MicroRNAs (miRNAs) are a class of small non-coding functional RNAs that mediate post-transcriptional regulation of target mRNAs in a sequence-specific manner. They affect a wide variety of cellular processes, ranging from cellular differentiation, proliferation, apoptosis, metabolism, infection and cancer. MicroRNAs are regulated by gene copy number alteration, transcription, and processing. Over the past few years, miRNAs have also been shown to be encoded in a number of viruses, including herpesviruses. The viral-encoded miRNAs are important regulators in both the viral life cycle and virus-host interaction, specifically viral oncogenesis. Kaposi’s Sarcoma-associated Herpesvirus encodes 12 viral miRNA genes. It is the causative agent of primary effusion lymphoma (PEL), a non-Hodgkin lymphoma (NHL) of B cell lineage, and Kaposi’s sarcoma (KS), a highly vascular AIDS-defining cancer of endothelial cell lineage.
Using real-time quantitative polymerase chain reaction (QPCR)-based arrays, changes were determined in miRNA gene copy number, pre-miRNA, and mature cellular miRNA levels for the largest set of PEL examined to date. This defined the miRNA signature of PEL, which differs from that of other NHL. Furthermore it showed that transcriptional regulation of pre-miRNA as well as mature miRNA levels contribute nonredundant information that can be used for the classification of human tumors. Not only the induction, but also the absence of specific cellular miRNAs can be used to determine tumor origin and proliferation state. Tumor suppressor miRNAs were significantly down regulated in PEL as well as in KS. These represent tumor-specific, rather than virus-specific miRNAs. Since many known tumor suppressor proteins are wild type in KS and PEL, down regulation of multiple tumor suppressor miRNAs, provides a novel, alternative mechanism of transformation. Finally, using precursor microRNA profiling by a novel real-time QPCR method progressive stages of endothelial cell transformation cumulating in KS was defined; and particular miRNAs that serve as biomarkers for tumor progression were identified. For the first time, comprehensive comparisons were possible between primary patient biopsies, well-established culture and mouse tumor models. All together, these results can be used to characterize the cellular miRNA signature in KSHV-associated malignancies, namely PEL and KS.
|Advisor:||Dittmer, Dirk P.|
|Commitee:||Ahmed, Shawn, Damania, Blossom, Giddings, Morgan, Marzluff, William F., Swanstrom, Ronald I.|
|School:||The University of North Carolina at Chapel Hill|
|Department:||Genetics & Molecular Biology|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 70/04, Dissertation Abstracts International|
|Keywords:||KSHV, Kaposi's sarcoma-associated herpesvirus, PEL, mRNAs|
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