Project description:Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas.
Project description:Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas. A total of 90 primary medulloblastoma specimens were profiled by Affymetrix exon array and gene-level analysis was performed.
Project description:Hepatocellular adenomas (HCA) are benign liver tumors divided in molecular subtypes characterized by mutations inactivating HNF1A, activating β-catenin or the IL-6/JAK/STAT inflammatory pathway. Molecular analyses of 533 HCA developed in 411 patients identified a new tumor subgroup with Sonic Hedgehog pathway activation due to focal deletions creating INHBE promoter/GLI1 fusions.
Project description:Physiologically, trophoblast progenitor cells differentiate into placental villous cytotrophoblast cells (CTBs). CTBs either differentiate into invasive lineage to yields extravillous cytotrophoblast cells (EVTs), or undergo cell fusion lineage to yields syncytiotrophoblast cells (STBs),Sonic hedgehog (Shh) together with indian hedgehog (Ihh) and desert hedgehog (Dhh) consist of ligand of hedgehog signaling pathway, which plays pivotal roles in regulating cell proliferation, cell differentiation, organogenesis and development, even involving in tumorigenesis and progression. previous study had summarized and indicatedthat hedgehog proteins played important roles in regulating hematopoiesis, vasculogenesis and angiogenesis during embryogenesis and development. Herein, we investigate the effect of the Sonic Hedgehog morphogen inhibitor Cyclopamine on JAR cells
Project description:Medulloblastoma, the most common malignant pediatric brain tumor, is highly heterogeneous with distinct molecular subtypes and cellular origins. Although current treatments improve survival rates, patients suffer severe treatment-related side effects and often relapse of tumors carrying resistance mutations, underscoring an urgent need for alternative targeted therapies. Currently, the genetic alterations underlying this disease are not fully understood. Here we identify GNAS, encoding the G-protein Gs-alpha, as a potent tumor suppressor gene in medulloblastoma. GNAS specifically defines a subset of aggressive Sonic Hedgehog (Shh)-group medulloblastomas. Gnas loss-of-function in distinct lineage progenitors of the developing hindbrain suffices to initiate medulloblastoma. We find that Gs-alpha is highly enriched at primary cilia of granule neuron precursors and suppresses Shh signaling not only by regulating classic cAMP-dependent pathway but also controlling ciliary trafficking of Smoothened. Concurrent cAMP elevation and Smoothened inhibition robustly arrests tumor cell growth in Gnas mutants. We further reveal oligodendrocyte progenitors as a novel cellular origin for anatomically-distinct Shh-associated medulloblastomas. Together, we identify a previously unrecognized tumor suppressor function of Gs-alpha in medulloblastoma partially mediated through inhibiting Shh signaling, and uncover Gs-alpha as a molecular link across disparate cells of origin among Shh-group medulloblastomas, pointing to G- protein modulation as a potential therapeutic avenue. Transgenic medulloblastoma mouse models were analyzed by Affymetrix Mouse Gene 1.1 ST Array in order to determine their molecular subgroup. Tumors extracted from hGFAP:GnasCKO and Oligo1:GnasCKO transgenic mice were analyzed in 8 replicates each, together with normal mouse cerebellum.
Project description:Medulloblastoma, the most common malignant pediatric brain tumor, is highly heterogeneous with distinct molecular subtypes and cellular origins. Although current treatments improve survival rates, patients suffer severe treatment-related side effects and often relapse of tumors carrying resistance mutations, underscoring an urgent need for alternative targeted therapies. Currently, the genetic alterations underlying this disease are not fully understood. Here we identify GNAS, encoding the G-protein Gs-alpha, as a potent tumor suppressor gene in medulloblastoma. GNAS specifically defines a subset of aggressive Sonic Hedgehog (Shh)-group medulloblastomas. Gnas loss-of-function in distinct lineage progenitors of the developing hindbrain suffices to initiate medulloblastoma. We find that Gs-alpha is highly enriched at primary cilia of granule neuron precursors and suppresses Shh signaling not only by regulating classic cAMP-dependent pathway but also controlling ciliary trafficking of Smoothened. Concurrent cAMP elevation and Smoothened inhibition robustly arrests tumor cell growth in Gnas mutants. We further reveal oligodendrocyte progenitors as a novel cellular origin for anatomically-distinct Shh-associated medulloblastomas. Together, we identify a previously unrecognized tumor suppressor function of Gs-alpha in medulloblastoma partially mediated through inhibiting Shh signaling, and uncover Gs-alpha as a molecular link across disparate cells of origin among Shh-group medulloblastomas, pointing to G- protein modulation as a potential therapeutic avenue. Transgenic medulloblastoma mouse models were analyzed by Affymetrix Mouse Gene 1.1 ST Array in order to determine their molecular subgroup.
Project description:We hypothesized that the occurrence of IVH would reduce interneuron neurogenesis in the medial ganglionic eminence and diminish the population of parvalbumin+ and somatostatin+ cortical interneurons. Since Sonic Hedgehog promotes the production of cortical interneurons, we also postulated that the activation of Sonic Hedgehog signaling might restore neurogenesis, cortical interneuron population, and neurobehavioral function in premature newborns with IVH.
Project description:The causative role of activated Hedgehog signaling in liver fibrosis was investigated in vivo. Using hydrodynamics-based transfection, a transgenic mouse model has been developed that expresses Sonic Hedgehog (SHH), a ligand for Hedgehog signaling, in the liver. Levels of hepatic fibrosis and fibrosis-related gene expression were assessed in the model.