Topoisomerase IIα mRNA and protein expression in ovarian carcinoma: correlation with clinicopathological factors and prognosis

Abstract

Topoisomerase IIa (Top IIa) is a nuclear enzyme that plays a central role in DNA metabolism, and is a molecular target for a variety of chemotherapeutic agents. Top IIa has recently gained attention as a biomarker for therapy response and patient survival. In this study, we attempted to assess the feasibility of measuring Top IIa gene expression in RNA, isolated from archival formalin-fixed paraffin-embedded tissue specimens, which are used routinely in pathology laboratories. We have employed a new technique on the basis of magnetic particles' separation and purification of nucleic acids, and evaluated both protein and mRNA expressions from the same routinely processed tissue blocks. We investigated the expression of Top IIa mRNA and protein by real-time reverse transcription polymerase chain reaction and immunohistochemistry, in a cohort of 133 primary ovarian carcinomas, and evaluated the association between Top IIa expression and clincopathological variables as well as patient outcome. Elevated Top IIa mRNA expression was observed in high-grade tumors (P ¼ 0.003) and advanced stage disease (P ¼ 0.011). In univariate Kaplan-Meier analysis, patients with higher expression of Top IIa nuclear protein had a significantly decreased overall survival (P ¼ 0.045). Interestingly, we detected cytoplasmic protein expression of Top IIa in a subset of samples. Cytoplasmic expression of Top IIa was associated with the expression of chromosomal region maintenance/exportin 1 (CRM1)-a nuclear export protein (P ¼ 0.008). Our study suggests that Top IIa overexpression is involved in the progression of ovarian cancer in a subset of the patients. Our results encourage the further evaluation of the prognostic and predictive values of Top IIa expression in ovarian carcinoma, which might help to assess the patients' risk profile, and the planning of an individualized therapy.

TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin

“…This prevalence is in agreement with those observed by Slamon et al [23] and Mano et al [9]. Different prevalence were reported for TOP2A expression in ovarian cancer evaluated using RT-PCR and immunohistochemistry in human cancer specimens [24][25][26][27], likely due to difficulties in obtaining a digital measure as that obtainable with FISH. Nevertheless, in our selected population of platinum resistant/refractory patients, we observed a high concordance between TOP2A gene gain and TOP2A protein overexpression.…”

Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed

“…Exportin (XPO1) mediates nuclear export of several proteins including TOP2A. In ovarian cancer, high cytoplasmic immunostaining of TOP2A was linked to XPO1 overexpression and associated with borderline significance for decreased overall survival (Faggad et al, 2009). We have observed significant overexpression of XPO1 in ACCs in two studies (Giordano et al, 2009; de Reynie`s et al, 2009), however, aberrant cytoplasmic expression of TOP2A has not been reported yet in ACCs (Figure 2).…”

New molecular biologist perspective and insight: DNA topoisomerases production by recombinant DNA technology for medical laboratory application and pharmaceutical industry

“…Over-expressions of DNA topoisomerases are associated with tumour growth, differentiation and poor survival prognosis in colorectal cancer (Braun et al 2008), ovarian carcinoma (Faggad et al 2009), breast cancer (Oakman et al 2009), lung cancer (Dingemans et al 1999) and oral squamous carcinoma (Oliveira-Costa et al 2012). The expression levels of these enzymes have been determined using reverse transcription PCR technique, microarray and qualitative analyses of immuno-stained tissues.…”