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2010
Doctoral Thesis
Titel
Three microRNAs synergistically repress androgen receptor signaling and are downregulated in prostate carcinoma
Abstract
Prostate cancer (PCa) as the second leading cause of cancer death in men in the Western world is of great interest for the clinic and for scientific research. An effective treatment and molecular markers for the agressive, hormone-refractory form of the cancer are still missing. During the last years, microRNAs, small regulatory non-coding RNAs (\'1822nt), involved in post-transcriptional regulation of mRNAs, have become an important study field of molecular biology and there are many microRNAs known to be associated with different cancers. However, only few microRNAs are reported for PCa. In this study global microRNA profiling of different prostate cancer cell lines and a nonmalignant prostate epithelial cell line was used to identify microRNAs that are deregulated in PCa. In a subsequent analysis in non-malignant prostate tissue and tumor samples of different progression stages, we found miR-130a, miR-203, and miR-205 to be most significantly downregulated in PCa. Reconstitution of these microRNAs induced cell growth arrest caused by apoptosis (miR-130a, miR-203) or cell cycle arrest (miR-203, miR-205), which was even stronger, if the microRNAs were concomitantly reconstituted. Using four different target identification approaches, most targets were found to be associated with the androgen receptor (AR) signaling pathway, the central pathway for PCa initiation and growth. These included AR coregulators, as well as members of the MAPK pathway, a known ligand-independent activator pathway of the AR. We conclude from this study that the microRNAs -130a, -203, and -205 act as tumor suppressors in PCa cells, by negatively regulating AR coactivators. This may have therapeutic implications in particular for castration resistant PCa.
ThesisNote
Leipzig, Univ., Diss., 2010
Verlagsort
Leipzig