Variant HNF1 Modulates Epithelial Plasticity of Normal and Transformed Ovary Cells
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 ti...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2008-12-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558608800929 |
| _version_ | 1828920606572150784 |
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| author | Antonella Tomassetti Giuseppina De Santis Giancarlo Castellano Silvia Miotti Mimma Mazzi Daniela Tomasoni Frans Van Roy Maria Luisa Carcangiu Silvana Canevari |
| author_facet | Antonella Tomassetti Giuseppina De Santis Giancarlo Castellano Silvia Miotti Mimma Mazzi Daniela Tomasoni Frans Van Roy Maria Luisa Carcangiu Silvana Canevari |
| author_sort | Antonella Tomassetti |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T21:48:56Z |
| format | Article |
| id | doaj.art-f29632e8fe304febab4940d6da3774f1 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-13T21:48:56Z |
| publishDate | 2008-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-f29632e8fe304febab4940d6da3774f12022-12-21T23:30:20ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022008-12-0110121481149210.1593/neo.81004Variant HNF1 Modulates Epithelial Plasticity of Normal and Transformed Ovary CellsAntonella Tomassetti0Giuseppina De Santis1Giancarlo Castellano2Silvia Miotti3Mimma Mazzi4Daniela Tomasoni5Frans Van Roy6Maria Luisa Carcangiu7Silvana Canevari8Unit of Molecular Therapies, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, ItalyUnit of Molecular Therapies, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, ItalyUnit of Molecular Therapies, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, ItalyUnit of Molecular Therapies, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, ItalyUnit of Molecular Therapies, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, ItalyUnit of Molecular Therapies, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, ItalyDepartment of Molecular Biomedical Research, VIB, Ghent, BelgiumUnit of Pathology C, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, ItalyUnit of Molecular Therapies, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, ItalyOvarian 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.http://www.sciencedirect.com/science/article/pii/S1476558608800929 |
| spellingShingle | Antonella Tomassetti Giuseppina De Santis Giancarlo Castellano Silvia Miotti Mimma Mazzi Daniela Tomasoni Frans Van Roy Maria Luisa Carcangiu Silvana Canevari Variant HNF1 Modulates Epithelial Plasticity of Normal and Transformed Ovary Cells Neoplasia: An International Journal for Oncology Research |
| title | Variant HNF1 Modulates Epithelial Plasticity of Normal and Transformed Ovary Cells |
| title_full | Variant HNF1 Modulates Epithelial Plasticity of Normal and Transformed Ovary Cells |
| title_fullStr | Variant HNF1 Modulates Epithelial Plasticity of Normal and Transformed Ovary Cells |
| title_full_unstemmed | Variant HNF1 Modulates Epithelial Plasticity of Normal and Transformed Ovary Cells |
| title_short | Variant HNF1 Modulates Epithelial Plasticity of Normal and Transformed Ovary Cells |
| title_sort | variant hnf1 modulates epithelial plasticity of normal and transformed ovary cells |
| url | http://www.sciencedirect.com/science/article/pii/S1476558608800929 |
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