Abstract
Analysis of our microRNA (miRNA) expression signature of pancreatic ductal adenocarcinoma (PDAC) revealed that microRNA-217 (miR-217) was significantly reduced in cancer tissues. The aim of this study was to investigate the antitumor roles of miR-217 in PDAC cells and to identify miR-217-mediated molecular pathways involved in PDAC aggressiveness. The expression levels of miR-217 were significantly reduced in PDAC clinical specimens. Ectopic expression of miR-217 significantly suppressed cancer cell migration and invasion. Transcription of actin-binding protein Anillin (coded by ANLN) was detected by our in silico and gene expression analyses. Moreover, luciferase reporter assays showed that ANLN was a direct target of miR-217 in PDAC cells. Overexpression of ANLN was detected in PDAC clinical specimens by real-time PCR methods and immunohistochemistry. Interestingly, Kaplan–Meier survival curves showed that high expression of ANLN predicted shorter survival in patients with PDAC by TCGA database analysis. Silencing ANLN expression markedly inhibited cancer cell migration and invasion capabilities of PDAC cell lines. We further investigated ANLN-mediated downstream pathways in PDAC cells. “Focal adhesion” and “Regulation of actin binding protein” were identified as ANLN-modulated downstream pathways in PDAC cells. Identification of antitumor miR-217/ANLN-mediated PDAC pathways will provide new insights into the potential mechanisms underlying the aggressive course of PDAC.
Highlights
Due to the aggressive nature of pancreatic ductal adenocarcinoma (PDAC), it is one of the most lethal malignancies in the world [1, 2]
We hypothesized that miR-217 suppressed novel metastatic pathways in PDAC cells
Expression of these clustered miRNAs were significantly downregulated in PDAC cells
Summary
Due to the aggressive nature of pancreatic ductal adenocarcinoma (PDAC), it is one of the most lethal malignancies in the world [1, 2]. We hypothesized that current genomic approaches might be used to elucidate the molecular mechanisms underlying PDAC metastasis and suggest improved treatments for this disease. A unique characteristic of human miRNAs is that a single miRNA species can regulate a large number of RNA transcripts [7, 8]. Dysregulated miRNAs can disrupt tightly controlled RNA networks and promote www.impactjournals.com/oncotarget cancer cell metastasis. Numerous studies have indicated that miRNAs are aberrantly expressed in several cancers, including PDAC [9,10,11]. The discovery of miRNAs and subsequent studies have deepened our understanding of the roles of miRNA in human cancer pathogenesis [12, 13]
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