MicroRNAs to Pathways in Prostate Cancer Progression
Technical Report,30 Sep 2012,29 Sep 2015
University of California San Francisco San Francisco United States
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The overall goal of this funded proposal was to dissect the relationship between the microRNA biogenesis machinery and AKT induced prostate cancer progression using mouse models. Preliminary data showed that removal of a microRNA biogenesis factor, DGCR8, suppressed tumor development in an in vivo prostate epithelium specific PTEN knockout model. Removal of PTEN activates the AKT pathway. Careful phenotypic characterization of PTEN, DGCR8 double knockout prostate epithelial cells showed a defect in expansion of the basal epithelial, a failure to overcome Akt induced senescence, and an associated block in progression from hyperplasia to dysplasia. These connections support a model where basal cell expansion and senescence form barriers for the transition to dysplasia. Furthermore, the central role of DGCR8 suggests that microRNAs are required to suppress senescence and to disregulate basal cell growth. Thus, we measured changes in microRNA levels during tumor progression following PTEN loss identifying six that significantly increase and thirteen that significantly decrease. We had hoped to test these microRNAs individually, but have found in vivo delivery of the microRNAs challenging. However, we will continue these experiments and believe we have a potential solution using shmimics, a viral delivery system for microRNAs. We plan to continue these studies. We have also shown human relevance by identifying a strong correlation between human tumors with increased Akt activity and increased expression of DGCR8, once again suggesting a requirement for increased microRNA biogenesis with tumor progression. Indeed in situ staining shows high DGCR8 in basal and tumor epithelial cells.