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  • A Novel VEGF-responsive lincRNA Regulates Angiogenesis in Glioblastoma

    Final Number:
    518

    Authors:
    Sunit Das MD PhD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2013 Annual Meeting

    Introduction: Large intergenic RNAs (lincRNA) are involved in numerous cellular processes, including those relevant to normal development and cancer progression. We speculated that differential lincRNAs expression would be important to fate specification in endothelial cells.

    Methods: To detect lincRNAs that are functionally important in the process of human angiogenesis, a custom microarray was used to profile long non-coding transcripts in human vascular endothelium in two-dimensional versus three-dimensional pro-angiogenic cultures, with or without VEGF-A165.

    Results: We identified a VEGF-A-responsive lincRNA near the VEGFR1 gene, which we termed LiVE1 (lincRNA-VEGFR1). Through knockdown and over-expression studies, we found LiVE1 to exert transcriptional control over multiple genes involved in the angiogenesis signaling cascade, including VEGFR1, VEGFR2, and Flt1, and to direct vascular maturation in vitro. Given its significance to endothelial cell differentiation and maturation, we postulated that LiVE1 could have a role in neoplastic angiogenesis in glioblastoma. Indeed, we found that LiVE1 is highly expressed in glioblastoma and is enriched in the CD133+ glioma stem cell and CD133+CD144+ endothelial progenitor populations. In vivo knockdown of the LIVE1 using nanoparticles-based RNAi decreased microvascular density and tumour volume in a heterotopic glioblastoma xenograft model, and resulted in local tumor control in an orthotopic xenograft model.

    Conclusions: Our studies affirm that lincRNAs are important cellular effector molecules that have significant therapeutic potential and merit attention as targets for pharmaceutical innovation. Knockdown of LiVE1 may be an effective means to target vascular neogenesis in glioblastoma.

    Patient Care: LiVE1 may be a therapeutic target in glioblastoma.

    Learning Objectives: By the conclusion of this session, participants should 1) Understand the identity of long non-coding RNAs and their relevance to cell biology; 2) Understand the role of LiVE1 in vascular maturation in glioblastoma.

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