MicroRNA involvement in colorectal cancer cell metabolism

Author: Ayla Orang

Orang, Ayla, 2020 MicroRNA involvement in colorectal cancer cell metabolism, Flinders University, College of Medicine and Public Health

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Colorectal cancer (CRC) is the third most prevalent cancer in the world. Metformin has been associated with cancer prevention and selectively represses cancer progression. MicroRNAs are small non-coding RNAs involved in most cellular processes. Although several metabolic effects 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 is yet to be explored.

RNA and small RNA next generation sequencing were performed for CRC cells treated with metformin. Following differential expression analysis, 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, high throughput functional screens of a miRNA mimic library, in combination with metformin, were undertaken and a secondary screen was performed to validate the lead miRNAs.

DE miRNAs and genes within specific biological pathways that are affected by metformin treatment were identified. Also, metformin treatment resulted in the downregulation of some pro-proliferative and upregulation of some anti-proliferative miRNAs. Furthermore, miRNAs were shown to sensitize CRC cells to the anti-cancer effect of metformin by enhancing its anti-proliferative effects. Identification of DE miRNAs and their potential target genes, as well as miRNAs that sensitize CRC cells to metformin, provides an advance towards identifying therapeutic interventions and confirms the feasibility of combining metformin with miRNAs to enhance therapeutic efficacy and overcome drug resistance. Future work includes confirmation of the mechanisms of action of newly discovered miRNAs in vivo in the context of metformin.

Keywords: Colorectal cancer, miRNA, Metformin, Metabolism

Subject: Medical Science thesis

Thesis type: Doctor of Philosophy
Completed: 2020
School: College of Medicine and Public Health
Supervisor: Michael Michael