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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 p53 R172H  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 p53 R172H , primary cell lines derived from mice with the same mutations and in  TP53  null cells with ectopic expression of the orthologous human mutation, p53 R175H . 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 p53 R172H . Inhibition or depletion of  Dnmt1  restores  miR-142-3p  expression. Overexpression of  miR-142-3p  attenuates the invasive capacity of p53 R172H -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.

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