Involvement of anti-tumor and its targets in the pathogenesis of pancreatic ductal adenocarcinoma: direct regulation of and by .

MicroRNAs (miRNAs) are unique in that a single miRNA molecule regulates a vast number of RNA transcripts. Thus, aberrantly expressed miRNAs disrupt tightly controlled RNA networks in cancer cells. Our functional screening showed that expression of was downregulated in pancreatic ductal adenocarcinoma (PDAC) tissues. Here, we aimed to investigate the anti-tumor roles of in PDAC cells and to identify -mediated oncogenic signaling in this disease. Ectopic expression of inhibited cancer cell migration and invasion in PDAC cells. Moreover, restoration of suppressed oncogenic signaling, as demonstrated by reduced phosphorylation of focal adhesion kinase, AKT, and extracellular signal-regulated kinase, in PDAC cells. Our database analyses and luciferase reporter assays showed that two cell-surface matrix receptors, integrin α3 () and integrin β1 (), were directly regulated by in PDAC cells. Overexpression of and was confirmed in PDAC clinical specimens. Interestingly, a large number of cohort analyses from TCGA database showed that high expressions of and were significantly associated with poor prognosis of patients with PDAC. Knockdown of and by siRNAs markedly suppressed the migration and invasion abilities of PDAC cells. Moreover, downstream oncogenic signaling was inhibited by ectopic expression of or knockdown of the two integrins. The discovery of anti-tumor miRNAs and miRNA-mediated oncogenic signaling may provide novel therapeutic targets for the treatment of PDAC.