RESUMEN
Patients with advanced stage ovarian clear cell carcinoma (OCCC) have a poor prognosis due to resistance to conventional platinum chemotherapy. Recent studies have demonstrated that PI3K/AKT/mTOR and ERK1/2 signaling pathways are involved in this chemoresistance. Progranulin (PGRN) overexpression contributes to cisplatin resistance of epithelial ovarian cancer cell lines. Also, PGRN expression is regulated by AKT/mTOR and ERK1/2 signaling pathways in different cell types. Thus, the present study was designed to identify if PGRN expression is regulated by AKT, mTOR, and ERK1/2 signaling pathways in the OCCC cell line TOV-21G. Cultured TOV-21G cells were incubated with different concentrations of pharmacological cell signaling inhibitors. PGRN expression and phosphorylation of ERK1/2, AKT, and mTOR were assessed by Western blotting. Inhibition of AKT, mTOR, and ERK1/2 significantly reduced PGRN expression. Cell viability was not affected, while cell proliferation significantly decreased with all inhibitors used in this study. These observations demonstrated that inhibition of PI3K/AKT/mTOR and ERK1/2 signaling pathways reduces PGRN expression in TOV-21G cells. Thus, PGRN could be considered as a candidate for explaining the high resistance to platinum-based treatment and a potential biomarker for therapy response to cell signaling inhibitors in patients with OCCC.
Asunto(s)
Antineoplásicos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias Ováricas/metabolismo , Progranulinas , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Progranulinas/análisis , Progranulinas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Línea Celular Tumoral , Cisplatino/administración & dosificación , Cisplatino/farmacología , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/farmacología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Ovario/enzimología , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , VorinostatRESUMEN
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.
Asunto(s)
Metaloproteinasa 8 de la Matriz/genética , Neoplasias Ováricas/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Estimación de Kaplan-Meier , México , Persona de Mediana Edad , Neoplasias Ováricas/mortalidadRESUMEN
BACKGROUND: According to the Histopathological Registry of Malignant Neoplasms in Mexico, endometrial cancer ranks third gynecological cancers after cervical cancer and ovarian cancer. In 2003 represented 2.16% of all female cancers and in 2007 was the cause of 2.8% of hospital discharges nationwide cancer. OBJECTIVE: To determine the possibility of coincidence of endometrial cancer in biopsy specimens of patients with endometrial hyperplasia. MATERIAL AND METHODS: We analyzed patients who underwent hysterectomy for hyperplasia preoperative biopsy between January 2007 and October 2008. RESULTS: We found 86 patients with biopsy specimens of hyperplasia who underwent hysterectomy, hyperplasia was confirmed in 70 (group A) and endometrioid endometrial cancer reported in 16 (group B). We found cancer in 2 of 61 patients with simple hyperplasia without atypia (3.2%), none of the 6 patients with atypical hyperplasia was found simple cAncer (0%) and 19 patients with complex hyperplasia with atypia was documented EC 14 (73.68%). Patients in group B are older vs 51.3 44.4 years, have a lower number of pregnancies 2.6 vs 3.1 and have a higher body mass index 34.71 vs 29.05 than group A. CONCLUSION: The percentage of agreement between complex endometrial hyperplasiaand endometrial cancer is the highest reported in the literature. Endometrial biopsy in our hospital has low sensitivity for predicting coexistence between complex endometrial hyperplasia and CE. Patients with endometrial biopsy complex endometrial hyperplasia associated with BMI greater than 30 and age over 50 years are at high risk for having coexistence with endometrial cancer. For the high frequency of coexistence with cancer, patients with preoperative biopsy complex endometrial hyperplasia should undergo hysterectomy with frozen section of the uterus to avoid reoperation in case of malignancy.