Gene Regulation by Antitumor miR-204-5p in Pancreatic Ductal Adenocarcinoma: The Clinical Significance of Direct RACGAP1 Regulation

Abstract

Previously, we established a microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) tissues using RNA sequencing and found significantly reduced expression of <i>miR-204-5p</i>. Here, we aimed to investigate the functional significance of <i>miR-204-5p</i> and to identify <i>miR-204-5p</i> target genes involved in PDAC pathogenesis. Cancer cell migration and invasion were significantly inhibited by ectopic expression of <i>miR-204-5p</i> in PDAC cells. Comprehensive gene expression analyses and <i>in silico</i> database searches revealed 25 putative targets regulated by <i>miR-204-5p</i> in PDAC cells. Among these target genes, high expression levels of <i>RACGAP1</i>, <i>DHRS9</i>, <i>AP1S3</i>, <i>FOXC1</i>, <i>PRP11</i>, <i>RHBDL2</i> and <i>MUC4</i> were significant predictors of a poor prognosis of patients with PDAC. In this study, we focused on <i>RACGAP1</i> (Rac guanosine triphosphatase-activating protein 1) because its expression was most significantly predictive of PDAC pathogenesis (overall survival rate: <i>p</i> = 0.0000548; disease-free survival rate: <i>p</i> = 0.0014). Overexpression of <i>RACGAP1</i> was detected in PDAC clinical specimens, and its expression enhanced the migration and invasion of PDAC cells. Moreover, downstream genes affected by <i>RACGAP1</i> (e.g., <i>MMP28</i>, <i>CEP55</i>, <i>CDK1</i>, <i>ANLN</i> and <i>S100A14</i>) are involved in PDAC pathogenesis. Our strategy to identify antitumor miRNAs and their target genes will help elucidate the molecular pathogenesis of PDAC.