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Alteration of non-coding RNAs as a mechanism of lung cancer gene deregulation Stewart, Gregory

Abstract

Lung cancer remains the deadliest form of cancer, and less than half of lung adenocarcinoma (LUAD) patients harbour clinically actionable driver genes, emphasizing the need to explore alternative mechanisms of cancer gene deregulation. The advent of next generation sequencing has begun to reveal the functional importance of long non-coding RNAs (lncRNAs) in human cell biology, which can be exploited by tumours to drive the hallmarks of cancer. Due to their complex tertiary structure and unknown binding motifs there is a growing disparity between number of lncRNAs identified and those that have been functionally characterized. As such, lncRNAs deregulated in cancer may represent critical members of cancer pathways that could hold therapeutic applicability. The goal of this thesis is to identify lncRNAs important to LUAD biology, discover shared features and mechanisms used to regulate cancer driving protein coding genes, and evaluate the clinical relevance of these non-coding genes. We discover and investigate three major mechanisms harnesses by lncRNAs in LUAD: (i) cis-acting regulation of neighbouring genes, (ii) trans-acting regulation through sequence homology and (iii) regulation through shared miRNAs. This work uncovers evidence to suggest that alteration of lncRNAs is a major mechanism of cancer gene regulation in LUAD. Further characterization of these understudied gene regulatory mechanisms could lead to novel therapies that silence oncogenes or reactivate tumour suppressor genes.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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