microRNAs (miRNAs) are ~22 nucleotide non-coding RNAs that usually repress genes by imperfectly binding to the 3'UTR of the target mRNA which causes translational repression and mRNA destabilization. miRNA dysregulation has been observed in many cancers and many miRNAs are not only involved in the initiation and progression of cancer but may have therapeutic potential because they target tumor suppressor genes or oncogenes. Bladder cancer, which usually presents as transitional cell carcinoma (TCC), is the fifth most common cancer in the United States. Preliminary results from miRNA profiling indicate that miRNA misexpression has severe consequences in TCC tumorigenesis and some miRNAs may be tumor suppressors or oncogenes. Our study also shows that some silenced tumor suppressor miRNAs can be reactivated by epigenetic treatment. Furthermore, we have developed a flexible platform using the CMV promoter to restore expression of multiple tumor suppressor miRNAs from a single engineered transcript. This novel expression vector can inhibit tumor cell growth by targeting multiple oncogenes or oncogenic pathways. In this proposal, based on our strong preliminary results, we plan to focus on: 1) identifying specific miRNAs for diagnostic and prognostic purposes for bladder cancer patients;2) reactivating silenced tumor suppressor miRNAs by epigenetic treatment; 3) characterizing the role of miRNAs during tumorigenesis and re-expressing identified tumor suppressor miRNAs in cancer cells with a multiple miRNA expression vector. Completion of these specific aims will provide an important step towards the clinical application of using miRNAs as diagnostic and/or prognostic markers and as therapeutic targets in bladder cancer patients.

Public Health Relevance

In the United States, bladder cancer is the fourth most common cancer diagnosis in men and the eighth most common in women with 50-80% of cases recurring. In 2009 there are estimated 70,980 new cases and 14,330 deaths due to bladder cancer according to the National Cancer Institute. miRNA dysregulation has been observed in many cancers and many miRNAs have therapeutic potential because they target tumor suppressor genes or oncogenes. Completion of this study will provide an exciting step towards the clinical application of using miRNAs as diagnostic and/or prognostic markers and as therapeutic targets in bladder cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138794-03
Application #
8282941
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Tricoli, James
Project Start
2010-08-09
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$260,852
Indirect Cost
$99,832
Name
University of Southern California
Department
Urology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Su, S-F; Chang, Y-W; Andreu-Vieyra, C et al. (2013) miR-30d, miR-181a and miR-199a-5p cooperatively suppress the endoplasmic reticulum chaperone and signaling regulator GRP78 in cancer. Oncogene 32:4694-701
Han, Han; Yang, Xiaojing; Pandiyan, Kurinji et al. (2013) Synergistic re-activation of epigenetically silenced genes by combinatorial inhibition of DNMTs and LSD1 in cancer cells. PLoS One 8:e75136
Qiu, Xiangning; Friedman, Jeffrey M; Liang, Gangning (2011) Creating a flexible multiple microRNA expression vector by linking precursor microRNAs. Biochem Biophys Res Commun 411:276-80