Expression of Human DNA Topoisomerase II-α in Squamous Cell Carcinoma of the Larynx and Its Correlation With Clinicopathologic Variables

Department of Otolaryngology, Head and Neck Surgery, Rabin Medical Center, Petach Tikva, Israel.
American Journal of Clinical Pathology (Impact Factor: 2.51). 12/2008; 130(6):934-9. DOI: 10.1309/AJCPROG61USKCBEI
Source: PubMed


The aggressiveness of laryngeal squamous cell carcinoma (SCC) is unpredictable. Topoisomerase (Topo) II-alpha is an essential nuclear enzyme; its expression rises at the end of the S-G2/M phase and drops at completion of mitosis. This study sought to determine if Topo II-alpha expression can serve as a prognostic factor in laryngeal SCC. Specimens from 56 consecutive patients were immunohistochemically stained for Topo II-alpha, and the number of positive cells in the areas of highest staining was counted in 3 highpower fields (X400) (Topo II-alpha index). Differences in the Topo II-alpha index by the presence or absence of recurrence, tumor stage and grade, and disease course were analyzed statistically. On multivariate Cox regression analysis, the Topo II-alpha index (>70 or < or =70) (P = .008) and tumor grade (P = .034) independently predicted disease-free survival. These findings suggest that high Topo II-alpha expression may be a useful indicator of tumor aggressiveness and poor outcome in laryngeal SCC.


