Unknown,Transcriptomics,Genomics,Proteomics

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Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway

ABSTRACT: Medulloblastoma is a malignant brain tumor that occurs predominantly in children. Current risk stratification based on the clinical parameters is inadequate for accurate prognostication. In order to get a better understanding of medulloblastoma biology, miRNA profiling of medulloblastomas was carried out in parallel with the expression profiling of protein- coding genes. miRNA profiling of medulloblastomas was carried out using Taqman Low Density Density Aarray v 1.0 having 365 human microRNAs. In parallel, genome--wide expression profiling of protein coding genes was carried out using Affymetrix gene 1.0 ST arrays. Both the profiling studies identified four molecular subtypes of medulloblastomas. Expression levels of select protein-coding genes and miRNAs could classify an independent set of medulloblastomas. Twelve of 31 medulloblastomas were found to overexpress genes belonging to the canonical WNT signaling pathway and carry a mutation in CTNNB1 gene. A number of miRNAs like miR-193a, miR-224/miR-452 cluster, miR-182/miR-183/miR-96 cluster, and miR-148a having potential tumor/metastasis suppressive activity were found to be overexpressed in the WNT signaling associated medulloblastomas. Exogenous expression of miR-193a and miR-224, two miRNAs that have the highest WNT pathway specific upregulation, was found to inhibit proliferation, increase radiation sensitivity and reduce anchorage-independent growth of medulloblastoma cells. Expression level of tumor/metastasis suppressive miRNAs in the WNT signaling associated medulloblastomas is likely to determine their response to treatment, and thus, these miRNAs would be important biomarkers for risk stratification within the WNT signaling associated medulloblastomas. A total of 19 human sporadic medulloblastomas were profiled using the Affymetrix Gene 1.0 ST array

ORGANISM(S): Homo sapiens

SUBMITTER: Neelam Shirsat

PROVIDER: E-GEOD-41842 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway.

Gokhale Amit A Kunder Ratika R Goel Atul A Sarin Rajiv R Moiyadi Aliasgar A Shenoy Asha A Mamidipally Chandrasekhar C Noronha Santosh S Kannan Sadhana S Shirsat Neelam Vishwanath NV

Journal of cancer research and therapeutics 20101001 4

<h4>Aim</h4>Medulloblastoma is a malignant brain tumor that occurs predominantly in children. Current risk stratification based on clinical parameters is inadequate for accurate prognostication. MicroRNA expression is known to be deregulated in various cancers and has been found to be useful in predicting tumor behavior. In order to get a better understanding of medulloblastoma biology, miRNA profiling of medulloblastomas was carried out in parallel with expression profiling of protein-coding ge ...[more]

PMID: 21358093

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Project description:Previous studies have evaluated the role of miRNAs in the initiation and progression of cancer. MiR-34a was found to be downregulated in several tumors, including medulloblastoma. We here analysed the function of miR-34a in vivo by targeted transgenesis to generate mice with constitutive deletion of the miR-34a gene, which resulted in the absence of mir-34a in all analysed tissues. Nevertheless, these mice were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters performed by the German Mouse Clinic revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significant downregulation as compared to human cerebellum. Re-expression of mir-34a in human medulloblastoma cells in vitro reduced cell viability, cell proliferation and induced apoptosis. Among the targets downregulated by miR-34a in human medulloblastoma cells were NMYC and SIRT1. Activation of the Shh pathway by targeted overexpression of SmoA1 causes medulloblastoma in mice, which is dependent on the presence and upregulation of NMYC. Analysis of miR-34a in ND2:SmoA1-derived medulloblastomas revealed significant suppression of miR-34a compared to normal cerebellum. Crossbreeding these mice with miR-34a knockout mice significantly accelerated medulloblastoma growth in mice deficient for miR-34a. Interestingly, NMYC and SIRT1 were highly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastoma. Strategies aiming to re-express miR-34a in tumors could therefore represent an efficient therapy option. For genome-wide expression analysis total RNA from brain and thymus of three or four male miR34a and four control mice was isolated using RNeasy Midi kit (Qiagen, Hilden, Germany). The cDNA microarrays were generated, hybridized and analysed as described (Horsch et al 2009). Two chip hybridizations were performed with total RNA for each individual mutant mouse against a reference RNA pool of the same organ.

Project description:Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups. We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the dataset. Immunohistochemistry for subgroup-specific ‘signature’ genes was used to determine subgroup affiliation for 294 non-overlapping medulloblastomas on two independent tissue microarrays (TMAs). Multiple unsupervised analyses of transcriptional profiles identified four distinct, non-overlapping molecular variants: WNT, SHH, Group C, and Group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (Group C), and KCNA1 (Group D) could reliably and uniquely classify formalin fixed medulloblastomas in ~98% of cases. Group C patients (NPR3 +ve tumors) exhibited a significantly diminished progression free and overall survival irrespective of their metastatic status. Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma sub-classification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma. A total of 103 primary medulloblastoma specimens were profiled by Affymetrix exon array and gene-level analysis was performed.

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Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway

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Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway.

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