MicroRNA Gene Regulatory Networks in Peripheral Nerve Sheath Tumors
Annual rept. 15 Aug 2011-14 Aug 2012
MINNESOTA UNIV MINNEAPOLIS
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In recent years, efforts to investigate the mechanisms of tumor initiation, progression and transformation have led to identification of several driver genes and pathways. We are interested in identifying miRNAs which can regulate those driver genes along with many others to drive tumor transformation. Based on the analysis of expression of miRNAs between MPNST and Schwann cells, miR29 family was found to be down-regulated in MPNSTs compared to normal Schwann cells. Many of the known gene targets of miR29 family were also found up-regulated in these conditions, implicating the loss of miR29 leading to deregulation of target genes. Some of those genes include PTEN, TGF, PDGF, SUZ12, DNMTs. Hence we proposed to knock-out all four miRNAs of miR29 family miR29a, miR29b1, miR29b2 and miR29c in mice which are present in two clusters. We have made gene targeting constructs for both miR29 clusters and currently screening for successfully targeted mouse ES cell colonies. We have also identified a novel pseudogene SUZ12P as potential factor contributing to tumor transformation through titrating out miRNAs which are critical for regulating key driver genes of cancer. Further, we have shown the pseudogene SUZ12P is regulated by various miRNAs and currently investigating the effects of SUZ12P on various miRNAs, genes and DNAchromatin modification pathways. Since SUZ12P is a pseudogene of a critical component of polycomb repressor complex SUZ12, This may have a crucial role in tumor transformation through miRNAs and polycomb mediated genemiRNA regulation.
- Anatomy and Physiology
- Medicine and Medical Research