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

Hdl Handle:
http://hdl.handle.net/10147/207028
Title:
Increased topoisomerase IIalpha expression in colorectal cancer is associated with advanced disease and chemotherapeutic resistance via inhibition of apoptosis.
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
Affiliation:
Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin,, Ireland.
Citation:
Cancer Lett. 2009 Apr 18;276(2):228-38. Epub 2008 Dec 25.
Journal:
Cancer letters
Issue Date:
1-Feb-2012
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
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
ISSN:
1872-7980 (Electronic); 0304-3835 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorCoss, Alanen_GB
dc.contributor.authorTosetto, Miriamen_GB
dc.contributor.authorFox, Edward Jen_GB
dc.contributor.authorSapetto-Rebow, Beataen_GB
dc.contributor.authorGorman, Sheeonaen_GB
dc.contributor.authorKennedy, Breandan Nen_GB
dc.contributor.authorLloyd, Andrew Ten_GB
dc.contributor.authorHyland, John Men_GB
dc.contributor.authorO'Donoghue, Diarmuid Pen_GB
dc.contributor.authorSheahan, Kieranen_GB
dc.contributor.authorLeahy, Dermot Ten_GB
dc.contributor.authorMulcahy, Hugh Een_GB
dc.contributor.authorO'Sullivan, Jacintha Nen_GB
dc.date.accessioned2012-02-01T10:28:39Z-
dc.date.available2012-02-01T10:28:39Z-
dc.date.issued2012-02-01T10:28:39Z-
dc.identifier.citationCancer Lett. 2009 Apr 18;276(2):228-38. Epub 2008 Dec 25.en_GB
dc.identifier.issn1872-7980 (Electronic)en_GB
dc.identifier.issn0304-3835 (Linking)en_GB
dc.identifier.pmid19111388en_GB
dc.identifier.doi10.1016/j.canlet.2008.11.018en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207028-
dc.description.abstractTopoisomerase 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.en_GB
dc.language.isoengen_GB
dc.subject.meshAdulten_GB
dc.subject.meshAgeden_GB
dc.subject.meshAged, 80 and overen_GB
dc.subject.meshAntigens, Neoplasm/analysis/genetics/*physiologyen_GB
dc.subject.mesh*Apoptosisen_GB
dc.subject.meshCell Proliferationen_GB
dc.subject.meshChromosomal Instabilityen_GB
dc.subject.meshColorectal Neoplasms/drug therapy/*enzymology/genetics/pathologyen_GB
dc.subject.meshDNA Topoisomerases, Type II/analysis/genetics/*physiologyen_GB
dc.subject.meshDNA-Binding Proteins/analysis/genetics/*physiologyen_GB
dc.subject.meshDrug Resistance, Neoplasmen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshHumansen_GB
dc.subject.meshMaleen_GB
dc.subject.meshMiddle Ageden_GB
dc.subject.meshReceptor, erbB-2/analysisen_GB
dc.titleIncreased topoisomerase IIalpha expression in colorectal cancer is associated with advanced disease and chemotherapeutic resistance via inhibition of apoptosis.en_GB
dc.contributor.departmentCentre for Colorectal Disease, St. Vincent's University Hospital, Dublin,, Ireland.en_GB
dc.identifier.journalCancer lettersen_GB
dc.description.provinceLeinster-

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