Download aberrant regulation in lung cancer and association with genomic

MicroRNAs in disease and health: aberrant regulation in lung cancer and
association with genomic variation
Urmo Võsa
Recent discoveries have demonstrated that the lion's share of RNA transcribed from human
genome is not encoding structural proteins but instead regulates the action of protein-coding
genes. The most widely studied class of non-coding RNAs are microRNAs, small ~20
nucleotide long molecules which regulate the activity of genes by binding the targeted RNAs.
MicroRNAs are important in most biological processes and are involved in pathogenesis of
several diseases, for example cancers. They can serve as potential drug targets and biomarkers
which could be used for earlier detection and better diagnosis.
In this thesis, microRNA expression changes in non-small cell lung cancer were investigated.
Cancer samples were collected from lung cancer patients and the expression levels of 858
microRNAs were measured. The analysis revealed 72 microRNAs with changed expression
pattern in cancer which could be involved in the formation of tumor or serve as potential
biomarkers. One microRNA showed association with patient post-operative survival. Because
results of this and other similar studies are quite variable, systematic meta-analysis was
conducted by special method enabling the comparison of ranked gene lists. Meta-analysis of
twenty studies revealed the robust set of seven up- and eight down-regulated microRNAs in
lung cancer.
Variable positions in human genome influence the expression levels of thousands of RNAs. In
this thesis, the hypothesis that variants mapping into microRNA binding sites may influence
the expression of mRNAs via microRNA binding was tested. For that, variable genomic
positions were intersected with bioinformatically predicted microRNA target sites. Several
genes were prioritized in which those variants are likely to play regulatory role. However, there
was no global overrepresentation of associations that agree with the logic of microRNA action
mechanism, suggesting that additional mechanisms may be involved in this process.
This thesis widened our knowledge about microRNA aberrations in lung cancer, helped to
systematize the previous knowledge and connected the regulatory potential of microRNAs with
normal genetic variation.