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Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer

BACKGROUND: The Dachshund homolog 2 (DACH2) gene has been implicated in development of the female genital tract in mouse models and premature ovarian failure syndrome, but to date, its expression in human normal and cancerous tissue remains unexplored. Using the Human Protein Atlas as a tool for can...

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Autores principales: Nodin, Björn, Fridberg, Marie, Uhlén, Mathias, Jirström, Karin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295641/
https://www.ncbi.nlm.nih.gov/pubmed/22284433
http://dx.doi.org/10.1186/1757-2215-5-6
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author Nodin, Björn
Fridberg, Marie
Uhlén, Mathias
Jirström, Karin
author_facet Nodin, Björn
Fridberg, Marie
Uhlén, Mathias
Jirström, Karin
author_sort Nodin, Björn
collection PubMed
description BACKGROUND: The Dachshund homolog 2 (DACH2) gene has been implicated in development of the female genital tract in mouse models and premature ovarian failure syndrome, but to date, its expression in human normal and cancerous tissue remains unexplored. Using the Human Protein Atlas as a tool for cancer biomarker discovery, DACH2 protein was found to be differentially expressed in epithelial ovarian cancer (EOC). Here, the expression and prognostic significance of DACH2 was further evaluated in ovarian cancer cell lines and human EOC samples. METHODS: Immunohistochemical expression of DACH2 was examined in tissue microarrays with 143 incident EOC cases from two prospective, population-based cohorts, including a subset of benign-appearing fallopian tubes (n = 32). A nuclear score (NS), i.e. multiplier of staining fraction and intensity, was calculated. For survival analyses, cases were dichotomized into low (NS < = 3) and high (NS > 3) using classification and regression tree analysis. Kaplan Meier analysis and Cox proportional hazards modelling were used to assess the impact of DACH2 expression on survival. DACH2 expression was analysed in the cisplatin sensitive ovarian cancer cell line A2780 and its cisplatin resistant derivative A2780-Cp70. The specificity of the DACH2 antibody was tested using siRNA-mediated silencing of DACH2 in A2780-Cp70 cells. RESULTS: DACH2 expression was considerably higher in the cisplatin resistant A2780-Cp70 cells compared to the cisplatin-sensitive A2780 cells. While present in all sampled fallopian tubes, DACH2 expression ranged from negative to strong in EOC. In EOC, DACH2 expression correlated with several proteins involved in DNA integrity and repair, and proliferation. DACH2 expression was significantly higher in carcinoma of the serous subtype compared to non-serous carcinoma. In the full cohort, high DACH2 expression was significantly associated with poor prognosis in univariable analysis, and in carcinoma of the serous subtype, DACH2 remained an independent factor of poor prognosis. CONCLUSIONS: This study provides a first demonstration of DACH2 protein being expressed in human fallopian tubes and EOC, with the highest expression in serous carcinoma where DACH2 was found to be an independent biomarker of poor prognosis. Future research should expand on the role of DACH2 in ovarian carcinogenesis and chemotherapy resistance.
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spelling pubmed-32956412012-03-07 Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer Nodin, Björn Fridberg, Marie Uhlén, Mathias Jirström, Karin J Ovarian Res Research BACKGROUND: The Dachshund homolog 2 (DACH2) gene has been implicated in development of the female genital tract in mouse models and premature ovarian failure syndrome, but to date, its expression in human normal and cancerous tissue remains unexplored. Using the Human Protein Atlas as a tool for cancer biomarker discovery, DACH2 protein was found to be differentially expressed in epithelial ovarian cancer (EOC). Here, the expression and prognostic significance of DACH2 was further evaluated in ovarian cancer cell lines and human EOC samples. METHODS: Immunohistochemical expression of DACH2 was examined in tissue microarrays with 143 incident EOC cases from two prospective, population-based cohorts, including a subset of benign-appearing fallopian tubes (n = 32). A nuclear score (NS), i.e. multiplier of staining fraction and intensity, was calculated. For survival analyses, cases were dichotomized into low (NS < = 3) and high (NS > 3) using classification and regression tree analysis. Kaplan Meier analysis and Cox proportional hazards modelling were used to assess the impact of DACH2 expression on survival. DACH2 expression was analysed in the cisplatin sensitive ovarian cancer cell line A2780 and its cisplatin resistant derivative A2780-Cp70. The specificity of the DACH2 antibody was tested using siRNA-mediated silencing of DACH2 in A2780-Cp70 cells. RESULTS: DACH2 expression was considerably higher in the cisplatin resistant A2780-Cp70 cells compared to the cisplatin-sensitive A2780 cells. While present in all sampled fallopian tubes, DACH2 expression ranged from negative to strong in EOC. In EOC, DACH2 expression correlated with several proteins involved in DNA integrity and repair, and proliferation. DACH2 expression was significantly higher in carcinoma of the serous subtype compared to non-serous carcinoma. In the full cohort, high DACH2 expression was significantly associated with poor prognosis in univariable analysis, and in carcinoma of the serous subtype, DACH2 remained an independent factor of poor prognosis. CONCLUSIONS: This study provides a first demonstration of DACH2 protein being expressed in human fallopian tubes and EOC, with the highest expression in serous carcinoma where DACH2 was found to be an independent biomarker of poor prognosis. Future research should expand on the role of DACH2 in ovarian carcinogenesis and chemotherapy resistance. BioMed Central 2012-01-27 /pmc/articles/PMC3295641/ /pubmed/22284433 http://dx.doi.org/10.1186/1757-2215-5-6 Text en Copyright ©2012 Nodin et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Nodin, Björn
Fridberg, Marie
Uhlén, Mathias
Jirström, Karin
Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer
title Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer
title_full Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer
title_fullStr Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer
title_full_unstemmed Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer
title_short Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer
title_sort discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295641/
https://www.ncbi.nlm.nih.gov/pubmed/22284433
http://dx.doi.org/10.1186/1757-2215-5-6
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