Synthetic lethality between Rb, p53 and miR-17~92 in retinal progenitors suppresses retinoblastoma formation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE39107 | GEO | 2012/07/05
SECONDARY ACCESSION(S): PRJNA170017
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2012-07-05 | E-GEOD-39107 | biostudies-arrayexpress
Project description:Although Dicer1 functions as a haploinsufficient tumour suppressor its complete loss of function is selected against during tumourigenesis. Here we show that homozygous loss of Dicer1 prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of the p53 and Rb tumor suppressor pathways. We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in absence of p53. The synthetic lethal interaction is mediated by the oncogenic miR-17?92 cluster since its deletion phenocopies Dicer1 loss in this context. Accordingly, miR-17?92- inactivation suppresses retinoblastoma formation in mice and co-silencing of miR17/20a and p53 cooperatively decrease the viability of pre-formed human retinoblastoma cells. These data provide important insights into what underlies selective pressure against loss of Dicer1 during tumorigenesis and indicate that targeting Dicer or miR-17-20a family members should be explored as a potential selective therapeutic approach for retinoblastoma prevention and/or treatment. 23 murine samples
2012-07-05 | E-GEOD-39106 | biostudies-arrayexpress
Project description:Although Dicer1 functions as a haploinsufficient tumour suppressor its complete loss of function is selected against during tumourigenesis. Here we show that homozygous loss of Dicer1 prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of the p53 and Rb tumor suppressor pathways. We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in absence of p53. The synthetic lethal interaction is mediated by the oncogenic miR-17∼92 cluster since its deletion phenocopies Dicer1 loss in this context. Accordingly, miR-17∼92- inactivation suppresses retinoblastoma formation in mice and co-silencing of miR17/20a and p53 cooperatively decrease the viability of pre-formed human retinoblastoma cells. These data provide important insights into what underlies selective pressure against loss of Dicer1 during tumorigenesis and indicate that targeting Dicer or miR-17-20a family members should be explored as a potential selective therapeutic approach for retinoblastoma prevention and/or treatment. 36 human samples
2012-07-05 | E-GEOD-39105 | biostudies-arrayexpress
Project description:Although Dicer1 functions as a haploinsufficient tumour suppressor its complete loss of function is selected against during tumourigenesis. Here we show that homozygous loss of Dicer1 prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of the p53 and Rb tumor suppressor pathways. We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in absence of p53. The synthetic lethal interaction is mediated by the oncogenic miR-17∼92 cluster since its deletion phenocopies Dicer1 loss in this context. Accordingly, miR-17∼92- inactivation suppresses retinoblastoma formation in mice and co-silencing of miR17/20a and p53 cooperatively decrease the viability of pre-formed human retinoblastoma cells. These data provide important insights into what underlies selective pressure against loss of Dicer1 during tumorigenesis and indicate that targeting Dicer or miR-17-20a family members should be explored as a potential selective therapeutic approach for retinoblastoma prevention and/or treatment.
2012-07-05 | GSE39106 | GEO
Project description:Although Dicer1 functions as a haploinsufficient tumour suppressor its complete loss of function is selected against during tumourigenesis. Here we show that homozygous loss of Dicer1 prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of the p53 and Rb tumor suppressor pathways. We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in absence of p53. The synthetic lethal interaction is mediated by the oncogenic miR-17∼92 cluster since its deletion phenocopies Dicer1 loss in this context. Accordingly, miR-17∼92- inactivation suppresses retinoblastoma formation in mice and co-silencing of miR17/20a and p53 cooperatively decrease the viability of pre-formed human retinoblastoma cells. These data provide important insights into what underlies selective pressure against loss of Dicer1 during tumorigenesis and indicate that targeting Dicer or miR-17-20a family members should be explored as a potential selective therapeutic approach for retinoblastoma prevention and/or treatment.
2012-07-05 | GSE39105 | GEO
Project description:Retinoblastoma is a childhood retinal tumour that initiates in response to biallelic RB1 inactivation and loss of functional retinoblastoma (Rb) protein. Although Rb has diverse tumour-suppressor functions and is inactivated in many cancers, germline RB1 mutations predispose to retinoblastoma far more strongly than to other malignancies. This tropism suggests that retinal cell-type-specific circuitry sensitizes to Rb loss, yet the nature of the circuitry and the cell type in which it operates have been unclear. Here we show that post-mitotic human cone precursors are uniquely sensitive to Rb depletion. Rb knockdown induced cone precursor proliferation in prospectively isolated populations and in intact retina. Proliferation followed the induction of E2F-regulated genes, and depended on factors having strong expression in maturing cone precursors and crucial roles in retinoblastoma cell proliferation, including MYCN and MDM2. Proliferation of Rb-depleted cones and retinoblastoma cells also depended on the Rb-related protein p107, SKP2, and a p27 downregulation associated with cone precursor maturation. Moreover, Rb-depleted cone precursors formed tumours in orthotopic xenografts with histological features and protein expression typical of human retinoblastoma. These findings provide a compelling molecular rationale for a cone precursor origin of retinoblastoma. More generally, they demonstrate that cell-type-specific circuitry can collaborate with an initiating oncogenic mutation to enable tumorigenesis.
