Abstract
Colorectal cancer (CRC) accounts for 10% of all cancer related deaths worldwide, and New Zealand has some of the highest incidence rates globally. Currently available targeted therapies are largely based on modulating protein function, however, only 1-2% of the human genome is protein coding. Long non-coding RNAs (lncRNAs) are ribonucleic acid transcripts >200 nucleotides that do not code for a protein. The lncRNA human Mammary Tumour Associated RNA 17 (hMaTAR17 ) is over-expressed in several different cancer types, including breast, lung, and colorectal. We hypothesised that hMaTAR17 also acts to modulate cancer related genes and pathways to impact CRC progression. We developed CRISPR/Cas9 knockout and CRISPRi knockdown models of hMaTAR17 in HCT116 colorectal cancer cells to investigate phenotypic changes upon hMaTAR17 loss-offunction in CRC. We performed cell characterisation assays, and identified a significant decrease in proliferation and migration of the hMaTAR17 knockout cells compared to control cells. RNA-Sequencing revealed a number of gene expression changes upon hMaTAR17 loss, including significantly reduced expression of vimentin, potentially implicating hMaTAR17 in epithelial-mesenchymal transition. Protein interaction studies revealed that hMaTAR17 is implicated with cancer and growth related proteins including lamin and TPI1 (Triosephosphate Isomerase 1), a glycolytic enzyme. We found that there was a significant correlation between hMaTAR17 expression and glycolytic metabolism in HCT116 cells. In addition, we showed that methylation could be driving differential expression of hMaTAR17 in patient data. Together, these results indicate that hMaTAR17 may serve as a promising potential new drug target for metastatic colorectal cancer.