Abstract
Mutations in the MCPH1 (Microcephalin) and ASPM (abnormal spindle-like microcephaly associated) genes cause primary microcephaly. Both are centrosomal associated proteins involved in mitosis. Microcephalin plays an important role in DNA damage response and ASPM is required for correct division of proliferative neuro-epithelial cells of the developing brain. Reduced MCPH1 mRNA expression and ASPM mRNA over-expression have been implicated in the development of human carcinomas. Epithelial ovarian cancer (EOC) is characterised by highly aneuploid tumours. Previously we have reported low Microcephalin and high ASPM protein levels and associations with clinico-pathological parameters in malignant cells from ascitic fluids. To confirm these previous findings on a larger scale Microcephalin and ASPM expression levels and localisations were evaluated by immunohistochemistry in two cohorts; a training set of 25 samples and a validation set of 322 EOC tissue samples. Results were correlated to the associated histopathological data. In normal ovarian tissues the Microcephalin nuclear staining pattern was consistently strong. In the cancer tissues, we identified low nuclear Microcephalin expression in high grade and advanced stage tumours (p<0.0001 and p = 0.0438 respectively). ASPM had moderate to high nuclear and low to moderate cytoplasmic expression in normal tissue. Cytoplasmic ASPM expression decreased with tumour grade and stage in the serous subtype of EOC (p = 0.023 and p = 0.011 respectively). Cytoplasmic ASPM increased with tumour stage in the endometrioid subtype (p = 0.023). Increasing tumour invasiveness (T3) and lymph node involvement (N1) also correlated with a decrease in cytoplasmic ASPM in EOC (p = 0.02 and p = 0.04 respectively). We have validated previous findings of deregulated expression of Microcephalin and ASPM in EOC by confirming associations for low nuclear Microcephalin levels and high cytoplasmic ASPM levels in a larger scale tumour tissue study. Microcephalin and ASPM may prove useful biomarkers in EOC.
Highlights
225,000 new cases of ovarian cancer were diagnosed in 2008 worldwide, comprising 4% of all female cancers [1,2]
Microcephalin is known as BRIT1 (BRCT-repeat inhibitor of hTERT expression), which was initially identified as a transcriptional repressor of human telomerase reverse transcriptase, the catalytic subunit of human telomerase [18]
Immunohistochemistry with these antibodies demonstrated that Microcephalin and ASPM were localized in the nucleus and in the cytoplasm of both the normal (Figure 1) and epithelial ovarian cancer (EOC) tissue samples (Figure 2)
Summary
225,000 new cases of ovarian cancer were diagnosed in 2008 worldwide, comprising 4% of all female cancers [1,2]. Investigating the function and expression of potential prognostic proteins is essential for the advancement of our understanding of the molecular pathogenesis of epithelial ovarian cancer (EOC). This is especially desirable with regards to the identification of diagnostic biomarkers for patient management [4]. The ASPM protein consists of 3477 amino acids [6] organised into a putative N-terminal microtubule binding domain [19,20], two Calponin homology repeat motifs, over 80 isoleucine-glutamine (IQ) repeats [6,21] which typically bind calmodulin and a C-terminus consisting of a single Armadillo like sequence and a region involved in cytokinesis [8,22]. ASPM localizes to the midbody during cytokinesis, suggesting that it plays a role in abscission [22,27]
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