University of Leicester
2015GODFREYJDPhD.pdf (14.21 MB)

The dysregulation of microRNAs due to mutant p53R172H expression in a mouse model of pancreatic ductal adenocarcinoma

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posted on 2015-12-02, 15:58 authored by Jack David Godfrey
Pancreatic cancer is one of the most aggressive of human malignancies, with incidence almost equalling mortality. The main reason for the poor prognosis is that the majority of pancreatic cancer cases are not diagnosed until the disease has metastasised. Mutations to p53 have been shown to have gain of function characteristics, which promote metastasis in pancreatic cancer. MicroRNAs are small endogenous molecules which inhibit gene expression, and have been shown to be dysregulated in a number of diseases, including cancer. Current therapeutic approaches to treatment of metastatic pancreatic cancer have poor clinical outcomes, with little hope of remission. Given this, it is necessary to understand the molecular events governing metastasis in pancreatic cancer, in order to develop novel therapeutic approaches for the treatment of this disease. This study has implemented a mouse model of pancreatic cancer to profile microRNA expression in primary tumours which express mutant p53R172H (p53R175H in humans). The experiments showed that a subset of microRNAs were dysregulated in mutant p53R172H expressing tissues, with the majority being downregulated, including miR-148a-3p and miR-142-3p. Reverse trans-well invasion assays were employed to investigate how modulation of some of these microRNAs may influence the invasive ability of cells. The experiments show that miR-148a-3p inhibits invasion of pancreatic cancer cells. Additionally, this study presents evidence to suggest that the methyltransferase DNMT1, is upregulated in mutant p53R172H expressing tumours. Depletion of DNMT1 is sufficient to rescue expression of miR-142-3p in mutant p53R172H expressing primary cells. This study presents data to suggest that a novel mechanism by which mutant p53R172H attains gain of function abilities, may be through promoting hypermethylation of microRNAs.



Bushell, Martin; Willis, Anne

Date of award


Author affiliation

MRC Toxicology Unit

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD



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