Abstract
We analysed the RNA sequence-based microRNA (miRNA) signature of pancreatic ductal adenocarcinoma (PDAC). Aberrantly expressed miRNAs were successfully identified in this signature. Using the PDAC signature, we focused on 4 clustered miRNAs, miR-216a-5p, miR-216a-3p, miR-216b-5p and miR-216b-3p on human chromosome 2p16.1. All members of the miR-216 cluster were significantly reduced in PDAC specimens. Ectopic expression of these miRNAs suppressed cancer cell aggressiveness, suggesting miR-216 cluster as anti-tumour miRNAs in PDAC cells. The impact of miR-216b-3p (passenger strand of pre-miR-216b) on cancer cells is still ambiguous. Forkhead box Q1 (FOXQ1) was directly regulated by miR-216b-3p and overexpression of FOXQ1 was confirmed in clinical specimens. High expression of FOXQ1 predicted a shorter survival of patients with PDAC by Kaplan–Meier analysis. Loss-of-function assays showed that cancer cell migration and invasion activities were significantly reduced by siFOXQ1 transfectants. We investigated pathways downstream from FOXQ1 by using genome-wide gene expression analysis. Identification of the miR-216-3p/FOXQ1-mediated network in PDAC should enhance understanding of PDAC aggressiveness at the molecular level.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, as the 5-year survival rate after diagnosis is only 5% [1, 2]
We recently showed that the passenger strand of miR-145-3p acted as an anti-tumour miRNA
Functional assays showed that proliferation, migration and invasion activities of cancer cells were significantly suppressed in miR-216a-5p, miR-216a-3p, miR-216b5p and miR-216b-3p transfectants compared with mock or miR-control transfectants (Figure 3)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, as the 5-year survival rate after diagnosis is only 5% [1, 2]. Transcription of all members of the miR216 cluster was significantly reduced in PDAC specimens, and ectopic expression of these miRNAs suppressed cancer cell aggressiveness. The expression levels of miR216a-5p, miR-216a-3p, miR-216b-5p and miR-216b-3p were significantly lower in tumour tissues than in normal pancreatic tissues (Figure 2). It was not recognized the significant relationships between any of the clinical parameters (i.e., TNM stage, metastasis or survival rate) and expression levels of any member of the miR-216family (data not shown). Expression levels of all clustered miRNAs in PDAC cells were significantly elevated by 5-aza-dc treatment (Supplementary Figure 1). Expression of miR-216 family members and the effects on cell growth, migration and invasion in PDAC cell lines
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