RESUMO
UNLABELLED: Cyclooxygenase-2 (COX-2) expression has been found to associate with poor prognosis in several types of carcinomas. HuR is an mRNA stability protein and it regulates the expression of COX-2. OBJECTIVES AND METHODS: We analyzed the expression of COX-2 and HuR in 64 mucinous ovarian carcinoma specimens by immunohistochemistry. RESULTS: In mucinous tumors, high COX-2 protein expression was found in epithelial cancer cells in 39% (22/56) and in stromal cells in 24% (13/55) of the specimens. The expression of COX-2 in cancer cells correlated with high grade (P = 0.0285), but stromal COX-2 expression had no correlation with any clinical parameter tested. Cytoplasmic HuR protein expression was observed in cancer cells in 47% (27/57) and in stromal cells in 7% (4/56) of the mucinous tumors, and it correlated with COX-2 expression in the cancer cells (P = 0.0162) but not in the stroma. CONCLUSION: Our results support the hypothesis that cytoplasmic HuR is connected to COX-2 expression in ovarian carcinoma, but that its role is restricted to the transformed epithelial cancer cells.
Assuntos
Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Antígenos de Superfície/biossíntese , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prostaglandina-Endoperóxido Sintases/biossíntese , Proteínas de Ligação a RNA/biossíntese , Adenocarcinoma Mucinoso/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclo-Oxigenase 2 , Citoplasma/enzimologia , Citoplasma/metabolismo , Proteínas ELAV , Proteína Semelhante a ELAV 1 , Células Epiteliais/enzimologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Imuno-Histoquímica , Proteínas de Membrana , Pessoa de Meia-Idade , Neoplasias Ovarianas/enzimologia , Células Estromais/enzimologia , Células Estromais/metabolismo , Células Estromais/patologiaRESUMO
PURPOSE AND EXPERIMENTAL DESIGN: Cyclooxygenase-2 (COX-2) is frequently expressed in human adenocarcinomas and inhibition of COX-2 suppresses tumor formation in various animal models of carcinogenesis. We analyzed expression of COX-2 protein in human serous ovarian carcinomas by immunohistochemistry (n = 442) and by Western blotting (n = 12) and COX-2 mRNA by reverse transcriptase PCR (n = 12). COX-2 immunoreactivity was correlated to clinicopathological variables and to expression of p53 and SMAD4 as detected by immunohistochemistry and to amplification of HER-2/neu as detected by in situ hybridization. RESULTS: COX-2 mRNA expression was detected in 75% (9 of 12) and COX-2 protein in 42% (5 of 12) of the serous ovarian adenocarcinoma specimens as detected by reverse transcriptase-PCR and Western blot analysis, respectively. Moderate to strong (elevated) immunoreactivity for COX-2 was detected in 70% (310 of 442) of the tumors. Elevated COX-2 expression associated with reduced disease-specific survival (P = 0.0011), high histological grade (P < 0.0001), residual tumor size > 1 cm (P = 0.0111), and age > 57 years (P = 0.0099). Tumors with altered immunostaining pattern for p53 or SMAD4 expressed more frequently elevated levels of COX-2 when compared with the tumors with normal staining pattern of these tumor suppressor genes (P < 0.0001 and P = 0.0004, respectively). In addition, elevated COX-2 expression associated with amplification of HER-2/neu oncogene (P = 0.0479). CONCLUSIONS: Our results suggest that elevated expression of COX-2 associates with reduced survival in serous ovarian carcinomas and that expression of COX-2 may be induced in these tumors by loss of tumor suppressor genes such as p53 and SMAD4 and by amplification of HER-2/neuoncogene.
Assuntos
Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/mortalidade , Proteínas de Ligação a DNA/biossíntese , Isoenzimas/biossíntese , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Prostaglandina-Endoperóxido Sintases/biossíntese , Receptor ErbB-2/biossíntese , Transativadores/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Ciclo-Oxigenase 2 , Proteínas de Ligação a DNA/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Proteínas de Membrana , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , RNA/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Smad4 , Transativadores/metabolismo , Resultado do Tratamento , Proteína Supressora de Tumor p53/metabolismoRESUMO
Cyclooxygenase-2 (COX-2) expression has been shown to associate with poor prognosis in ovarian cancer, and an mRNA stability protein HuR has been shown to enhance expression of COX-2 in tissue culture conditions. We found cytoplasmic immunoreactivity for HuR protein in 52% (233 of 445) of serous-type ovarian carcinoma specimens, and it associated with high COX-2 expression (P = 0.0045) and with clinicopathological variables, including poor prognosis (P < 0.0001) and high grade (P < 0.0001). In ovarian cancer cells in vitro, a small interfering RNA against HuR and leptomycin B, an inhibitor of nucleocytoplasmic translocation of HuR, inhibited COX-2 expression. Our results show that cytoplasmic HuR expression associates with poor outcome in ovarian cancer, and one plausible explanation for this finding may be related to the ability of HuR to induce COX-2 expression.