RESUMEN
Forkhead box M1 (FOXM1) is a proliferation-associated transcription factor essential for cell cycle progression. Numerous studies have documented that FOXM1 has multiple functions in tumorigenesis and its elevated levels are frequently associated with cancer progression. Here, we characterized the role of ERK/FOXM1 signaling in mediating the metastatic potential of ovarian cancer cells. Immunohistochemical (IHC), immunoblotting and semi-quantitative RT-PCR analyses found that both phospho-ERK and FOXM1 were frequently upregulated in ovarian cancers. Intriguingly, the overexpressed phospho-ERK (p<0.001) and FOXM1 (p<0.001) were significantly correlated to high-grade ovarian tumors with aggressive behavior such as metastasized lymph node (5 out of 6). Moreover, the expressions of phospho-ERK and FOXM1 had significantly positive correlation (p<0.001). Functionally, ectopic expression of FOXM1B remarkably enhanced cell migration/invasion, while FOXM1C not only increased cell proliferation but also promoted cell migration/invasion. Conversely, inhibition of FOXM1 expression by either thiostrepton or U0126 could significantly impair FOXM1 mediated oncogenic capacities. However, the down-regulation of FOXM1 by either thiostrepton or U0126 required the presence of p53 in ovarian cancer cells. Collectively, our data suggest that over-expression of FOXM1 might stem from the constitutively active ERK which confers the metastatic capabilities to ovarian cancer cells. The impairment of metastatic potential of cancer cells by FOXM1 inhibitors underscores its therapeutic value in advanced ovarian tumors.
Asunto(s)
Movimiento Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Factores de Transcripción Forkhead/metabolismo , Transducción de Señal , Western Blotting , Butadienos/farmacología , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/genética , Femenino , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunohistoquímica , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica , Nitrilos/farmacología , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tioestreptona/farmacología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Low-grade (LG) serous ovarian carcinoma is believed to arise from serous borderline ovarian tumors; yet the progression from serous borderline tumors to LG serous ovarian carcinoma remains poorly understood. The purpose of this study was to identify differentially expressed genes between the 2 groups. Expression profiles were generated from 6 human ovarian surface epithelia, 8 serous borderline ovarian tumors (SBOTs), 13 LG serous ovarian carcinomas, and 24 high-grade (HG) serous ovarian carcinomas. The anterior gradient homolog 3 (AGR3) gene was found to be highly upregulated in serous borderline ovarian tumors. This finding was validated by real-time quantitative reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemistry. Anti-AGR3 immunohistochemistry was performed on an additional 56 LG and 103 HG tissues, and the results were correlated with clinical data. Expression profiling determined that 1254 genes were differentially expressed (P<0.005) among SBOT, LG, and HG tumors. SBOTs exhibited robust positive staining for AGR3, with a lower percentage of tumor cells stained in LG and HG. Immunofluorescence staining indicated that AGR3 expression was limited to ciliated cells. Tumor samples with a high percentage (>10%) of AGR3 positively stained tumor cells were associated with improved longer median survival in both the LG (P=0.013) and HG (P=0.008) serous ovarian carcinoma groups. The progression of SBOT to LG serous ovarian carcinoma may involve the dedifferentiation of ciliated cells. AGR3 could serve as a prognostic marker for survival in patients with LG and HG serous ovarian carcinomas.