Abstract
Prostate cancer is a leading cause of tumor mortality. To characterize the underlying molecular mechanisms, we have compared the microRNA (miRNA) profile of primary prostate cancers and noncancer prostate tissues using deep sequencing. MiRNAs are small noncoding RNAs of 21 to 25 nucleotides that regulate gene expression through the inhibition of protein synthesis. We find that 33 miRNAs were upregulated or downregulated >1.5-fold. The deregulation of selected miRNAs was confirmed by both Northern blotting and quantitative reverse transcription-PCR in established prostate cancer cell lines and clinical tissue samples. A computational search indicated the 3'-untranslated region (UTR) of the mRNA for myosin VI (MYO6) as a potential target for both miR-143 and miR-145, the expression of which was reduced in the tumor tissues. Upregulation of myosin VI in prostate cancer was previously shown by immunohistochemistry. The level of MYO6 mRNA was significantly induced in all primary tumor tissues compared with the nontumor tissue from the same patient. This finding was matched to the upregulation of myosin VI in established prostate cancer cell lines. In luciferase reporter analysis, we find a significant negative regulatory effect on the MYO6 3'UTR by both miR-143 and miR-145. Mutation of the potential binding sites for miR-143 and miR-145 in the MYO6 3'UTR resulted in a loss of responsiveness to the corresponding miRNA. Our data indicate that miR-143 and miR-145 are involved in the regulation of MYO6 expression and possibly in the development of prostate cancer.
Highlights
MicroRNAs are small, noncoding RNAs of about 21 to 25 nucleotides in length that usually bind to partially complementary sites in the 3′-untranslated region (UTR) of their mRNA targets [1, 2]
MiRNA Gene Expression in Prostate Cancer Two pooled miRNA cDNA libraries of each normal prostate and primary prostate cancer samples were generated with each library containing five pooled samples from normal and tumor tissue, respectively
The comparison of the two libraries from normal prostate tissue showed a high degree of homology in the miRNA expression pattern, whereas the two tumor libraries exhibited a slight variation in the miRNA profile (Supplementary Table S3-5)
Summary
MicroRNAs (miRNAs) are small, noncoding RNAs of about 21 to 25 nucleotides in length that usually bind to partially complementary sites in the 3′-untranslated region (UTR) of their mRNA targets [1, 2]. MiRNAencoding genes are transcribed in the nucleus by RNA polymerases II and III and are processed to miRNA precursors of ∼70 nucleotides These pre-miRNAs are Authors' Affiliations: Departments of 1Virology, 2Urology, and 3Pathology, University of Saarland Medical School, Homburg/Saar, Germany; 4University Clinic of Urology and 5Department of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; 6University Clinic of Urology, University Regensburg, Regensburg, Germany; and 7Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
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