Project description:This SuperSeries is composed of the following subset Series: GSE17827: Integrated bioinformatic and wet-lab approach to identify potential oncogenic networks in neuroblastoma: MEIS1 GSE18271: Analysis of TALE homeobox genes in neuroblastic tumors: ganglioneuroblastoma and ganglioneuroma Refer to individual Series
Project description:A large proportion of patients suffering from the malignant pediatric tumor neuroblastoma die of progressive disease despite intensive therapy. Neuroblastomas belong to the group of neuroblastic tumors, together with the more benign, differentiated ganglioneuroblastomas and ganglioneuromas. Little is known of the genes driving the differentiation processes in these tumor types. A search for the transcription factors differentially expressed between ganglioneuromas, ganglioneuroblastomas, and neuroblastomas in a series of 110 neuroblastic tumors (NB110) identified a large number of HOX- and TALE (Three Amino acid Loop Extension)-class homeobox transcription factor genes. The MEIS1-3, PBX1 and -3, and PKNOX1 TALE genes showed highest expression in neuroblastomas and lowest in ganglioneuromas and ganglioneuroblastomas. The PKNOX2 and TGIF1-2 genes showed the opposite expression pattern. This suggests an involvement of TALE genes in neuroblastoma differentiation. Expression of MEIS1, a known oncogene in haematopoietic tumors, was high in all neuroblastomas, and strongly correlated with undifferentiated histology. Consequently, we generated IMR-32 neuroblastoma cells capable of inducible shRNA-mediated MEIS1 knockdown. We observed differentiation, growth arrest and induction of apoptosis upon MEIS1 down-regulation. Affymetrix profiling of time-course experiments using these cells allowed the identification of MEIS1 target genes. Analysis of the target genes in the NB110 series showed that 323 of these were also significantly correlated to MEIS1 expression and to tumor differentiation in neuroblastic tumors. Genes involved in the cell cycle and in developmental pathways were over-represented in this gene set. We conclude that MEIS1 governs several of the signal transduction routes important for neuroblastoma survival and differentiation. 12 ganglioneuroma (gn) and 10 ganglioneuroblastoma (gnb) were analyzed.
Project description:A large proportion of patients suffering from the malignant pediatric tumor neuroblastoma die of progressive disease despite intensive therapy. Neuroblastomas belong to the group of neuroblastic tumors, together with the more benign, differentiated ganglioneuroblastomas and ganglioneuromas. Little is known of the genes driving the differentiation processes in these tumor types. A search for the transcription factors differentially expressed between ganglioneuromas, ganglioneuroblastomas, and neuroblastomas in a series of 110 neuroblastic tumors (NB110) identified a large number of HOX- and TALE (Three Amino acid Loop Extension)-class homeobox transcription factor genes. The MEIS1-3, PBX1 and -3, and PKNOX1 TALE genes showed highest expression in neuroblastomas and lowest in ganglioneuromas and ganglioneuroblastomas. The PKNOX2 and TGIF1-2 genes showed the opposite expression pattern. This suggests an involvement of TALE genes in neuroblastoma differentiation. Expression of MEIS1, a known oncogene in haematopoietic tumors, was high in all neuroblastomas, and strongly correlated with undifferentiated histology. Consequently, we generated IMR-32 neuroblastoma cells capable of inducible shRNA-mediated MEIS1 knockdown. We observed differentiation, growth arrest and induction of apoptosis upon MEIS1 down-regulation. Affymetrix profiling of time-course experiments using these cells allowed the identification of MEIS1 target genes. Analysis of the target genes in the NB110 series showed that 323 of these were also significantly correlated to MEIS1 expression and to tumor differentiation in neuroblastic tumors. Genes involved in the cell cycle and in developmental pathways were over-represented in this gene set. We conclude that MEIS1 governs several of the signal transduction routes important for neuroblastoma survival and differentiation.
Project description:We have sequenced miRNA libraries from human embryonic, neural and foetal mesenchymal stem cells. We report that the majority of miRNA genes encode mature isomers that vary in size by one or more bases at the 3’ and/or 5’ end of the miRNA. Northern blotting for individual miRNAs showed that the proportions of isomiRs expressed by a single miRNA gene often differ between cell and tissue types. IsomiRs were readily co-immunoprecipitated with Argonaute proteins in vivo and were active in luciferase assays, indicating that they are functional. Bioinformatics analysis predicts substantial differences in targeting between miRNAs with minor 5’ differences and in support of this we report that a 5’ isomiR-9-1 gained the ability to inhibit the expression of DNMT3B and NCAM2 but lost the ability to inhibit CDH1 in vitro. This result was confirmed by the use of isomiR-specific sponges. Our analysis of the miRGator database indicates that a small percentage of human miRNA genes express isomiRs as the dominant transcript in certain cell types and analysis of miRBase shows that 5’ isomiRs have replaced canonical miRNAs many times during evolution. This strongly indicates that isomiRs are of functional importance and have contributed to the evolution of miRNA genes