Wilms' tumor protein induces an epithelial-mesenchymal hybrid differentiation state in clear cell renal cell carcinoma

• Published in: PloS one Vol. 9; no. 7; p. e102041
• Main Authors: Sampson, Valerie B, David, Justin M, Puig, Isabel, Patil, Pratima U, de Herreros, Antonio García, Thomas, George V, Rajasekaran, Ayyappan K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15-07-2014; Public Library of Science (PLoS)
• Subjects: Animals; Biology and life sciences; Cadherins - genetics; Cadherins - metabolism; Cancer; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Cell adhesion & migration; Cell differentiation; Cell Line, Tumor; Clear cell-type renal cell carcinoma; Developmental biology; Differentiation (biology); E-cadherin; Epithelial-Mesenchymal Transition - genetics; Fetge Càncer; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genotype & phenotype; Humans; Hypoxia; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidneys; Laboratories; Medical research; Medicine and Health Sciences; Mesenchyme; Metastasis; Neoplasia; Proteins; Renal cell carcinoma; Snail Family Transcription Factors; Snail protein; Stem cells; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor suppressor genes; Tumors; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; Wilms' tumor; Wnt Proteins - genetics; WT1 Proteins - genetics; Oregon; Delaware; United States > US; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0102041

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.