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

Abstract

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.

Epigenetically Upregulated MicroRNA-602 Is Involved in a Negative Feedback Loop with FOXK2 in Esophageal Squamous Cell Carcinoma

“…31 Similar to tumor suppressors, dysregulation of tumor suppressor-type miRNAs by epigenetic silencing is often observed in human cancers, such as miR-142-3p, miR-142-3p, and miR-183. [32][33][34] We supposed that the upregulated miR-602 was epigenetically activated by DNA hypomethylation. Correspondingly, CpG site hypomethylation of miR-602 was observed in ESCC clinical samples, and this further verified that hypomethylation by 5-aza-CdR could dramatically augment the expression of miR-602 in ESCC cell lines.…”

miR-142-3p Reduces the Size, Migration and Contractility of Endometrial and Endometriotic Stromal Cells by Targeting Integrin- and Rho GTPase-related Pathways that Regulate Cytoskeletal Function

“…Dysregulated miR-142-3p has been previously implicated in impaired hematopoiesis [20]. More recently, several studies found miR-142-3p to be hypermethylated and downregulated in aggressive metastatic cancers, including pancreatic ductal adenocarcinoma [21] and breast cancer [22], suggesting this microRNA affects cellular invasion across several cell types. Furthermore, an effect of miR-142-3p on cellular motility was seen in knockout miR-142 -/-mice, which exhibited abnormal skin wound healing upon infection [23].…”

Nuclear Factor κB Signaling and Its Related Non-coding RNAs in Cancer Therapy

“…The miRNA family is also significant in the anti-proliferative and pro-apoptotic processes regulated by p53 through binding cell cycle genes and proto-oncogenes 65, 66, 67, 68. In other studies, miR-142-3p, miR-155-5p, miR-518, miR-211, miR-1307, and miR-30a can all directly or indirectly stimulate the p53 signaling pathway, which shows the close relationship between miRNA and p53 69, 70, 71, 72, 73, 74…”