Available from: Eitan Yaniv, Oct 02, 2015
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    • "Horibe et al (19) performed an immunohistochemical analysis of 63 cases of early glottic laryngeal carcinoma and 10 cases of normal laryngeal mucosa, and showed that the expression of Topo II-α protein was significantly increased in early glottic laryngeal carcinoma tissue when compared with the normal laryngeal mucosa. Furthermore, Shvero et al (20) immunohistochemically analyzed Topo II-α protein expression in 50 cases of laryngeal carcinoma, and demonstrated that the expression level of Topo II-α protein was associated with the pathological grade, clinical stage, postoperative survival and recurrence rate, indicating that Topo II-α protein overexpression is associated with a poor prognosis. In addition, Deng et al (21) investigated Topo II-α protein expression in 24 cases of laryngeal squamous cell carcinoma and eight cases of vocal cord polyps using immunohistochemistry and found that the positive expression of Topo II-α protein was significantly higher in patients with laryngeal squamous cell carcinoma compared with that in patients with vocal cord polyps and that the levels of Topo II-α expression were associated with the degree of tumor differentiation. "
    [Show abstract] [Hide abstract] ABSTRACT: DNA topoisomerase II-α (Topo II-α) is essential for numerous cell processes, including DNA replication, transcription, recombination, and chromosome separation and condensation. Altered Topo II-α expression may lead to carcinogenesis and cancer progression. The aim of the present study was to investigate the association between Topo II-α expression levels and clinicopathological data from laryngeal cancer patients. Immunohistochemistry was used to analyze Topo II-α expression in laryngeal squamous cell carcinoma and distant healthy tissues obtained from 70 patients. In addition, fluorescence in situ hybridization was used to detect Topo II-α amplification and chromosome 17 ploidy using a laryngeal cancer tissue microarray. The expression of Topo II-α protein was detected in 71.43% (50/70) of laryngeal carcinoma tissues, in contrast to 9% of healthy tissues (2/22). Furthermore, the expression of Topo II-α protein was found to be associated with tumor de-differentiation and advanced tumor T stage. However, the expression of Topo II-α protein was not identified to be associated with Topo II-α amplification in laryngeal carcinoma, although was found to positively correlate with chromosome 17 aneuploidy (P<0.05). A higher aneuploidy rate contributed to increased expression levels of Topo II-α protein. Aberrant Topo II-α expression and chromosome 17 aneuploidy contributed to the development and progression of laryngeal cancer, indicating that targeting Topo II-α may provide a treatment strategy for patients with laryngeal cancer.
    Full-text · Article · Oct 2014 · Oncology letters
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    • "High levels of TOP2A expression are generally associated with high levels of cellular proliferation and poor histologic differentiation of tumors [24] . The relationship between overexpression of this enzyme and poor prognosis has been reported in different neoplasias, like breast cancer [19], urothelial bladder carcinoma [12], larynx cancer [15], bladder cancer [24] , and ovarian can- cer [17]. On the other hand, although most studies on literature correlates high levels of TOP2A expression with poorer survival rates and more aggressive tumors, there are studies showing the opposite. "
    [Show abstract] [Hide abstract] ABSTRACT: Background TOP2A encodes for topoisomerase IIα, a nuclear enzyme that controls DNA topological structure and cell cycle progression. This enzyme is a marker of cell proliferation in normal and neoplastic tissues; however, little information is available about its expression in prostate cancer (PCa). Methods Immunohistochemistry (IHC) was automated using mouse monoclonal antibody against TOP2A (clone SWT3D1; DAKO, Carpenteria, CA, USA) at dilution 1:800 and Flex Plus detection system in autostainer 48Ultra (DAKO). FISH was performed using TOP2A (17q21)/ CEP17 probe kit (Kreateck Biotechnology, San Diego, CA, USA). Biochemical and pathological data from 193 patients with PCa were retrieved for the analysis, whose significance was considered when p < 0.05. Also, fractal analysis was performed in a subset of 20 randomly selected cases. Results TOP2A protein expression correlated with higher Gleason scores and higher levels of preoperative PSA (p = 0.018 and p = 0.011). Patients with higher levels of TOP2A presented shorter biochemical recurrence-free survival (BRFS) (p = 0.001). In multivariate analysis, we found that TOP2A remained an independent prognostic factor of BRFS, with a relative risk of 1.98 (p = 0.001; 95% CI, 1.338–2.93); thus, cases that expressed high levels of this enzyme had a shorter BRFS compared with TOP2A-negative or TOP2A-low cases. No alterations in TOP2A gene status nor correlation between FISH and IHC results were observed. Concerning fractal analysis, patients who expressed higher levels of TOP2A have angiolymphatic invasion and presented higher Gleason scores (p = 0.033 and p = 0.025, respectively). Also, patients with higher expression of TOP2A presented shorter BRFS (p = 0.001). Conclusions This is the first study to perform TOP2A protein and gene digital assessment and fractal analysis in association with BRFS in a large series of PCa. Also, we show that TOP2A gene copy number alterations are not observed in this type of tumor. So, higher protein expression of TOP2A is not related to gene amplification in PCa. Furthermore, TOP2A protein assessment has prognostic importance and, due to its relation with poor outcome, TOP2A IHC evaluation in the biopsy can represent an important tool for selecting the most suitable surgical and clinical approach for patients with PCa.
    Full-text · Article · Feb 2013 · Journal of Translational Medicine
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    • "[20]. TOP2A has been reported to be over-expressed in pancreatic adenocarci- noma [21], renal medullary carcinomas [22], ovarian cancer [23] , acute lymphocytic leuke- mia [24], colorectal cancer [25], gastric carcinoma [26] and laryngeal squamous cell carcinoma [27]. CCNB2 (Cyclin B2), found commonly upregulated, is a member of the cyclin family, specifically the B-type cyclins. "
    [Show abstract] [Hide abstract] ABSTRACT: Genes differentially expressed by tumor cells represent promising drug targets for anti-cancer therapy. Such candidate genes need to be validated in appropriate animal models. This study examined the suitability of rodent models of bladder cancer in B6D2F1 mice and Fischer-344 rats to model clinical bladder cancer specimens in humans. Using a global gene expression approach cross-species analysis showed that 13-34% of total genes in the genome were differentially expressed between tumor and normal tissues in each of five datasets from humans, rats, and mice. About 20% of these differentially expressed genes overlapped among species, corresponding to 2.6 to 4.8% of total genes in the genome. Several genes were consistently dysregulated in bladder tumors in both humans and rodents. Notably, CNN1, MYL9, PDLIM3, ITIH5, MYH11, PCP4 and FM05 were found to commonly down-regulated; while T0P2A, CCNB2, KIF20A and RRM2 were up-regulated. These genes are likely to have conserved functions contributing to bladder carcinogenesis. Gene set enrichment analysis detected a number of molecular pathways commonly activated in both humans and rodent bladder cancer. These pathways affect the cell cycle, HIF-1 and MYC expression, and regulation of apoptosis. We also compared expression changes at mRNA and protein levels in the rat model and identified several genes/proteins exhibiting concordant changes in bladder tumors, including ANXA1, ANXA2, CA2, KRT14, LDHA, LGALS4, SERPINA1, KRT18 and LDHB. In general, rodent models of bladder cancer represent the clinical disease to an extent that will allow successful mining of target genes and permit studies on the molecular mechanisms of bladder carcinogenesis.
    Full-text · Article · Jan 2010 · American Journal of Translational Research
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