PMID- 19111388
OWN - NLM
STAT- MEDLINE
DCOM- 20090320
LR  - 20220330
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Linking)
VI  - 276
IP  - 2
DP  - 2009 Apr 18
TI  - Increased topoisomerase IIalpha expression in colorectal cancer is associated 
      with advanced disease and chemotherapeutic resistance via inhibition of 
      apoptosis.
PG  - 228-38
LID - 10.1016/j.canlet.2008.11.018 [doi]
AB  - 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.
FAU - Coss, Alan
AU  - Coss A
AD  - Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, 
      Ireland.
FAU - Tosetto, Miriam
AU  - Tosetto M
FAU - Fox, Edward J
AU  - Fox EJ
FAU - Sapetto-Rebow, Beata
AU  - Sapetto-Rebow B
FAU - Gorman, Sheeona
AU  - Gorman S
FAU - Kennedy, Breandan N
AU  - Kennedy BN
FAU - Lloyd, Andrew T
AU  - Lloyd AT
FAU - Hyland, John M
AU  - Hyland JM
FAU - O'Donoghue, Diarmuid P
AU  - O'Donoghue DP
FAU - Sheahan, Kieran
AU  - Sheahan K
FAU - Leahy, Dermot T
AU  - Leahy DT
FAU - Mulcahy, Hugh E
AU  - Mulcahy HE
FAU - O'Sullivan, Jacintha N
AU  - O'Sullivan JN
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081225
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Poly-ADP-Ribose Binding Proteins)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 5.99.1.3 (DNA Topoisomerases, Type II)
RN  - EC 5.99.1.3 (TOP2A protein, human)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antigens, Neoplasm/analysis/genetics/*physiology
MH  - *Apoptosis
MH  - Cell Proliferation
MH  - Chromosomal Instability
MH  - Colorectal Neoplasms/drug therapy/*enzymology/genetics/pathology
MH  - DNA Topoisomerases, Type II/analysis/genetics/*physiology
MH  - DNA-Binding Proteins/analysis/genetics/*physiology
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Poly-ADP-Ribose Binding Proteins
MH  - Receptor, ErbB-2/analysis
EDAT- 2008/12/30 09:00
MHDA- 2009/03/21 09:00
CRDT- 2008/12/30 09:00
PHST- 2008/08/07 00:00 [received]
PHST- 2008/10/10 00:00 [revised]
PHST- 2008/11/10 00:00 [accepted]
PHST- 2008/12/30 09:00 [entrez]
PHST- 2008/12/30 09:00 [pubmed]
PHST- 2009/03/21 09:00 [medline]
AID - S0304-3835(08)00896-3 [pii]
AID - 10.1016/j.canlet.2008.11.018 [doi]
PST - ppublish
SO  - Cancer Lett. 2009 Apr 18;276(2):228-38. doi: 10.1016/j.canlet.2008.11.018. Epub 
      2008 Dec 25.