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

• Main Authors: Muhammad Khalid, Tetsuya Idichi, Naohiko Seki, Masumi Wada, Yasutaka Yamada, Haruhi Fukuhisa, Hiroko Toda, Yoshiaki Kita, Yota Kawasaki, Kiyonori Tanoue, Hiroshi Kurahara, Yuko Mataki, Kosei Maemura, Shoji Natsugoe
• Format: Article
• Language: English
• Published: MDPI AG 2019-03-01
• Series: Cancers
• Subjects: microRNA; miR-204-5p; antitumor; pancreatic ductal adenocarcinoma; pathogenesis; RACGAP1
• Online Access: http://www.mdpi.com/2072-6694/11/3/327

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.