The role of EP-2 receptor expression in cervical intraepithelial neoplasia

Abstract

Prostaglandin induced signalling is involved in different cancers. As previously described, the EP3 receptor expression decreases with increasing stage of cervical intraepithelial lesions (CIN). In addition, in cervical cancer EP3 is an independent prognosticator for overall survival and correlates with FIGO stages. Currently the role of Prostaglandin 2 receptor 2 (EP2) in CIN is unknown. The aim of this study was to analyse the expression of EP2 for potential prognostic value for patients with cervical dysplasia. EP2 expression was analysed by immunohistochemistry in 33 patient samples (CIN1-3) using the immune-reactivity scoring system (IRS). Expression levels were correlated with clinical outcome to analyse prognostic relevance in patients with CIN2. Data analysis was performed using non parametric Kruskal-Wallis and Spearman rank sum test. Cytoplasmic expression levels of EP2 correlated significantly (p < 0.001) with different grades of cervical dysplasia. Median EP2-IRS in CIN1 was 2 (n = 8), 3 in CIN2 (n = 9) and 6 in CIN3 (n = 16). Comparing regressive (n = 3, median IRS = 2) to progressive (n = 6, median IRS = 4) CIN2 cases the median IRS differed significantly (p = 0.017). Staining intensity (p = 0.009) and IRS (p = 0.005) of EP2 and EP3 correlate inversely. EP2 expression level significantly increases with higher grade of CIN and could qualify as a potential prognostic marker for the regressive or progressive course in CIN2 lesions. These findings emphasize the significant role of PGE2 signalling in CIN and could help to identify targets for future therapies.

Keywords: CIN; Cervical cancer HPV; Cervical intraepithelial neoplasia; EP-receptor; EP2; Prostaglandin E2.

Fig. 1

The expression of EP2-receptors in the cytoplasm increased significantly with increasing grade of cervical dysplasia, displayed by boxplots. The median value is stated above the median-line within the boxes (a). The images show representative microphotographs of EP2 staining in CIN1 (b IRS 2), CIN2 (c IRS 6) and CIN3 (d IRS 9). 200× magnification was used for picture b, c and d. Scale bars refer to 100 µm. Asterisk represents statistically significant differences in the staining results of CIN1-3

Fig. 2

The median IR-score in regressive cases and in progressive cases differs significantly as shown by the boxplots (a). The different staining results with the anti-EP2-antibody in regressive (b IRS 1) versus progressive (c IRS 6) CIN2 samples (p = 0.017). 200× magnification was used for picture b and c. Scale bars refer to 100 µm. Asterisk represents statistically significant differences comparing regressive and progressive CIN2 cases

Fig. 3

Correlation diagram for IR-score of EP2 and EP3 representing the inverse correlation of the two prostaglandin receptors in CIN tissues (a).The comparison of the staining results in a tissue sample of the same patient with CIN1 for a staining with the anti-EP2-antibody (b) and the anti-EP3-antibody (c) represents this inverse correlation. EP2 was not detected in the staining (IRS 0) whereas EP3 was seemingly highly expressed (IRS 12). 200× magnification was used for picture b and c. Scale bars refer to 100 µm