ZYG11A Is Expressed in Epithelial Ovarian Cancer and Correlates With Low Grade Disease

Abstract

The insulin-like growth factors (IGF) are important players in the development of gynecological malignancies, including epithelial ovarian cancer (EOC). The identification of biomarkers that can help in the diagnosis and scoring of EOC patients is of fundamental importance in clinical oncology. We have recently identified the ZYG11A gene as a new candidate target of IGF1 action. The aim of the present study was to evaluate the expression of ZYG11A in EOC patients and to correlate its pattern of expression with histological grade and pathological stage. Furthermore, and in view of previous analyses showing an interplay between ZYG11A, p53 and the IGF1 receptor (IGF1R), we assessed a potential coordinated expression of these proteins in EOC. In addition, zyg11a expression was assessed in ovaries and uteri of growth hormone receptor (GHR) knock-out mice. Tissue microarray analysis was conducted on 36 patients with EOC and expression of ZYG11A, IGF1R and p53 was assessed by immunohistochemistry. Expression levels were correlated with clinical parameters. qPCR was employed to assess zyg11a mRNA levels in mice tissues. Our analyses provide evidence of reduced ZYG11A expression in high grade tumors, consistent with a putative tumor suppressor role. In addition, an inverse correlation between ZYG11A and p53 levels in individual tumors was noticed. Taken together, our data justify further exploration of the role of ZYG11A as a novel biomarker in EOC.

Keywords: IGF1 receptor; ZYG11A; insulin-like growth factor-1 (IGF1); ovarian cancer; p53.

Figure 1

Immunohistochemical staining of ZYG11A and p53 in EOC patients. Immunohistochemical analysis of ZYG11A (A, B) and p53 (C, D) was conducted in seven patients with low grade serous carcinoma (A, C) and 29 patients with high grade serous carcinoma (B, D) (x40). TMA analyses were conducted as described in Materials and Methods. The figure shows the images of four representative LGSC and HSGC patients.

Figure 2

Immunohistochemical staining of IGF1R. Representative samples of IGF1R staining in early (A) and advanced (B) ovarian serous carcinoma patients (x40).

Figure 3

Correlation between ZYG11A, p53 and IGF1R expression in EOC. Pearson correlation analysis was conducted between ZYG11A and p53 expression values (A) and between IGF1R and ZYG11A values (B) in individual EOC patients (P < 0.05).

Figure 4

Expression of zyg11a mRNA in ovaries and uteri of GHRKO and WT mice. Ovaries and uteri tissue of young (7-months old) and 20-month old WT mice and 20-month old GHRKO mice were obtained and total RNA was prepared as described in Materials and Methods. Zyg11a mRNA levels were measured by qPCR and normalized to the corresponding β-actin mRNA values. Bars represent mean ± SD of 4-5 animals. (A, C) a value of 100% was given to the zyg11a mRNA values in young mice. (B, D) a value of 100% was given to the zyg11a mRNA values in 20-month old WT mice. Differences between groups in all four graphs were highly significant (P<0.01). When not shown, error bars were smaller than the symbol size.