It has been recently demonstrated that progranulin is overexpressed in ovarian cancer and that this protein is involved in the stimulation of cell proliferation, malignancy, and chemoresistance in ovarian cancer. The goal of the present study was to establish the differences in progranulin expression among normal, benign, and malignant ovarian tissues and to identify the signal transduction pathways activated by progranulin in an ovarian cancer cell line. Compared with benign tumors and normal ovarian tissue, progranulin mRNA and protein were overexpressed in malignant tumors. Survival analysis by the Kaplan-Meier method showed a correlation between high mRNA expression levels with poor survival outcome. Progranulin activated the MAPK-signaling pathway in NIH-OVCAR-3 cells. Progranulin expression may be potentially involved in the pathogenesis and malignant progression of ovarian cancer, and thus may represent a therapeutic target for this particular malignancy.

Survival rate in ovarian cancer depends on the stage of the disease. RSK4, which has been considered as a tumor suppressor factor, controls cells invasion due to its antiinvasive and antimetastatic properties. Modulation of RSK4 expression could be an important event to increase the survival rate in ovarian cancer patients. Thus, the goal of the present study was to establish the differences in RSK4 expression among normal, benign and malignant ovarian tissues and to determine whether antineoplastic drugs regulate its expression in SKOV3 and TOV-112D cells. RSK4 levels in 30 malignant ovarian tumors, 64 benign tumors and 36 normal ovary tissues were determined by reverse transcription polymerase chain reaction and Western blot. Modulation of RSK4 expression by two antineoplastic drugs (cisplatin and vorinostat) was also studied in the SKOV3 and TOV-112D ovarian cancer cell lines using the same techniques. RSK4 mRNA and protein levels were decreased in malignant ovarian tumors as compared to benign tumors and normal tissue. These low-RSK4 levels were significantly associated with advanced stages of ovarian cancer. RSK4 expression was increased after incubation of SKOV3 and TOV-112D cell lines with cisplatin and vorinostat for 24 h. The combination of these antineoplastic drugs did not produce a synergistic or additive effect. These results suggest that RSK4 is expressed at low levels in malignant ovarian tumors, which correlates with advanced stages of the disease. Additionally, RSK4 expression is regulated by cisplatin and vorinostat in two ovarian cancer cell lines.

Increased levels of matrix metalloproteinase-8 (MMP-8) have been associated with tumor grade and stage in ovarian cancer. Also, it has been reported that higher concentrations of this enzyme in fluid from malignant ovarian cysts compared with benign ovarian cysts. However, no genetic analysis has been conducted yet to assess the contribution of MMP-8 polymorphisms in ovarian cancer. Thus, this study was performed to investigate the frequencies of MMP-8 genotypes in Mexican women with ovarian cancer. MMP-8 promoter genotypes were examined in 35 malignant ovarian tumors, 51 benign tumors, and 37 normal ovary tissues. Two single nucleotide polymorphisms were selected and characterized using polymerase chain reaction-restriction fragment length polymorphism analysis. The chi-square test was used to calculate statistical significance. Haplotype analysis was performed using the SNPstats web tool. Of the two polymorphisms, only the MMP-8 -799 T/T genotype was significantly associated with an increased risk of ovarian cancer (OR 3.78, 95 % CI 1.18-12.13). The Kaplan-Meier analysis for this polymorphism showed that patients with the T/T genetic variant had a tendency toward significant worse overall survival compared with patients with the C/C + C/T genotypes. Haplotype analysis revealed no significant differences in haplotype distribution between benign ovarian tumors, malignant ovarian cancer, and controls. This study suggests that MMP-8 promoter gene polymorphism -799 T/T is significantly associated with an increased risk of ovarian cancer in Mexican women.

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