title: 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.
authors.affiliation: Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, USA. sraj@medsci.udel.edu
authors.forename: Sigrid A
authors.initials: SA
authors.lastname: Rajasekaran
authors.forename: Thu P
authors.initials: TP
authors.lastname: Huynh
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Wolle
authors.forename: Cromwell E
authors.initials: CE
authors.lastname: Espineda
authors.forename: Landon J
authors.initials: LJ
authors.lastname: Inge
authors.forename: Anna
authors.initials: A
authors.lastname: Skay
authors.forename: Charles
authors.initials: C
authors.lastname: Lassman
authors.forename: Susanne B
authors.initials: SB
authors.lastname: Nicholas
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Harper
authors.forename: Anna E
authors.initials: AE
authors.lastname: Reeves
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Ahmed
authors.forename: James M
authors.initials: JM
authors.lastname: Leatherman
authors.forename: James M
authors.initials: JM
authors.lastname: Mullin
authors.forename: Ayyappan K
authors.initials: AK
authors.lastname: Rajasekaran
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D004848:Epithelium / Q000201:enzymology / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D055785:Gene Knockdown Techniques; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology; D018374:LLC-PK1 Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008648:Mesoderm / Q000201:enzymology / Q000473:pathology*; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010641:Phenotype; D021122:Protein Subunits / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013552:Swine; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D014408:Biomarkers, Tumor; D021122:Protein Subunits; D016212:Transforming Growth Factor beta; D012964:Sodium; D048049:Extracellular Signal-Regulated MAP Kinases; D000254:Sodium-Potassium-Exchanging ATPase