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Project description:Retinoblastoma, the most common intraocular malignant tumor in children, is characterized by the loss of both functional alleles of RB1 gene, which however alone cannot maintain malignant characteristics of retinoblastoma cells. Nevertheless, the investigation of other molecular aberrations such as matrix metalloproteinases (MMPs) and miRNAs is still lacking. In this study, we demonstrate that STAT3 is activated in retinoblastoma cells, Ki67-positive areas of in vivo orthotopic tumors in BALB/c nude mice, and human retinoblastoma tissues of the advanced stage. Furthermore, target genes of STAT3 including BCL2, BCL2L1, BIRC5, and MMP9 are up-regulated in retinoblastoma cells compared to other retinal constituent cells. Interestingly, STAT3 inhibition by targeted siRNA suppresses the proliferation of retinoblastoma cells and the formation of in vivo orthotopic tumors. In line with these results, STAT3 siRNA effectively induces down-regulation of target genes of STAT3. In addition, miRNA microarray analysis and further real-time PCR experiments with STAT3 siRNA treatment show that STAT3 activation is related to the up-regulation of miR-17-92 clusters in retinoblastoma cells via positive feedback loop between them. In conclusion, we suggest that STAT3 inhibition could be a potential therapeutic approach in retinoblastoma through the suppression of tumor proliferation.
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Project description:Neuronal differentiation with respect to the acquisition of synaptic competence needs to be regulated precisely during neurogenesis to ensure proper formation of circuits at the right place and time in development. This regulation is particularly important for synaptic triads among photoreceptors, horizontal cells (HCs), and bipolar cells in the retina, because HCs are among the first cell types produced during development, and bipolar cells are among the last. HCs undergo a dramatic transition from vertically oriented neurites that form columnar arbors to overlapping laminar dendritic arbors with differentiation. However, how this process is regulated and coordinated with differentiation of photoreceptors and bipolar cells remains unknown. Previous studies have suggested that the retinoblastoma (Rb) tumor suppressor gene may play a role in horizontal cell differentiation and synaptogenesis. By combining genetic mosaic analysis of individual synaptic triads with neuroanatomic analyses and multiphoton live imaging of developing HCs, we found that Rb plays a cell-autonomous role in the reorganization of horizontal cell neurites as they differentiate. Aberrant vertical processes in Rb-deficient HCs form ectopic synapses with rods in the outer nuclear layer but lack bipolar dendrites. Although previous reports indicate that photoreceptor abnormalities can trigger formation of ectopic synapses, our studies now demonstrate that defects in a postsynaptic partner contribute to the formation of ectopic photoreceptor synapses in the mammalian retina.
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Project description:The miR-17?92. or oncomiR-1, cluster encodes oncogenic microRNAs (miRNAs), and it also promotes retinoblastoma (RB) tumor formation. Antagomir and miRNA mimics based approaches are widely tried against oncogenic and tumor suppressive miRNAs. Other methods for targeting cancer related miRNAs are still under development. In the current study, we focused on the pri-miRNA-17?92 aptamer (pri-apt), which can potentially replace the mix of five antagomirs by one aptamer that function to abrogate the maturation of miR-17, miR-18a, and miR-19b (P<0.05) for targeting RB. We used RB cell lines WERI-Rb1 and Y79 as an in vitro model. Cellular changes upon transfecting the pri-apt led to S-phase arrest in WERI-Rb1 cells and onset of apoptosis in both Y79 and WERI-Rb1 cell lines. There was increased cytotoxicity as measured by lactate dehydrogenase activity in pri-apt treated Y79 cells (P<0.05), and significant inhibition of cell proliferation was observed in both of the cell lines. Thus we showed the antiproliferative property of pri-apt in RB cell lines, which can be readily modified by developing appropriate vectors for the delivery of the aptamer specifically to cancer cells.
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Project description:We have previously demonstrated that loss of miR-17~92 in nephron progenitors in a mouse model results in renal hypodysplasia and chronic kidney disease. Clinically, decreased congenital nephron endowment because of renal hypodysplasia is associated with an increased risk of hypertension and chronic kidney disease, and this is at least partly dependent on the self-renewal of nephron progenitors. Here, we present evidence for a novel molecular mechanism regulating the self-renewal of nephron progenitors and congenital nephron endowment by the highly conserved miR-17~92 cluster. Whole transcriptome sequencing revealed that nephron progenitors lacking this cluster demonstrated increased Cftr expression. We showed that one member of the cluster, miR-19b, is sufficient to repress Cftr expression in vitro and that perturbation of Cftr activity in nephron progenitors results in impaired proliferation. Together, these data suggest that miR-19b regulates Cftr expression in nephron progenitors, with this interaction playing a role in appropriate nephron progenitor self-renewal during kidney development to generate normal nephron endowment.
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