Abstract
Highly aneuploid tumours are common in epithelial ovarian cancers (EOC). We investigated whether NuMA expression was associated with this phenomenon.NuMA protein levels in normal and tumour tissues, ovarian cell lines and primary cultures of malignant cells derived from ovarian ascitic fluids were analysed by Affymetrix microarray analysis, immunoblotting, immunohistochemistry (IHC) and immunofluorescence (IF), with results correlated to associated clinical data. Aneuploidy status in primary cultures was determined by FACS analysis.Affymetrix microarray data indicated that NuMA was overexpressed in tumour tissue, primary cultures and cell lines compared to normal ovarian tissue. IHC revealed low to weak NuMA expression in normal tissues. Expression was upregulated in tumours, with a significant association with disease stage in mucinous EOC subtypes (p = 0.009), lymph node involvement (p = 0.03) and patient age (p = 0.04). Additional discontinuous data analysis revealed that high NuMA levels in tumours decreased with grade (p = 0.02) but increased with disease stage (p = 0.04) in serous EOC. NuMA expression decreased in late disease stage 4 endometrioid EOCs. High NuMA levels decreased with increased tumour invasion in all subtypes (p = 0.03). IF of primary cultures revealed that high NuMA levels at mitotic spindle poles were significantly associated with a decreased proportion of cells in cytokinesis (p = 0.05), increased binucleation (p = 0.021) and multinucleation (p = 0.007), and aneuploidy (p = 0.008).NuMA is highly expressed in EOC tumours and high NuMA levels correlate with increases in mitotic defects and aneuploidy in primary cultures.
Highlights
The 238 kDa nuclear mitotic apparatus (NuMA) protein is a component of the interphase nucleus and the mitotic spindle pole matrix [1]
In this study we aimed to investigate NuMA1 expression in epithelial ovarian cancers (EOC) and relate this to aneuploidy found in this cancer type
We confirmed this observation at the protein level by IHC, noting that nuclear NuMA was present at low levels in the nuclei of normal ovarian stroma and epithelium whereas ovarian primary tumours had elevated NuMA levels
Summary
The 238 kDa nuclear mitotic apparatus (NuMA) protein is a component of the interphase nucleus and the mitotic spindle pole matrix [1]. An additional interphase role as a nuclear scaffolding protein has been proposed [4,5,6]. NuMA is ubiquitously expressed [6,7]. The nuclear and spindle pole localisations of NuMA are well characterised in normal tissue [8,9] and in tumour tissues by immunohistochemistry (IHC) in the Human Protein Atlas. The role that mitotic proteins such as NuMA might play in cancer has recently become a subject of renewed interest as it has become apparent that aneuploidy is a common feature of tumours that might drive their progression [10,11]
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