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 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.

Genome‐wide association study identifies an early onset pancreatic cancer risk locus

“…116940) 28 . CDK1 is the catalytic subunit of a protein kinase complex essential for G2/M transition the aberrant expression of which is associated with PDAC 29 …”

Y-Box Binding Protein-1 Promotes Epithelial-Mesenchymal Transition in Sorafenib-Resistant Hepatocellular Carcinoma Cells

“…DYNC1H1, a dynein motor protein, and KIF18B, KIF23 and KIF4A, members of kinesin superfamily motor proteins, assist cargo transport along microtubules to various subcellular locations, such as the leading edge of migrating cells [ 30 ]. ALDOA and RACGAP1 are tubulin binding proteins important for the microtubule filaments system, and are mainly responsible for metastasis and invasiveness in various carcinomas [ 31 , 32 ]. Not only the microtubule system, some of the identified upregulated molecules are involved in cellular metastasis and carcinogenesis through dysregulating cell division, including cell cycle regulators, CDCA8, CDK1, CDK2, CEP55 and CHEK1 [ 33 , 34 , 35 , 36 , 37 , 38 ].…”

Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression?

“…The so-called other MMPs (i.e., MMP12, MMP19, MMP20, MMP21, MMP27 and MMP28) are not very well characterized in PDAC. Although some members seem to be overexpressed in PDAC [106,111,112] and may be associated with tumor stage and patients survival (Table 1) [111][112][113], no preclinical studies have addressed the role of these MMPs in PDAC (Table 2). Therefore, their actual importance remains to be established.…”

“…Pancreatic cancer (PC); pancreatitis (CP); healthy control (CO); benign tumor (BT); immunohistochemistry (IHC); Western blot (WB); zymography (DG). not indicated RNA OS [113] Pancreatic cancer (PC); pancreatitis (CP); healthy control (CO); benign tumor (BT); immunohistochemistry (IHC); Western blot (WB); zymography (DG); overall survival (OS); disease-free survival (DF); lymph node metastasis (LM); perineural invasion (PNI); venous invasion (VI); distant metastasis (DM); differentiation (DIF). Note: All experiments were performed using mice unless indicated otherwise.…”