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Na,K-ATPase subunits as markers for epithelial-mesenchymal transition in cancer and fibrosis.

ABSTRACT: Epithelial-to-mesenchymal transition (EMT) is an important developmental process, participates in tissue repair, and occurs during pathologic processes of tumor invasiveness, metastasis, and tissue fibrosis. The molecular mechanisms leading to EMT are poorly understood. Although it is well documented that transforming growth factor (TGF)-beta plays a central role in the induction of EMT, the targets of TGF-beta signaling are poorly defined. We have shown earlier that Na,K-ATPase beta(1)-subunit levels are highly reduced in poorly differentiated kidney carcinoma cells in culture and in patients' tumor samples. In this study, we provide evidence that Na,K-ATPase is a new target of TGF-beta(1)-mediated EMT in renal epithelial cells, a model system used in studies of both cancer progression and fibrosis. We show that following treatment with TGF-beta(1), the surface expression of the beta(1)-subunit of Na,K-ATPase is reduced, before well-characterized EMT markers, and is associated with the acquisition of a mesenchymal phenotype. RNAi-mediated knockdown confirmed the specific involvement of the Na,K-ATPase beta(1)-subunit in the loss of the epithelial phenotype and exogenous overexpression of the Na,K-ATPase beta(1)-subunit attenuated TGF-beta(1)-mediated EMT. We further show that both Na,K-ATPase alpha- and beta-subunit levels are highly reduced in renal fibrotic tissues. These findings reveal for the first time that Na,K-ATPase is a target of TGF-beta(1)-mediated EMT and is associated with the progression of EMT in cancer and fibrosis.

SUBMITTER: Rajasekaran SA

PROVIDER: S-EPMC2884047 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Na,K-ATPase subunits as markers for epithelial-mesenchymal transition in cancer and fibrosis.

Rajasekaran Sigrid A SA Huynh Thu P TP Wolle Daniel G DG Espineda Cromwell E CE Inge Landon J LJ Skay Anna A Lassman Charles C Nicholas Susanne B SB Harper Jeffrey F JF Reeves Anna E AE Ahmed Mansoor M MM Leatherman James M JM Mullin James M JM Rajasekaran Ayyappan K AK

Molecular cancer therapeutics 20100525 6

Epithelial-to-mesenchymal transition (EMT) is an important developmental process, participates in tissue repair, and occurs during pathologic processes of tumor invasiveness, metastasis, and tissue fibrosis. The molecular mechanisms leading to EMT are poorly understood. Although it is well documented that transforming growth factor (TGF)-beta plays a central role in the induction of EMT, the targets of TGF-beta signaling are poorly defined. We have shown earlier that Na,K-ATPase beta(1)-subunit ...[more]

PMID: 20501797

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Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective treatment. The epithelial-mesenchymal transition (EMT) is a critical stage during the development of fibrosis. To assess the effect of sulforaphane (SFN) on the EMT and fibrosis using an in vitro transforming growth factor (TGF)-?1-induced model and an in vivo bleomycin (BLM)-induced model.In vitro studies, cell viability, and cytotoxicity were measured using a Cell Counting Kit-8. The functional TGF-?1-induced EMT and fibrosis were assessed using western blotting and a quantitative real-time polymerase chain reaction. The lungs were analyzed histopathologically in vivo using hematoxylin and eosin and Masson's trichrome staining. The BLM-induced fibrosis was characterized by western blotting and immunohistochemical analyses for fibronectin, TGF-?1, E-cadherin (E-cad), and ?-smooth muscle actin (SMA) in lung tissues.SFN reversed mesenchymal-like changes induced by TGF-?1 and restored cells to their epithelial-like morphology. The results confirmed that the expression of the epithelial marker, E-cadherin, increased after SFN treatment, while expression of the mesenchymal markers, N-cadherin, vimentin, and ?-SMA decreased in A549 cells after SFN treatment. In addition, SFN inhibited TGF-?1-induced mRNA expression of the EMT-related transcription factors, Slug, Snail, and Twist. The SFN treatment attenuated TGF-?1-induced expression of fibrosis-related proteins, such as fibronection, collagen I, collagen IV, and ?-SMA in MRC-5 cells. Furthermore, SFN reduced the TGF-?1-induced phosphorylation of SMAD2/3 protein in A549 cells and MRC-5 cells. BLM induced fibrosis in mouse lungs that was also attenuated by SFN treatment, and SFN treatment decreased BLM-induced fibronectin expression, TGF-?1 expression, and the levels of collagen I in the lungs of mice.SFN showed a significant anti-fibrotic effect in TGF-?-treated cell lines and BLM-induced fibrosis in mice. These findings showed that SFN has anti-fibrotic activity that may be considered in the treatment of IPF.

Dataset Information

Na,K-ATPase subunits as markers for epithelial-mesenchymal transition in cancer and fibrosis.

Publications

Na,K-ATPase subunits as markers for epithelial-mesenchymal transition in cancer and fibrosis.

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