Loss of secreted frizzled-related protein 4 correlates with an aggressive phenotype and predicts poor outcome in ovarian cancer patients
| Autor: | Rosmarie Caduff, Jake Olivier, Viola Heinzelmann-Schwarz, Daniela Hornung, Neville F. Hacker, Renato Mueller, Francis Jacob, Sheri Nixdorf, Daniel Fink, Kristjan Ukegjini, Rea Guertler, James Scurry, Caroline E. Ford |
|---|---|
| Přispěvatelé: | University of Zurich |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Frizzled
Cellular differentiation lcsh:Medicine Malignant transformation Cohort Studies Prostate cancer 0302 clinical medicine Molecular Cell Biology lcsh:Science Ovarian Neoplasms 0303 health sciences Multidisciplinary Wnt signaling pathway Ascites Obstetrics and Gynecology Genomics Prognosis Immunohistochemistry 10174 Clinic for Gynecology 3. Good health Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Phenotype Treatment Outcome Oncology 030220 oncology & carcinogenesis Medicine Female SFRP4 Research Article medicine.medical_specialty Histology Tumor suppressor gene 610 Medicine & health 1100 General Agricultural and Biological Sciences Biology 03 medical and health sciences 1300 General Biochemistry Genetics and Molecular Biology 10049 Institute of Pathology and Molecular Pathology Internal medicine Cell Line Tumor Proto-Oncogene Proteins medicine Humans Neoplasm Invasiveness 030304 developmental biology 1000 Multidisciplinary Cell Membrane lcsh:R medicine.disease Survival Analysis Endocrinology Cancer research Women's Health lcsh:Q Ovarian cancer |
| Zdroj: | PLoS ONE, Vol 7, Iss 2, p e31885 (2012) PLoS ONE PLos One |
| ISSN: | 1932-6203 |
| Popis: | Background: Activation of the Wnt signaling pathway is implicated in aberrant cellular proliferation in various cancers. In 40% of endometrioid ovarian cancers, constitutive activation of the pathway is due to oncogenic mutations in b-catenin or other inactivating mutations in key negative regulators. Secreted frizzled-related protein 4 (SFRP4) has been proposed to have inhibitory activity through binding and sequestering Wnt ligands. Methodology/Principal Findings: We performed RT-qPCR and Western-blotting in primary cultures and ovarian cell lines for SFRP4 and its key downstream regulators activated b-catenin, b-catenin and GSK3b. SFRP4 was then examined by immunohistochemistry in a cohort of 721 patients and due to its proposed secretory function, in plasma, presenting the first ELISA for SFRP4. SFRP4 was most highly expressed in tubal epithelium and decreased with malignant transformation, both on RNA and on protein level, where it was even more profound in the membrane fraction (p,0.0001). SFRP4 was expressed on the protein level in all histotypes of ovarian cancer but was decreased from borderline tumors to cancers and with loss of cellular differentiation. Loss of membrane expression was an independent predictor of poor survival in ovarian cancer patients (p = 0.02 unadjusted; p = 0.089 adjusted), which increased the risk of a patient to die from this disease by the factor 1.8. Conclusions/Significance: Our results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers via inhibition of the Wnt signaling pathway. This has not only predictive implications but could also facilitate a therapeutic role using epigenetic targets. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|