Neuroblastoma (NBL) presently accounts for 15% of all pediatric cancer deaths, and although numerous recurrent large-scale chromosomal imbalances have been identified in these tumors, some of which correlate with poor prognosis, the genes and genetic pathways affected by these alterations have largely remained elusive. The identification of new biological targets that contribute to the aggressive pathogenecity of this disease, along with the development of reagents that will interfere with the function of these targets, is a necessary prerequisite for improving patient survival. My laboratory has recently demonstrated in published pilot studies that many miRNA loci are differentially expressed in favorable and unfavorable NBL subtypes, and that ectopic over-expression of some loci can induce a caspase mediated apoptotic pathway. We also have shown that expression of some miRNA loci are highly altered in NBL cell lines following exposure to retinoic acid or the histone deacetylase inhibitor trichostatin A (TSA), agents which induce differentiation or apoptosis. Thus, the central hypothesis of this grant applicaiton, that the dysregulation of numerous miRNA sequences contribute to the aggressive pathogenicity of NBL, is firmly supported by our published preliminary studies. We plan to carry out the following specific aims: 1) extend our miRNA expression profiling studies to include a larger set of loci and a larger, more representative set of primary NBL tumors, along with profiling of cell lines undergoing differentiaiton or apoptosis in order identify candidate loci for functional testing and to evaluate the utility of miRNA expression for classifying tumors;2) test the hypothesis that chromosomal imbalances significantly contribute to the dysregulation of miRNA expression in NBL;3) perform functional studies on the biological effects of forced over or under-expression of miRNA loci in NBL cell lines;4) validate miRNAs that target MYCN or upstream regulators of MYCN, allowing us to identify naturally occurring miRNAs capable of suppressing MYCN activity and 5) identify miRNAs that are directly regulated by MYCN which may be involved with apoptotic or differentiation pathways. The completion of these specific aims is expected to fill in many gaps in our knowledge on the role of miRNA dysregulation in NBL pathogenesis and lead to the identification of targets for potential therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA127496-05
Application #
8205430
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mietz, Judy
Project Start
2008-02-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$184,409
Indirect Cost
$13,660
Name
Royal College of Surgeons in Ireland
Department
Type
DUNS #
986127454
City
Dublin
State
Country
Ireland
Zip Code
DUBLI-N 2
Bryan, Kenneth; Terrile, Marta; Bray, Isabella M et al. (2014) Discovery and visualization of miRNA-mRNA functional modules within integrated data using bicluster analysis. Nucleic Acids Res 42:e17
Althoff, Kristina; Beckers, Anneleen; Odersky, Andrea et al. (2013) MiR-137 functions as a tumor suppressor in neuroblastoma by downregulating KDM1A. Int J Cancer 133:1064-73
Wilzen, Annica; Krona, Cecilia; Sveinbjornsson, Baldur et al. (2013) ERBB3 is a marker of a ganglioneuroblastoma/ganglioneuroma-like expression profile in neuroblastic tumours. Mol Cancer 12:70
Das, S; Bryan, K; Buckley, P G et al. (2013) Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs. Oncogene 32:2927-36
Sridhar, Srishma; Al-Moallem, Batool; Kamal, Hawra et al. (2013) New insights into the genetics of neuroblastoma. Mol Diagn Ther 17:63-9
Creevey, Laura; Ryan, Jacqueline; Harvey, Harry et al. (2013) MicroRNA-497 increases apoptosis in MYCN amplified neuroblastoma cells by targeting the key cell cycle regulator WEE1. Mol Cancer 12:23
Lynch, Jennifer; Fay, Joanna; Meehan, Maria et al. (2012) MiRNA-335 suppresses neuroblastoma cell invasiveness by direct targeting of multiple genes from the non-canonical TGF-? signalling pathway. Carcinogenesis 33:976-85
Stallings, Raymond L; Foley, Niamh H; Bray, Isabella M et al. (2011) MicroRNA and DNA methylation alterations mediating retinoic acid induced neuroblastoma cell differentiation. Semin Cancer Biol 21:283-90
Bray, Isabella; Tivnan, Amanda; Bryan, Kenneth et al. (2011) MicroRNA-542-5p as a novel tumor suppressor in neuroblastoma. Cancer Lett 303:56-64
Buckley, Patrick G; Das, Sudipto; Bryan, Kenneth et al. (2011) Genome-wide DNA methylation analysis of neuroblastic tumors reveals clinically relevant epigenetic events and large-scale epigenomic alterations localized to telomeric regions. Int J Cancer 128:2296-305

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