MiR-142-3p is downregulated in aggressive p53 mutant mouse models of pancreatic ductal adenocarcinoma by hypermethylation of its locus

Godfrey, J. D., Morton, J. P. , Wilczynska, A., Sansom, O. J. and Bushell, M. D. (2018) MiR-142-3p is downregulated in aggressive p53 mutant mouse models of pancreatic ductal adenocarcinoma by hypermethylation of its locus. Cell Death and Disease, 9(6), 644. (doi: 10.1038/s41419-018-0628-4) (PMID:29844410) (PMCID:PMC5973943)

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Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognostic implications. This is partly due to a large proportion of PDACs carrying mutations in TP53, which impart gain-of-function characteristics that promote metastasis. There is evidence that microRNAs (miRNAs) may play a role in both gain-of-function TP53 mutations and metastasis, but this has not been fully explored in PDAC. Here we set out to identify miRNAs which are specifically dysregulated in metastatic PDAC. To achieve this, we utilised established mouse models of PDAC to profile miRNA expression in primary tumours expressing the metastasis-inducing mutant p53R172H and compared these to two control models carrying mutations, which promote tumour progression but do not induce metastasis. We show that a subset of miRNAs are dysregulated in mouse PDAC tumour tissues expressing mutant p53R172H, primary cell lines derived from mice with the same mutations and in TP53 null cells with ectopic expression of the orthologous human mutation, p53R175H. Specifically, miR-142-3p is downregulated in all of these experimental models. We found that DNA methyltransferase 1 (Dnmt1) is upregulated in tumour tissue and cell lines, which express p53R172H. Inhibition or depletion of Dnmt1 restores miR-142-3p expression. Overexpression of miR-142-3p attenuates the invasive capacity of p53R172H-expressing tumour cells. MiR-142-3p dysregulation is known to be associated with cancer progression, metastasis and the miRNA is downregulated in patients with PDAC. Here we link TP53 gain-of-function mutations to Dnmt1 expression and in turn miR-142-3p expression. Additionally, we show a correlation between expression of these genes and patient survival, suggesting that they may have potential to be therapeutic targets.

Item Type:Articles
Additional Information:J.D.G., A.W. and M.D.B. were funded by the Medical Research Council, UK. J.P.M. and O.J.S. were core funded by Cancer Research UK (A12481, A11650 and A17196).
Glasgow Author(s) Enlighten ID:Morton, Professor Jen and Sansom, Professor Owen
Authors: Godfrey, J. D., Morton, J. P., Wilczynska, A., Sansom, O. J., and Bushell, M. D.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Death and Disease
Publisher:Nature Publishing Group
ISSN (Online):2041-4889
Published Online:29 May 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Cell Death and Disease 9(6): 644
Publisher Policy:Reproduced under a Creative Commons License

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