The acquisition of cancer traits in rare cells is accompanied and caused by a huge variety of driver genetic events. These include chromosomal deletions, translocations, point mutations, and insertions. The acquisition of a metastatic phenotype is currently the biggest problem in cancer treatment. However, genetic driver events that cause metastasis have been elusive and thus treatment to stop metastasis is not available in many cases. It has become recently appreciated that certain cancer traits are conferred by changes in microRNAs (miRNAs). MicroRNAs are a class of small endogenous RNAs that regulate the expression of other genes by binding to and destabilizing mRNAs and/or suppressing their translation. In this work we used a comparative oncogenomics approach to discover miRNAs that cause osteosarcoma progression and investigated their function in vivo and in vitro. In the first chapter, I review the evidence for a genetic origin of human cancer. Then, I review hallmarks of cancer, with a focus on metastasis and the failure of DNA sequence changes to fully explain metastasic process. Then, I review the role of miRNAs in biology and cancer development. The second chapter focuses on osteosarcoma development, the known roles that miRNAs play in this disease, and the chance that this understanding could lead to better treatments. The third chapter describes my investigation into the role of the miR-17-92 cluster in OS progression and metastasis. Finally, in the fourth chapter, I provide a summary and future perspectives for this work.
University of Minnesota Ph.D. dissertation. May 2016. Major: Veterinary Medicine. Advisor: David Largaespada. 1 computer file (PDF); ix, 153 pages.
Role of MicroRNA-17-92 cluster in the Osteosarcoma Development and Progression.
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