ABSTRACT
Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer.
Subject(s)
Biomarkers, Tumor/metabolism , Brain Neoplasms/secondary , Cerebellar Neoplasms/pathology , Medulloblastoma/pathology , Octamer Transcription Factor-3/metabolism , Animals , Apoptosis , Biomarkers, Tumor/genetics , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Cell Movement , Cell Proliferation , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/metabolism , Female , Humans , Medulloblastoma/genetics , Medulloblastoma/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Octamer Transcription Factor-3/genetics , Prognosis , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Soybean isoflavonoids have received significant attention due to their potential anticarcinogenic and antiproliferative effects and possible role in many signal transduction pathways. However, their mechanisms of action and their molecular targets remain to be further elucidated. In this paper, we demonstrated that two soybean isoflavones (genistein and daidzein) reduced the proliferation of the human colon adenocarcinoma grade II cell line (HT-29) at concentrations of 25 and 50-100 µM, respectively. We then investigated the effects of genistein and daidzein by RT-PCR on molecules that involved in tumor development and progression by their regulation of cell proliferation. At a concentration of 50 µM genistein, there was suppressed expression of ß-catenin (CTNNBIP1). Neither genistein nor daidzein affected APC (adenomatous polyposis coli) or survivin (BIRC5) expression when cells were treated with concentrations of 10 or 50 µM. These data suggest that the down-regulation of ß-catenin by genistein may constitute an important determinant of the suppression of HT-29 cell growth and may be exploited for the prevention and treatment of colon cancer.
Subject(s)
Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adenomatous Polyposis Coli Protein/genetics , Anticarcinogenic Agents/pharmacology , Cell Growth Processes/drug effects , Cell Growth Processes/genetics , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Gene Expression/drug effects , Genistein/pharmacology , Inhibitor of Apoptosis Proteins/genetics , Intracellular Signaling Peptides and Proteins/genetics , Isoflavones/pharmacology , Phytoestrogens/pharmacology , Adaptor Proteins, Signal Transducing , Adenomatous Polyposis Coli Protein/metabolism , Adenomatous Polyposis Coli Protein/physiology , Anticarcinogenic Agents/therapeutic use , Dose-Response Relationship, Drug , Gene Expression/genetics , Genistein/therapeutic use , HT29 Cells , Humans , Inhibitor of Apoptosis Proteins/metabolism , Inhibitor of Apoptosis Proteins/physiology , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/physiology , Isoflavones/therapeutic use , Phytoestrogens/therapeutic use , Phytotherapy , Glycine max , SurvivinABSTRACT
Isoflavones are phenolic compounds widely distributed in plants and found in a high percentage in soybeans. They have important biological properties and are regarded as potential chemopreventive agents. The aim of this study was to verify the preventive effect of two soy isoflavones (genistein and daidzein) by a micronucleus assay, analysis of GST activity, and real-time RT-PCR analysis of GSTa2 gene expression. Mutagens of direct (doxorubicin) and indirect (2-aminoanthracene) DNA damage were used. Hepatoma cells (HTC) were treated with genistein or daidzein for 26 h at noncytotoxic concentrations; 10 µM when alone, and 0.1, 1.0 and 10 µM when combined with genotoxic agents. The micronucleus test demonstrated that both isoflavones alone had no genotoxic effect. Genistein showed antimutagenic effects at 10 µM with both direct and indirect DNA damage agents. On phase II enzyme regulation, the current study indicated an increase in total cytoplasmic GST activity in response to genistein and daidzein at 10 µM supplementation. However, the mRNA levels of GSTa2 isozymes were not differentially modulated by genistein or daidzein. The results point to an in vitro antimutagenic activity of genistein against direct and indirect DNA damage-induced mutagenicity.
