1. Toxicogenomics Unit, National Institute of Public Health, Srobarova 48, 100 42 Prague 10, Czech Republic;
2. Third Faculty of Medicine, Charles University, Ruska 87, 100 00 Prague 10, Czech Republic;
3. Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic;
4. Department of Gynecology and Obstetrics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Alej Svobody 80, 304 60 Pilsen, Czech Republic;
5. Department of Gynecology and Obstetrics, Third Faculty of Medicine and Vinohrady University Hospital, Charles University, Srobarova 50, 100 34 Prague 10, Czech Republic;
6. Department of Pathology and Molecular Medicine, Second Faculty of Medicine and Motol University Hospital, Charles University, V Uvalu 84, 150 06 Prague 5, Czech Republic;
7. Department of Oncology, Palacky University Medical School and University Hospital, I. P. Pavlova 6, 779 00 Olomouc, Czech Republic.
Epithelial ovarian cancer (EOC) has the highest mortality among gynecological carcinomas. The lack of specific markers for prognostic determination of EOC progression hinders the search for novel effective therapies.
The aim of the present study was (i) to explore differences in expressions of ATP-binding cassette (ABC) and solute carrier (SLC) transporter genes, genes associated with drug metabolism and cell cycle regulation between control ovarian tissues (n = 14), primary EOCs (n = 44) and intraperitoneal metastases (n = 29); (ii) to investigate associations of gene expression levels with prognosis of patients with intraperitoneal metastases.
In all tissue samples, transcript levels of the above target genes were assessed using quantitative real-time PCR. Gene expression levels were compared between particular tissue types and evaluated with regard to progression-free survival (PFS) and drug-resistance status of patients with metastases.
Gene expression of ABCA7 significantly increased and that of ESR2 decreased in the order control ovarian tissues - primary EOCs - metastases. High expressions of ABCA2/8/9/10, ABCB1, ABCC9, ABCG2, ATP7A, SLC16A14, and SOD3 genes were significantly associated with longer progression-free survival of patients. In intraperitoneal metastases, expression of all of these genes highly correlated and indicated prognostic profile. Transporters from the ABCA family, ABCG2, and ESR2 are involved mainly in lipid metabolism, membrane transport, and cell proliferation. These processes are thus probably the most important for EOC progression.
Based on these results, we have proposed novel markers of ovarian carcinoma progression and metastatic spread which might be potentially useful as therapeutic targets. Their significance should be further explored on a larger independent set of patients.
Keywords: epithelial ovarian cancer, progression, metastases, markers, gene expression.