title: Wilms' tumor protein induces an epithelial-mesenchymal hybrid differentiation state in clear cell renal cell carcinoma.
abstract: The Wilms' tumor transcription factor (WT1) was originally classified as a tumor suppressor, but it is now known to also be associated with cancer progression and poor prognosis in several malignancies. WT1 plays an essential role in orchestrating a developmental process known as mesenchymal-to-epithelial transition (MET) during kidney development, but also induces the reverse process, epithelial-to-mesenchymal transition (EMT) during heart development. WT1 is not expressed in the adult kidney, but shows elevated expression in clear cell renal cell carcinoma (ccRCC). However, the role of WT1 in this disease has not been characterized. In this study, we demonstrate that WT1 is upregulated in ccRCC cells that are deficient in the expression of the von Hippel-Lindau tumor suppressor protein (VHL). We found that WT1 transcriptionally activated Snail, a master transcriptional repressor that is known to induce EMT. Although Snail represses E-cadherin and induces mesenchymal characteristics, we found partial maintenance of E-cadherin and associated epithelial characteristics in kidney cells and ccRCC cells that express WT1, since WT1 upregulates E-cadherin expression and competes with Snail repression. These findings support a novel paradigm in which WT1 induces an epithelial-mesenchymal hybrid transition (EMHT), characterized by Snail up-regulation with E-cadherin maintenance, a tumor cell differentiation state in which cancer cells keep both EMT and MET characteristics which may promote tumor cell plasticity and tumor progression.
authors.affiliation: Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America.
authors.forename: Valerie B
authors.initials: VB
authors.lastname: Sampson
authors.affiliation: Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America; Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America.
authors.forename: Justin M
authors.initials: JM
authors.lastname: David
authors.affiliation: IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Puig
authors.affiliation: Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America; Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America.
authors.forename: Pratima U
authors.initials: PU
authors.lastname: Patil
authors.affiliation: IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain.
authors.forename: Antonio García
authors.initials: AG
authors.lastname: de Herreros
authors.affiliation: Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon, United States of America.
authors.forename: George V
authors.initials: GV
authors.lastname: Thomas
authors.affiliation: Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America.
authors.forename: Ayyappan K
authors.initials: AK
authors.lastname: Rajasekaran
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D025721:WT1 Proteins / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics*
chemical_list: D015820:Cadherins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025721:WT1 Proteins; D051153:Wnt Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human