Variant HNF1 modulates epithelial plasticity of normal and transformed ovary cells

Antonella Tomassetti, Giuseppina De Santis, Giancarlo Castellano, Silvia Miotti, Mimma Mazzi, Daniela Tomasoni, Frans Van Roy, Maria Luisa Carcangiu, Silvana Canevari

Research output: Contribution to journalArticle

Abstract

Ovarian carcinoma arises from the ovarian surface epithelium, which undergoes phenotypic changes characteristic of müllerian epithelium during the first stages of tumorigenesis. The variant isoform of the hepatocyte nuclear factor 1 (vHNF1) is a transcription factor involved in the development of tissues derived from the müllerian duct. Here, we show that vHNF1 knockdown in two ovarian carcinoma cell lines, SKOV3 and IGROV1, leads to reduced E-cadherin (E-cadh) expression and decreased proliferation rate. Accordingly, SKOV3 cells ectopically expressing a dominant-negative (DN) vHNF1 mutant undergo an epithelial-mesenchymal-like transition, acquiring a spindle-like morphology, loss of E-cadh, and disrupted cell-cell contacts. Gene expression profiling of DNvHNF1 cells on the basis of a newly compiled list of epithelial-mesenchymal transition-related genes revealed a correlation between vHNF1 loss-of-function and acquisition of the mesenchymal phenotype. Indeed, phenotypic changes were associated with increased Slug transcription and functionality. Accordingly, vHNF1-transfected immortalized ovarian surface epithelial cells showed down-regulation of Snail and Slug transcripts. In DNvHNF1-transfected SKOV3 cells, growth rate decreased, and in vHNF1-transfected immortalized ovarian surface epithelial cells, growth rate increased. By immunohistochemistry, we found a strong association of vHNF1 with E-cadh in clear cell and in a subset of serous carcinomas, data that could potentially contribute in distinguishing different types of ovarian tumors. Our results may help in understanding the biology of ovarian carcinoma, identifying early detection markers, and opening potential avenues for therapeutic intervention.

Original languageEnglish
Pages (from-to)1481-1492
Number of pages12
JournalNeoplasia (United States)
Volume10
Issue number12
DOIs
Publication statusPublished - Dec 2008

ASJC Scopus subject areas

  • Cancer Research

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    Tomassetti, A., De Santis, G., Castellano, G., Miotti, S., Mazzi, M., Tomasoni, D., Van Roy, F., Carcangiu, M. L., & Canevari, S. (2008). Variant HNF1 modulates epithelial plasticity of normal and transformed ovary cells. Neoplasia (United States), 10(12), 1481-1492. https://doi.org/10.1593/neo.81004