrated that CFTR-altered LCSC properties were inversely correlated with Wnt signaling activations, and the expression of stem cell markers OCT4, SOX2 and ALDH1. In contrast, an activated and inactivated Wnt/β-catenin signaling led a suppression and argumentation of CFTR expression, along with an inhibited and enhanced capacity of LCSCs, respectively. Immunoprecipitation assay further revealed interactions of CFTR and Wnt/β-catenin signaling APC, Dishevelled 2 and β-catenin. This study thus provides a novel mechanism by which CFTR modulates Wnt/β-catenin signaling to inhibit LCSC properties and indicates a potential therapeutic target for lung cancer.