Abstract
This study was to validate changes in the levels of folate receptor-α (FOLR1), dihydrofolate reductase (DHFR), and methionine synthase reductase (MTRR) in the tissue of OC patients. The expression of FOLR1, DHFR, and MTRR was evaluated in 80 cases of primary OC, 50 cases of benign ovarian tumors, and 30 normal ovarian tissues. Associations between protein expression and clinicopathological characters were assessed, and diagnostic and prognostic evaluation of FOLR1, DHFR, and MTRR was performed. Results showed that upregulated FOLR1 and MTRR and downregulated DHFR were detected in OC. Patients with abnormality of FOLR1, DHFR, and MTRR tend to have a higher percentage of platinum resistance. Moreover, the areas under receiver operating characteristic curves (AUCs-ROC) for FOLR1, DHFR, and MTRR were 0.723, 0.717, and 0.714, respectively. The combination of FOLR1, DHFR, and MTRR could produce an area of 0.864 under the receiver-operating characteristic curve in distinguishing platinum-resistant patients from platinum-sensitive patients (P < 0.0001). Correlations were present between the expression of FOLR1, DHFR, and MTRR. Furthermore, Kaplan-Meier curves indicated that the patients with overexpressed MTRR had a poorer overall survival time compared to those with low expression (P < 0.05). Thus, folate metabolic enzymes could provide a potential promising biomarker for diagnosis platinum-resistant in OC.
Highlights
Ovarian cancer is the fourth most common cancer in women worldwide, and it has the most noteworthy lethal rate around gynecologic malignancies
Quantitative analysis of Western blotting analysis showed that Folate receptor 1 (FOLR1) and MTRR have the highest expression in OC tissues, while Dihydrofolate reductase (DHFR) has the highest expression in benign tumor tissues (Figure 1(a))
DHFR and MTRR expression was clearly elevated in platinum-resistant OC compared with platinumsensitive OC, while FOLR1 expression in platinum-resistant OC was lower than in platinum-sensitive OC (Figure 1(b))
Summary
Ovarian cancer is the fourth most common cancer in women worldwide, and it has the most noteworthy lethal rate around gynecologic malignancies. Two most critical barriers to treatment of ovarian malignancy are absence of early diagnostic markers and advancement of drug resistance after therapy, especially in advanced stages. Recent progresses in our understanding of molecular pathogenesis of ovarian malignancy have dramatically provided potential new targets for molecularly targeted therapies. There is a critical need for improved biological markers and therapies for ovarian carcinoma, which will come from a better understanding of the biology of the disease. Folate is an essential component in DNA synthesis, replication and repair, protein synthesis, and methylation reactions. This is especially true for rapidly dividing cells [1]. Methionine synthase reductase (MTRR) is an enzyme controlling the activity of MTR in folate metabolism by transferring the methyl group of methyltetrahydrofolate to homocysteine via the methionine synthase, which is responsible for DNA methylation [5]
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