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

Valerie B. Sampson, Justin M. David, Isabel Puig, Pratima U. Patil, Antonio García De Herreros, George Thomas, Ayyappan K. Rajasekaran

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere102041
JournalPLoS One
Volume9
Issue number7
DOIs
StatePublished - Jul 15 2014

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Wilms Tumor
kidney cells
Epithelial-Mesenchymal Transition
Renal Cell Carcinoma
cadherins
carcinoma
Tumors
Cadherins
Cells
snails
neoplasms
Neoplasms
Proteins
proteins
cells
Von Hippel-Lindau Tumor Suppressor Protein
Snails
kidneys
Kidney
Up-Regulation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Sampson, V. B., David, J. M., Puig, I., Patil, P. U., De Herreros, A. G., Thomas, G., & Rajasekaran, A. K. (2014). Wilms' tumor protein induces an epithelial-mesenchymal hybrid differentiation state in clear cell renal cell carcinoma. PLoS One, 9(7), [e102041]. https://doi.org/10.1371/journal.pone.0102041

Wilms' tumor protein induces an epithelial-mesenchymal hybrid differentiation state in clear cell renal cell carcinoma. / Sampson, Valerie B.; David, Justin M.; Puig, Isabel; Patil, Pratima U.; De Herreros, Antonio García; Thomas, George; Rajasekaran, Ayyappan K.

In: PLoS One, Vol. 9, No. 7, e102041, 15.07.2014.

Research output: Contribution to journalArticle

Sampson, Valerie B. ; David, Justin M. ; Puig, Isabel ; Patil, Pratima U. ; De Herreros, Antonio García ; Thomas, George ; Rajasekaran, Ayyappan K. / Wilms' tumor protein induces an epithelial-mesenchymal hybrid differentiation state in clear cell renal cell carcinoma. In: PLoS One. 2014 ; Vol. 9, No. 7.
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