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, AlanTosetto, 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
Affiliation
Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin,, Ireland.Issue Date
2012-02-01T10:28:39ZMeSH
AdultAged
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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Cancer Lett. 2009 Apr 18;276(2):228-38. Epub 2008 Dec 25.Journal
Cancer lettersDOI
10.1016/j.canlet.2008.11.018PubMed ID
19111388Abstract
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
engISSN
1872-7980 (Electronic)0304-3835 (Linking)
ae974a485f413a2113503eed53cd6c53
10.1016/j.canlet.2008.11.018
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