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Expanding the liver small-RNA transcriptome : discovery of novel and oncofetal non-coding RNAs with roles in hepatocellular carcinoma

University of British Columbia

The major clinical challenges for liver cancer patients are the late stage of diagnosis and the lack of therapeutic targets with low hepatotoxicity. Hepatocellular carcinoma (HCC) accounts for over 80% of all liver cancer cases. Although mutations affecting protein-coding genes have been described in HCC, very few are considered genetic drivers or druggable targets. Therefore, new strategies for discovering effective and therapeutic targets are desperately needed. Recent approval of the first small RNA-based therapy points to the small non-coding RNA (sncRNA) transcriptome as a promising source of new diagnostic and therapeutic targets. This thesis examines the liver small RNA transcriptome from organogenesis to pathogenesis to identify regulatory networks that drive HCC. Through the in-silico analysis of fetal, non-malignant and tumour liver tissues we discovered 309 microRNA transcripts that are not represented in the current miRBase annotation of human microRNAs, expanding the liver microRNA transcriptome by 26%. These novel miRNAs display liver-specific and context-specific expression patterns that differentiate liver from other tissues types. The reactivation of developmental pathways has long been proposed as a driving mechanism for tumour initiation and aggressiveness. Pathways associated with human fetal development are usually repressed or tightly regulated in healthy adult tissue; thus, targeting these pathways is expected to spare normal adult cells from toxicity, representing a promising therapeutic strategy. However, the limited accessibility to fetal tissue samples has hampered the exploration of fetal gene reactivation in human cancer. In this thesis, I report the identification of 43 small non-coding RNA transcripts similarly expressed between fetal and tumour liver tissues, not expressed in non-malignant adult samples. These oncofetal sncRNAs were predicted to modulate the expression of transcription factors and protein-coding genes known to play major roles in liver organogenesis and HCC development. This thesis represents the first large-scale characterization of the human liver small RNA transcriptome in fetal, non-malignant and tumour tissues. The identification of oncofetal sncRNAs provides novel molecular targets for the development of diagnostic and therapeutic strategies for liver cancer.

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2019-04-17

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/69757

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/