MicroRNAs are predicted to regulate a majority of genes in human cells and both overexpression and loss of expression of some miRNAs are correlated with malignant phenotypes in different cancer cells. A decrease in miRNA activity is most commonly observed and may be important for the plasticity of tumor cells to undergo transitions between differentiation states and to grow in different niches. One of the major objectives of this proposal is to investigate the functions of subsets of miRNAs in contributing to the properties of tumor cells and specifically to the ability of these cells to respond to stress. Many therapeutic treatments of cancer induce stress due to DNA damage, presence of unfolded proteins, deprivation of survival signals, and oxygen. We found that loss of miRNA regulation renders many types of cancer cells hypersensitive to such stress agents. For example, deletion of Dicer, a double strand endonuclease required for synthesis of most miRNAs, in many cancer cells yields viable cells that can in fact produce tumors in xenograft challenges but are hypersensitive to stress. Dicer- null human cancers have not been observed but recently sequencing of a haploid Dicer gene in several different types of human cancers identified a specific point mutation that inactivated one RNase III domain. This indicates that these tumor cells are being strongly selected for loss of a subset of miRNAs and for retention of other miRNAs. Cells expressing this mutant Dicer are defective for expression of the let-7 miRNA family but express near normal levels of other miRNAs. The four specific aims of this proposal build from progress over the past four years. First, we will further investigate the nature of factors targeting Argonaute 2 (Ago2) to specific RNA sequences in Dicer null cells. We will also investigate how this targeting enhances the quantitative level of silencing by co-binding miRNA. Second, we will characterize the subset of miRNAs generated by mutations of specific functions of Dicer and determine the consequences of expression of these subsets on tumor phenotype and response to stress. Third we will test if an inhibitor of Dicer should be considered as a promising objective for drug development to treat cancer in conjunction with chemotherapy. And fourth, we will investigate the function of Argonaute that is essential for viability in embryonic stem cells defective for synthesis of miRNAs, i.e. null for Dicer!" "

Public Health Relevance

The burden of cancer in public health is apparent in both human suffering and the cost of healthcare. The proposed research will provide the basis for new therapeutics to better treat cancer and thus improve public health.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA133404-06
Application #
8501813
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mietz, Judy
Project Start
2008-03-31
Project End
2018-03-31
Budget Start
2013-06-20
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$459,706
Indirect Cost
$160,497
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Gosline, Sara J C; Gurtan, Allan M; JnBaptiste, Courtney K et al. (2016) Elucidating MicroRNA Regulatory Networks Using Transcriptional, Post-transcriptional, and Histone Modification Measurements. Cell Rep 14:310-9
Doucet, Aurélien J; Wilusz, Jeremy E; Miyoshi, Tomoichiro et al. (2015) A 3' Poly(A) Tract Is Required for LINE-1 Retrotransposition. Mol Cell 60:728-41
Ran, F Ann; Cong, Le; Yan, Winston X et al. (2015) In vivo genome editing using Staphylococcus aureus Cas9. Nature 520:186-91
Kuhn, Claus-D; Wilusz, Jeremy E; Zheng, Yuxuan et al. (2015) On-enzyme refolding permits small RNA and tRNA surveillance by the CCA-adding enzyme. Cell 160:644-58
Chen, Sidi; Sanjana, Neville E; Zheng, Kaijie et al. (2015) Genome-wide CRISPR screen in a mouse model of tumor growth and metastasis. Cell 160:1246-60
Xue, Wen; Chen, Sidi; Yin, Hao et al. (2014) CRISPR-mediated direct mutation of cancer genes in the mouse liver. Nature 514:380-4
Liang, Dongming; Wilusz, Jeremy E (2014) Short intronic repeat sequences facilitate circular RNA production. Genes Dev 28:2233-47
Platt, Randall J; Chen, Sidi; Zhou, Yang et al. (2014) CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell 159:440-55
Wu, Xuebing; Kriz, Andrea J; Sharp, Phillip A (2014) Target specificity of the CRISPR-Cas9 system. Quant Biol 2:59-70
Jangi, Mohini; Sharp, Phillip A (2014) Building robust transcriptomes with master splicing factors. Cell 159:487-98

Showing the most recent 10 out of 33 publications