Harnessing miRNAs to enhance the anti-cancer properties of metformin in colorectal cancer

Orang AV, McKinnon RA, Petersen J and Michael MZ

Flinders Centre for Innovation in Cancer, Flinders University, Flinders Medical Centre, Adelaide, South Australia 5042.

Colorectal cancer (CRC) is the third most prevalent cancer in the world. The diabetes medication, metformin, is linked to cancer prevention and may selectively repress cancer proliferation. MicroRNAs are small non-coding RNAs involved in most cellular processes. Although metabolic consequences of metformin treatment have been investigated, detailed analysis of the resultant changes in gene expression is still required. Also, the effect of metformin treatment in combination with anti-cancer miRNAs has yet to be explored. Full transcriptome and small RNA next generation sequencing were performed for CRC cells treated with metformin. Following differential expression, functional enrichment and network analyses, CRC cells were transfected with miRNA mimics to explore the anti-cancer effect of differentially expressed (DE) miRNAs. In addition, unbiased high throughput functional screens of a synthetic miRNA library, in combination with metformin treatment, were used to identify additional miRNAs that impact the metformin response. Potential protein-protein interactions, within specific biological pathways that are affected by metformin treatment, were extrapolated from DE mRNAs and miRNAs and used to build system networks. Also, metformin treatment resulted in downregulation of some pro-proliferative and upregulation of some anti-proliferative miRNAs. Furthermore, miRNAs that sensitize CRC cells to the anti-cancer effect of metformin were experimentally validated. Identification of miRNAs that sensitise CRC cells to metformin, and their potential transcript targets, are early steps in the design of innovative therapeutic strategies.