MicroRNAs are 17-24 nucleotide-long, single-stranded RNA molecules that profoundly impact the gene expression program of a cell by annealing to and suppressing the expression of many target genes. Changes in expression of specific microRNAs and other types of short RNAs are involved in different types of malignancies, including prostate cancer. We know that progression of prostate cancer is accompanied by changes in the gene expression program, but the role of microRNA and other short RNAs in progression have not been studied. In this proposal we will clone and sequence Solexa/lllumina libraries of small RNAs from prostate cancer cells to identify microRNAs and other short RNAs that are (a) regulated by PTEN loss, (b) regulated by overexpression of PKN1 and (c) correlated with progression to androgen independence. We will also follow the changes in known microRNAs by hybridization to locked-nueleic acid microarrays. These results will identify new short RNAs involved in prostate cancer progression and test the hypothesis that specific molecular genetic lesions are correlated with specific microRNA changes during the progression of prostate cancer. We will determine whether microRNAs repressed during prostate cancer progression contribute to the phenotype of progression, both in vitro and in vivo, starting with four microRNAs (in two families) that have already been validated in preliminary results. Finally, we will identify targets of these microRNAs whose de-repression during cancer progression leads to worsening ofthe malignant phenotype. We will identify the targets of two key microRNA families involved in cancer progression by a novel combination of experiments and computational target prediction, starting with eight targets that have already passed the experimental filters. Thus new technologies, short RNA cloning and ultrahigh-throughput sequencing, and new combinations of assays for identification of relevant targets will be applied to the molecular analysis of prostate cancer progression, and the function of key microRNAs In this process will be dissected. The results are expected to open new avenues of research, therapy, and diagnosis of prostate cancers.

Public Health Relevance

Although prostate cancers are initially very responsive to anti-androgens, they activate signal transduction pathways and recur as androgen-independent cancers that metastasize and lead to death. To treat aggressive prostate cancers, we need to understand the changes in gene expression mediated by changes in short RNAs as prostate cancers activate signal transduction pathways and become androgen independent..

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01CA104106-09
Application #
8744395
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
DUNS #
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Kumar, Pankaj; Kuscu, Canan; Dutta, Anindya (2016) Biogenesis and Function of Transfer RNA-Related Fragments (tRFs). Trends Biochem Sci 41:679-89
Agarwal, Neeraj; Dancik, Garrett M; Goodspeed, Andrew et al. (2016) GON4L Drives Cancer Growth through a YY1-Androgen Receptor-CD24 Axis. Cancer Res 76:5175-85
Reon, Brian J; Dutta, Anindya (2016) Biological Processes Discovered by High-Throughput Sequencing. Am J Pathol 186:722-32
Sakurai, Kouhei; Reon, Brian J; Anaya, Jordan et al. (2015) The lncRNA DRAIC/PCAT29 Locus Constitutes a Tumor-Suppressive Nexus. Mol Cancer Res 13:828-38
Mueller, Adam C; Cichewicz, Magdalena A; Dey, Bijan K et al. (2015) MUNC, a long noncoding RNA that facilitates the function of MyoD in skeletal myogenesis. Mol Cell Biol 35:498-513
Borah, Sumit; Xi, Linghe; Zaug, Arthur J et al. (2015) Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science 347:1006-10
Kumar, Pankaj; Mudunuri, Suresh B; Anaya, Jordan et al. (2015) tRFdb: a database for transfer RNA fragments. Nucleic Acids Res 43:D141-5
Earl, Julie; Rico, Daniel; Carrillo-de-Santa-Pau, Enrique et al. (2015) The UBC-40 Urothelial Bladder Cancer cell line index: a genomic resource for functional studies. BMC Genomics 16:403
Dillon, Laura W; Kumar, Pankaj; Shibata, Yoshiyuki et al. (2015) Production of Extrachromosomal MicroDNAs Is Linked to Mismatch Repair Pathways and Transcriptional Activity. Cell Rep 11:1749-59
Zboray, Lori; Pluciennik, Anna; Curtis, Dana et al. (2015) Preventing the Androgen Receptor N/C Interaction Delays Disease Onset in a Mouse Model of SBMA. Cell Rep 13:2312-23

Showing the most recent 10 out of 59 publications