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Discovery of oncofetal microRNA-gene networks associated with lung cancer aggressiveness

University of British Columbia

Each year about 1.5 million people die from lung cancer worldwide. In order to develop more effective strategies to manage this disease, it is essential to have a better understanding of molecular mechanisms underlying lung tumourigenesis. A recognized fact about cancer in general is that it shares many biological similarities with normal fetal development, such as intense cell proliferation, migration, angiogenesis and immune evasion. These features are gained as a consequence of changes in gene expression, which can result from the disruption in miRNAs. This class of small non-coding RNAs plays a fundamental role in regulating gene expression during normal development and tumourigenesis, nevertheless, comprehensive analyses of miRNAs in the context of lung development and lung cancer had not been previously explored. My hypothesis is that a better understanding of the similarities between human fetal lung development and lung cancer ― in the context of miRNAs ― will provide new insights into biological networks that might be critical to lung cancer pathogenesis. In this thesis, we performed for the first time a comprehensive characterization of miRNA expression in human fetal lung tissue, and identified numerous miRNAs that recapitulate their fetal expression patterns in non-small cell lung cancer (NSCLC). Investigation of genes potentially regulated by these oncofetal miRNAs, led us to discover miRNA-gene networks associated with tumour aggressiveness. Nuclear Factor I/B (NFIB), a transcription factor essential for lung development, was identified as the most prominent target of oncofetal miRNAs. Concordantly, analysis of NFIB expression in multiple NSCLC cohorts revealed its frequent underexpression (in ~40-70% of tumours). We further show that low expression of NFIB was significantly associated with biologically more aggressive subclasses of lung adenocarcinoma, and ultimately, poorer survival in patients with this subtype of NSCLC. Collectively, this work reasserted commonalities between the processes regulating normal development and tumourigenesis, and identified oncofetal miRNA-gene networks biologically relevant to NSCLC. Our study suggests that NFIB may serve as a biomarker for lung adenocarcinomas with poor prognosis, and indicates the possibility that restoration of NFIB expression in these tumours may induce lung cell differentiation, and therefore has the potential to reduce tumour aggressiveness.

eng

Vancouver : University of British Columbia Library

10.14288/1.0378360

Doctor of Philosophy - PhD

Medicine, Faculty of

2019-05

Graduate

DSpace