RESUMEN
Aberrant regulation of BCL6 plays crucial oncogenic roles in various malignant tumors; howbeit, the function of BCL6 in tumorigenesis of ovarian cancer remains unclear. The aim of this study is to investigate the role of BCL6 in ovarian cancer. The methods of immunohistochemical staining, quantitative real-time polymerase chain reaction, immunocytochemical staining, and gene expression profile enrichment analysis were performed to identify the possible role of BCL6 in ovarian cancer. We observed that the expression of BCL6 was significantly higher in ovarian cancer tissues and correlated with higher tumor burden including advanced International Federation of Gynecology and Obstetrics stages, poor differentiation, Type II ovarian cancer, the presence of >1 cm residual tumor size, and appearance of recurrence or death (all p < 0.05). The expression patterns of Lewis y were similar to these of BCL6. Multivariate Cox analysis demonstrated that advanced International Federation of Gynecology and Obstetrics stage, lymph node metastasis, residual tumor size >1 cm, as well as high expressions of BCL6 and Lewis y antigen were independent factors of worse progression-free survival and overall survival (all p < 0.05). There was a positive correlation of the expressions of BCL6 and Lewis y antigen. The associated genes with BCL6 in response to Lewis y antigen were identified, including four upregulated genes ( SOCS3, STAT1, PPARG, and GADD45A) and three downregulated genes ( ACAN, E2F3, and ZBTB7B). In conclusion, the high expressions of BCL6 and Lewis y antigen are associated with development, high tumor burden, and worse prognosis of ovarian cancer and targeting BCL6 could be a novel therapeutic strategy for ovarian cancer treatment.
Asunto(s)
Antígenos del Grupo Sanguíneo de Lewis/biosíntesis , Recurrencia Local de Neoplasia/genética , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/genética , Proteínas Proto-Oncogénicas c-bcl-6/biosíntesis , Adolescente , Adulto , Anciano , Carcinoma Epitelial de Ovario , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/patología , Pronóstico , Carga Tumoral/genética , Adulto JovenRESUMEN
The aim of this study was to identify differentially expressed genes (DEGs) in response to α1,2-fucosyl transferase (FUT1) gene transfection in epithelial ovarian cancer cells. Human whole-genome oligonucleotide microarrays were used to determine whether gene expression profile may differentiate the epithelial ovarian cell line Caov-3 transfected with FUT1 from the empty plasmid-transfected cells. Quantitative real-time PCR and immunohistochemical staining validated the microarray results. Gene expression profile identified 215 DEGs according to the selection criteria, in which 122 genes were upregulated and 93 genes were downregulated. Gene Ontology (GO) and canonical pathway enrichment analysis were applied, and we found that these DEGs are involved in BioCarta mammalian target of rapamycin (mTOR) pathway, BioCarta eukaryotic translation initiation factor 4 (EIF4) pathway, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in cancer. Interaction network analysis predicted genes participating in the regulatory connection. Highly differential expression of TRIM46, PCF11, BCL6, PTEN, and FUT1 genes was validated by quantitative real-time PCR in two cell line samples. Finally, BCL6 and Lewis Y antigen were validated at the protein level by immunohistochemistry in 103 paraffin-embedded ovarian cancer tissues. The identification of genes in response to FUT1 may provide a theoretical basis for the investigations of the molecular mechanism of ovarian cancer.
Asunto(s)
Fucosiltransferasas/genética , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/genética , Carcinoma Epitelial de Ovario , Línea Celular Tumoral , Análisis por Conglomerados , Fucosiltransferasas/metabolismo , Ontología de Genes , Redes Reguladoras de Genes , Humanos , Inmunohistoquímica , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Glandulares y Epiteliales/patología , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Transfección , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
Ovarian cancer is the most lethal gynecological malignancy worldwide. A better understanding of the pathogenesis of ovarian cancer may help to improve the overall survival. Our previous studies have demonstrated that alpha-(1,2)-fucosyltransferase 1 (FUT1) is an oncogenic glycogene in ovarian cancer. However, the underlying mechanism is not fully clarified. In this study, we identified a microRNA as an important downstream regulator for the carcinogenic effect of FUT1 in ovarian cancer. miR-5193 was found down-regulated in ovarian cancer cells, FUT1-overexpression ovarian cancer cells and ovarian tumor samples. MTT, flow cytometry and Transwell assays demonstrated that miR-5193 inhibited the proliferation and migration, and induced the cell cycle arrest and apoptosis of ovarian cancer cells. Real-time PCR and western blot assays showed that miR-5193 downregulated the expression of TRIM11 and upregulated the expression of p53 and p21. Dual luciferase reporter assay indicated that TRIM11 was a direct target of miR5193. Rescue experiments confirmed that miR-5193 functioned in ovarian cancer cells by directly targeting TRIM11. Moreover, transfection with miR-5193 mimic in FUT1-overexpression ovarian cancer cells reversed the carcinogenic effect of FUT1. Taken together, our results suggest that miR-5193 is an essential suppressor of human ovarian cancer development, and is an important downstream regulator regarding the carcinogenesis of FUT1 in ovarian cancer.