Small non-coding RNAs in cancer

Abstract: The complex genetics of cancer, which allows tumours to grow and spread while bypassing the control circuitry of the cell, involves dysregulation of the genome, transcriptome and proteome. The importance of protein-coding genes such as growth factors and hormone receptors is well established. Recently, non-coding RNAs have emerged as important players in tumour development with potential to be explored as biomarkers and therapeutic targets. The aim of this thesis was to study the impact of small non-coding RNAs in cancer. MicroRNAs (miRNAs) are one of several types of ~20-30 nucleotide regulatory small non-coding RNAs. They regulate gene expression post-transcriptionally by base pairing to complementary sequences in the messenger RNAs (mRNAs) of protein-coding genes. We used traditional cloning and next-generation sequencing to map the small RNA transcriptome of breast cancer. By sequencing paired samples of tumour and normal breast tissue we detected differentially expressed miRNAs and found several hundred candidate new miRNA genes. We also identified a new type of small RNA derived from the RNA component of the vault particle, a ribonucleoprotein complex implicated in multi-drug resistance in tumour cells. These small vault RNAs (svRNAs) regulate gene expression similar to miRNAs. CYP3A4, an enzyme involved in drug metabolism, was validated as a target, establishing a possible link between the vault RNA and multi-drug resistance. Finally, we used microarrays to show that miRNA expression efficiently separates clinically relevant subgroups of bladder cancer. In summary, we have expanded the repertoire of small RNAs with findings that may have important clinical implications.