Gene Expression Profiling Reveals Novel Candidate Markers of Ovarian Carcinoma Intraperitoneal Metastasis

Abstract

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; gene expression.; markers; metastases; progression.

Figure 1

Kaplan-Meier plots representing results of survival analysis of ABCA10 and SLC16A14 genes. Survival curves for patients with the intratumoral ABCA10 or SLC16A14 expression levels above the median (solid line) vs. patients with lower expression than the median (dashed line) are displayed. The difference in the mean PFS between the compared groups of patients was evaluated by the log rank test.

Figure 2

Mutual correlations of gene expression levels in (A) intraperitoneal EOC metastases; (B) primary tumors; (C) control tissues. Only genes that were significantly associated with PFS of patients with EOC metastases were evaluated. Associations highlighted in grey are significant. Dark grey: p < 0.001; light grey: p < 0.005

Figure 3

Intersection of significant results of (i) comparison of gene expression in controls, primary ovarian carcinomas and metastases; (ii) comparison of gene expression in primary ovarian carcinomas and metastases; (iii) survival analysis, i.e., association of gene expression level in intraperitoneal metastases with PFS of patients. C = controls, pT = primary tumors, M = metastases Red: up-regulation, blue: down-regulation Deregulation of genes in bold remained significant either after the FDR correction or the Cox regression, respectively.