Malignant transformation represents the phenotypic endpoint of successive genetic lesions that confer uncontrolled proliferation and survival, unlimited replicative potential, and invasive growth. Recent evidence has suggested that non-coding RNAs, in particular, microRNAs (miRNAs), are subjected to changes in gene structure and expression regulation in tumors. I identified a polycistronic miRNA cluster, mir17-92, as a target of chromosome 13q31 amplicon found in human B-cell lymphomas. In a mouse model for B-cell lymphoma, enforced mir17-92 expression cooperates with c-myc and accelerates tumor growth by repressing cell death. These findings provided some of the first functional evidence that changes in miRNAs could contribute to oncogenesis. The work described in this application continues my studies on the oncogenic effects of mir17-92 using both cell culture systems and animal tumor models. First, I propose to identify the oncogenic miRNA components within the mir17-92 cluster, and to dissect the molecular basis for the tumorigenic effects of mir17-92. Second, the effects of mir17-92 in tumor maintenance and therapy response will be investigated. Finally, combined expression studies, copy number studies and functional characterization will be applied to examine more broadly the miRNA pathways in the oncogenic and tumor suppressor network. These studies, if successful, will produce fundamental insights into the functions of miRNAs during tumor development and tumor maintenance, which can be applied for discovery of both diagnostic markers and therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA126186-04
Application #
7759579
Study Section
Special Emphasis Panel (ZCA1-RTRB-A (O1))
Program Officer
Howcroft, Thomas K
Project Start
2006-12-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
4
Fiscal Year
2010
Total Cost
$246,721
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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Choi, Yong Jin; Lin, Chao-Po; Ho, Jaclyn J et al. (2011) miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol 13:1353-60
Jiang, Shan; Li, Chaoran; Olive, Virginie et al. (2011) Molecular dissection of the miR-17-92 cluster's critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation. Blood 118:5487-97
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Olive, Virginie; Jiang, Iris; He, Lin (2010) mir-17-92, a cluster of miRNAs in the midst of the cancer network. Int J Biochem Cell Biol 42:1348-54
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Ma, Cong; Liu, YuFei; He, Lin (2009) MicroRNAs - powerful repression comes from small RNAs. Sci China C Life Sci 52:323-30
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