Large intergenic RNAs (lincRNA) are involved in numerous cellular processes, including many relevant to normal development and cancer progression. In my doctoral research, we hypothesized that lncRNAs are functionally important to human endothelial biology, more specifically, to the process of human blood vessel formation or angiogenesis. To detect lincRNAs that are functionally important to human angiogenesis, a custom microarray was used to profile long noncoding transcripts in human vascular endothelium in two-dimensional versus three-dimensional pro-angiogenic cultures, with or without VEGF-A165. We identified a VEGF-A-responsive lincRNA near the VEGFR1 gene, which we termed lincRNA-VEGFR1 (LIVE1). Unbiased mRNA microarrays defined a number of potential target genes when LIVE1 was functionally disrupted using RNA interference. Importantly, knockdown and over-expression studies indicated that LIVE1 exerts transcriptional control over VEGFR1 as well as other VEGF receptors and direct angiogenesis in vitro. Furthermore, we found that LIVE1 is highly expressed in glioblastoma, and is enriched in glioma stem cell (GSC) fractions and neoplastic endothelial progenitor populations. In vivo knockdown of LIVE1 in a glioblastoma xenograft model decreased microvascular density, vascular perfusion, pericyte coverage, tumor volume and slowed tumour progression. Our results establish LIVE1 as a key mediator of angiogenesis and demonstrate the potential of lincRNA-based therapeutics.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/44140 |
| Date | 02 April 2014 |
| Creators | Wang, Jenny Jing |
| Contributors | Marsden, Philip A. |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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