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    Increased topoisomerase IIalpha expression in colorectal cancer is associated with advanced disease and chemotherapeutic resistance via inhibition of apoptosis.

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    Authors
    Coss, Alan
    Tosetto, Miriam
    Fox, Edward J
    Sapetto-Rebow, Beata
    Gorman, Sheeona
    Kennedy, Breandan N
    Lloyd, Andrew T
    Hyland, John M
    O'Donoghue, Diarmuid P
    Sheahan, Kieran
    Leahy, Dermot T
    Mulcahy, Hugh E
    O'Sullivan, Jacintha N
    Show allShow less
    Affiliation
    Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin,, Ireland.
    Issue Date
    2012-02-01T10:28:39Z
    MeSH
    Adult
    Aged
    Aged, 80 and over
    Antigens, Neoplasm/analysis/genetics/*physiology
    *Apoptosis
    Cell Proliferation
    Chromosomal Instability
    Colorectal Neoplasms/drug therapy/*enzymology/genetics/pathology
    DNA Topoisomerases, Type II/analysis/genetics/*physiology
    DNA-Binding Proteins/analysis/genetics/*physiology
    Drug Resistance, Neoplasm
    Female
    Humans
    Male
    Middle Aged
    Receptor, erbB-2/analysis
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    Citation
    Cancer Lett. 2009 Apr 18;276(2):228-38. Epub 2008 Dec 25.
    Journal
    Cancer letters
    URI
    http://hdl.handle.net/10147/207028
    DOI
    10.1016/j.canlet.2008.11.018
    PubMed ID
    19111388
    Abstract
    Topoisomerase IIalpha is a nuclear enzyme that regulates the tertiary structure of DNA. The influence of topoisomerase IIalpha gene (TOP2A) or protein alterations on disease progression and treatment response in colorectal cancer (CRC) is unknown. The study investigated the clinical relevance of topoisomerase IIalpha in CRC using in vivo and in vitro models. Differentially expressed genes in early and late-stage CRC were identified by array comparative genomic hybridization (CGH). Cellular location of gene amplifications was determined by fluorescence in situ hybridization (FISH). Topoisomerase IIalpha levels, proliferation index, and HER2 expression were examined in 228 colorectal tumors by immunohistochemistry. Overexpression of topoisomerase IIalpha in vitro was achieved by liposome-based transfection. Cell growth inhibition and apoptosis were quantified using the crystal violet assay and flow cytometry, respectively, in response to drug treatment. Amplification of TOP2A was identified in 3 (7.7%) tumors using array CGH and confirmed using FISH. At the protein level, topoisomerase IIalpha staining was observed in 157 (69%) tumors, and both staining and intensity levels were associated with an aggressive tumor phenotype (p values 0.04 and 0.005, respectively). Using logistic regression analysis, topoisomerase IIalpha remained significantly associated with advanced tumor stage when corrected for tumor proliferation (p=0.007) and differentiation (p=0.001). No association was identified between topoisomerase IIalpha and HER2. In vitro, overexpression of topoisomerase IIalpha was associated with resistance to irinotecan (p=0.001) and etoposide chemotherapy (p=0.03), an effect mediated by inhibition of apoptosis. Topoisomerase IIalpha overexpression is significantly associated with alterations in tumor behavior and response to drug treatment in CRC. Our results suggest that gene amplification may represent an important mechanism underlying these changes.
    Language
    eng
    ISSN
    1872-7980 (Electronic)
    0304-3835 (Linking)
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.canlet.2008.11.018
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