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MiR-17-92 Cluster Regulation in Differentiated T-cells

Kohanbash, Gary (2009) MiR-17-92 Cluster Regulation in Differentiated T-cells. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Data from our group and others have demonstrated that tumor-derived factors directly skew T-cell differentiation from an effective tumor fighting Th1 state to a less effective Th2 state, allowing for tumor growth. Why the Th1 response is more effective is largely still unknown. The recently discovered microRNAs (miRNAs) are a large family of small regulatory RNAs that control diverse aspects of cell functions such as cell proliferation, apoptosis, development, differentiation and immune regulation. We thereby sought to examine miRNAs differentially expressed in Th1 and Th2 cells in an effort to better understand the enhanced ability of Th1 cells in tumor immunity. MicroRNA microarray analyses revealed that the miR-17-92 cluster of microRNAs (miR-17-92) is consistently over-expressed in murine Th1 cells compared to Th2 cells. Quantitative RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Furthermore, disruption of IL-4 signaling through either IL-4 neutralizing antibody or knockout of STAT6 reversed the miR-17-92 cluster suppression in Th2 cells. MiR-17-92 expression correlated with differential proliferation capacity as Th1 cells proliferated at higher levels than Th2 cells, dependent on IL-4 and STAT6. Th1 cells consistently expressed lower levels of anti-proliferative transcription factors E2F1 and E2F2, which are the known targets of miR-17-92. Collectively, our data suggests that the Th2 skewing tumor microenvironment can induce the down-regulation of miR-17-92 expression in CD4+T cells, thereby diminishing the effective proliferation of tumor-specific T cells and tumor destruction. This has significant public health relevance as we propose that therapy targeting miR-17-92 cluster may provide enhanced T-cell function and prevent tumor growth.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kohanbash, Garygkohanbash@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairReinhart, Toddreinhar@pitt.eduREINHAR
Committee MemberOkada, HidehoOkadah@upmc.edu
Committee MemberMartinson, Jeremyjmartins@pitt.eduJMARTINS
Date: 29 September 2009
Date Type: Completion
Defense Date: 29 July 2009
Approval Date: 29 September 2009
Submission Date: 28 July 2009
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: MicroRNA; Proliferation; T-cells; Th1; Th2
Other ID: http://etd.library.pitt.edu/ETD/available/etd-07282009-112806/, etd-07282009-112806
Date Deposited: 10 Nov 2011 19:54
Last Modified: 15 Nov 2016 13:47
URI: http://d-scholarship.pitt.edu/id/eprint/8689

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