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      EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer

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          Abstract

          Background

          The epithelial to mesenchymal transition (EMT) is a molecular process through which an epithelial cell undergoes transdifferentiation into a mesenchymal phenotype. The role of EMT in embryogenesis is well-characterized and increasing evidence suggests that elements of the transition may be important in other processes, including metastasis and drug resistance in various different cancers.

          Methods

          Agilent 4 × 44 K whole human genome arrays and selected reaction monitoring mass spectrometry were used to investigate mRNA and protein expression in A2780 cisplatin sensitive and resistant cell lines. Invasion and migration were assessed using Boyden chamber assays. Gene knockdown of snail and slug was done using targeted siRNA. Clinical relevance of the EMT pathway was assessed in a cohort of primary ovarian tumours using data from Affymetrix GeneChip Human Genome U133 plus 2.0 arrays.

          Results

          Morphological and phenotypic hallmarks of EMT were identified in the chemoresistant cells. Subsequent gene expression profiling revealed upregulation of EMT-related transcription factors including snail, slug, twist2 and zeb2. Proteomic analysis demonstrated up regulation of Snail and Slug as well as the mesenchymal marker Vimentin, and down regulation of E-cadherin, an epithelial marker. By reducing expression of snail and slug, the mesenchymal phenotype was largely reversed and cells were resensitized to cisplatin. Finally, gene expression data from primary tumours mirrored the finding that an EMT-like pathway is activated in resistant tumours relative to sensitive tumours, suggesting that the involvement of this transition may not be limited to in vitro drug effects.

          Conclusions

          This work strongly suggests that genes associated with EMT may play a significant role in cisplatin resistance in ovarian cancer, therefore potentially leading to the development of predictive biomarkers of drug response or novel therapeutic strategies for overcoming drug resistance.

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          Most cited references 41

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          The basics of epithelial-mesenchymal transition.

          The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.
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            Analyzing real-time PCR data by the comparative CT method

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              Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis.

              The epithelial-mesenchymal transition is a highly conserved cellular program that allows polarized, immotile epithelial cells to convert to motile mesenchymal cells. This important process was initially recognized during several critical stages of embryonic development and has more recently been implicated in promoting carcinoma invasion and metastasis. In this review, we summarize and compare major signaling pathways that regulate the epithelial-mesenchymal transitions during both development and tumor metastasis. Studies in both fields are critical for our molecular understanding of cell migration and morphogenesis.
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                Author and article information

                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central
                1471-2407
                2012
                19 March 2012
                : 12
                : 91
                Affiliations
                [1 ]Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart Street, Kingston, ON, K7L3N6, Canada
                [2 ]Division of Gynaecologic Oncology, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON, K1H8L6, Canada
                [3 ]NCIC Clinical Trials Group, Cancer Research Institute, 10 Stuart Street, Kingston, ON, K7L3N6, Canada
                [4 ]Ontario Cancer Biomarker Network, 101 College Street, Toronto, ON, M5G 1L7, Canada
                Article
                1471-2407-12-91
                10.1186/1471-2407-12-91
                3342883
                22429801
                Copyright ©2012 Haslehurst et al; licensee BioMed Central Ltd.

                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.

                Categories
                Research Article

                Oncology & Radiotherapy

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