Abstract
Glutathione peroxidase 3 (GPX3) is one of the key enzymes in the cellular defense against oxidative stress and the hepatocyte growth factor receptor, (MET) has been suggested to be influenced by the GPX3 gene expression. In a previous microarray study performed by our group, Gpx3 was identified as a potential biomarker for rat endometrial adenocarcinoma (EAC), since the expression was highly downregulated in rat EAC tumors. Herein, we have investigated the mRNA expression and Gpx3 and Met in rat EAC by real time quantitative PCR (qPCR), and the methylation status of Gpx3. In addition we have examined the expression of GPX3 and MET in 30 human EACs of different FIGO grades and 20 benign endometrial tissues. We found that the expression of GPX3 was uniformly down regulated in both rat and human EAC, regardless of tumor grade or histopathological subtype, implying that the down-regulation is an early event in EAC. The rate of Gpx3 promoter methylation reaches 91%, where biallelic methylation was present in 90% of the methylated tumors. The expression of the Met oncogene was slightly upregulated in EACs that showed loss of expression of Gpx3, but no tumor suppressor activity of Gpx3/GPX3 was detected. Preliminary results also suggest that the production of H2O2 is higher in rat endometrial tumors with down-regulated Gpx3 expression. A likely consequence of loss of GPX3 protein function would be a higher amount of ROS in the cancer cell environment. Thus, the results suggest important clinical implications of the GPX3 expression in EAC, both as a molecular biomarker for EAC and as a potential target for therapeutic interventions.
Highlights
Endometrial carcinoma (EC) is the most common gynecological malignancy observed in the western society with an incidence rate of approximately 15-20 per 100.000 women per year
In order to verify the results from the BDII endometrial cancer rat model in human, we examined the mRNA expression of Glutathione peroxidase 3 (GPX3) and MET in human endometroid tumor samples of FIGO grade I, II and III and benign samples
The mRNA expression of GPX3 in the human material assessed in 30 human Endometrioid adenocarcinoma (EAC) in FIGO grade I-III (10 tumors from each grade), and 21 benign endometrial samples differed significantly between normal and malignant tissues (P < 0.001), but no differences among the different groups of malignant tumors were seen (P > 0.5) (Table 2)
Summary
Endometrial carcinoma (EC) is the most common gynecological malignancy observed in the western society with an incidence rate of approximately 15-20 per 100.000 women per year. Endometrioid adenocarcinoma (EAC) arises from cells that form the glands in the endometrium. It is the most prevalent subtype constituting approximately 80% of all endometrial cancers. Endometroid andenocarcinoma can be histologically graded according to the FIGO system (International Federation of Gynecology and Obstretics) or classified as low grade or high grade by an alternative architectural binary grading system. The disease may either be an estrogendependent low-grade endometroid variant (type I) or a non-estrogen-dependent high grade variant (type II).
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