MicroRNAs are small non-coding RNAs that have recently emerged as important modulators of gene expression in metazoans and in plants. In addition to playing important roles in normal development and differentiation, some miRNAs have been shown to act as oncogenes and tumor suppressors. In particular, several lines of evidence indicate that the miR-17~92 cluster includes at least one oncogenic miRNA. Amplification and overexpression of this cluster are frequently observed in a subset of human B-cell lymphomas and in a significant number of other human cancers. The goal of this project is to investigate the biological functions, the physiological targets and the oncogenic properties of this cluster and its two paralogs: miR-106b~25 and miR-106a~363. We propose to use the laboratory mouse as the model organism for these studies and we have already generated mice carrying conditional and constitutive loss-of-function alleles of these three clusters. This application is articulated in three specific aims.
In aim 1 we will investigate the functions of miR-17~92 and its two paralogs in mammalian development. The experiments proposed in this aim will allow us to genetically dissect the miR-17~92 cluster and to assign specific biological functions to the six microRNAs that it encodes. In addition they will allow us to determine the extent of functional overlap between miR-17~92 and its two paralogs, miR-106~363 and miR-106b~25.
In aim 2, we will investigate the role of miR-17~92 in tumor maintenance in the context of c-Myc induced B cell lymphomas. The rationale for this specific aim is based on the observation that c-Myc is a potent transcriptional transactivator of miR-17~92 and on our own preliminary studies showing that acute deletion of miR-17~92 leads to a dramatic reduction in the proliferation of E?-Myc B-lymphoma cells. The ultimate goal of this aim is to determine the therapeutic potential of pharmacological antagonists of miR-17~92 in a preclinical model of B cell lymphomas. The objective of aim 3 is to identify the set of genes that are physiologic targets of miR-17~92 and to validate their functional relevance in cell-based experiments and in vivo. These goals will be achieved by combining a computation and an experimental approached that takes advantage of the conditional knockout allele of miR- 17~92 that we have recently generated. The work we are proposing will increase our understanding of the biological functions and mechanism of action of this important class of non-coding genes. Of even greater relevance for human health, it will provide insights into the role of miRNAs in the development to human cancer and may pave the way for novel therapeutic approaches based on their pharmacological inhibition.

Public Health Relevance

In this grant application, we propose to study the biological functions of a class of non-coding RNAs called microRNAs. In particular, we will focus on three clusters of microRNAs that have been demonstrated to play a central role in the pathogenesis of human cancers. Our goals are to understand the physiologic functions of this subset of microRNAs, to determine how their deregulation promotes tumor formation, and to test the therapeutic potential of microRNAs antagonists in a preclinical tumor model. As such, the studies we propose have the potential to significantly impact public health and could pave the way for novel anticancer strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA149707-05
Application #
8607518
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Howcroft, Thomas K
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$345,811
Indirect Cost
$164,663
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Vidigal, Joana A; Ventura, Andrea (2015) The biological functions of miRNAs: lessons from in vivo studies. Trends Cell Biol 25:137-47
Yang, Jr-Shiuan; Phillips, Michael D; Betel, Doron et al. (2011) Widespread regulatory activity of vertebrate microRNA* species. RNA 17:312-26
de Pontual, Loic; Yao, Evelyn; Callier, Patrick et al. (2011) Germline deletion of the miR-17ýýý92 cluster causes skeletal and growth defects in humans. Nat Genet 43:1026-30
Sage, Julien; Ventura, Andrea (2011) miR than meets the eye. Genes Dev 25:1663-7
Mu, Ping; Han, Yoon-Chi; Betel, Doron et al. (2009) Genetic dissection of the miR-17~92 cluster of microRNAs in Myc-induced B-cell lymphomas. Genes Dev 23:2806-11