Abstract
Previously, we established a microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) tissues using RNA sequencing and found significantly reduced expression of miR-204-5p. Here, we aimed to investigate the functional significance of miR-204-5p and to identify miR-204-5p target genes involved in PDAC pathogenesis. Cancer cell migration and invasion were significantly inhibited by ectopic expression of miR-204-5p in PDAC cells. Comprehensive gene expression analyses and in silico database searches revealed 25 putative targets regulated by miR-204-5p in PDAC cells. Among these target genes, high expression levels of RACGAP1, DHRS9, AP1S3, FOXC1, PRP11, RHBDL2 and MUC4 were significant predictors of a poor prognosis of patients with PDAC. In this study, we focused on RACGAP1 (Rac guanosine triphosphatase-activating protein 1) because its expression was most significantly predictive of PDAC pathogenesis (overall survival rate: p = 0.0000548; disease-free survival rate: p = 0.0014). Overexpression of RACGAP1 was detected in PDAC clinical specimens, and its expression enhanced the migration and invasion of PDAC cells. Moreover, downstream genes affected by RACGAP1 (e.g., MMP28, CEP55, CDK1, ANLN and S100A14) are involved in PDAC pathogenesis. Our strategy to identify antitumor miRNAs and their target genes will help elucidate the molecular pathogenesis of PDAC.
Highlights
Due to its aggressive nature, pancreatic ductal adenocarcinoma cancer (PDAC) is the deadliest of all solid cancers [1]
Cancer cell migration and invasion were significantly inhibited in si-RACGAP1-transfected cells (Figure 4C, lower). These results suggest that miR-204-5p directly binds to putative binding site within compared with mock- or siRNA-control-transfected PDAC cells
We focused on miR-204-5p and its regulated genes involved in PDAC pathogenesis
Summary
Due to its aggressive nature, pancreatic ductal adenocarcinoma cancer (PDAC) is the deadliest of all solid cancers [1]. Patients with PDAC often present without symptoms and, by the time of diagnosis, exhibit lymph node and distant metastases as well as vessel invasion [2]. The prognosis of patients with PDAC has not been improved by surgery or current chemotherapy, with the 5-year survival rate remaining at only 5−7% [3]. Molecular target therapies for several cancers have. Cancers 2019, 11, 327 shown remarkable therapeutic efficacy; no targeted therapeutics are currently approved for treatment of PDAC [4]. Previous studies have demonstrated that KRAS, TP53 and SMAD are driver oncogenes in PDAC [5]. Further studies are required to identify anticancer molecules.
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