Involvement of anti-tumor <i>miR-124-3p</i> and its targets in the pathogenesis of pancreatic ductal adenocarcinoma: direct regulation of <i>ITGA3</i> and <i>ITGB1</i> by <i>miR-124-3p</i>

Abstract

// Tetsuya Idichi 1 , Naohiko Seki 2 , Hiroshi Kurahara 1 , Haruhi Fukuhisa 1 , Hiroko Toda 1 , Masataka Shimonosono 1 , Yasutaka Yamada 2 , Takayuki Arai 2 , Yoshiaki Kita 1 , Yuko Kijima 1 , Yuko Mataki 1 , Kosei Maemura 1 and Shoji Natsugoe 1 1 Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan 2 Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan Correspondence to: Naohiko Seki, email: naoseki@faculty.chiba-u.jp Keywords: microRNA; miR-124-3p; ITGA3; ITGB1; pancreatic ductal adenocarcinoma Received: April 07, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: May 24, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: June 22, 2018 ABSTRACT 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 miR-124-3p was downregulated in pancreatic ductal adenocarcinoma (PDAC) tissues. Here, we aimed to investigate the anti-tumor roles of miR-124-3p in PDAC cells and to identify miR-124-3p -mediated oncogenic signaling in this disease. Ectopic expression of miR-124-3p inhibited cancer cell migration and invasion in PDAC cells. Moreover, restoration of miR-124-3p suppressed oncogenic signaling, as demonstrated by reduced phosphorylation of focal adhesion kinase, AKT, and extracellular signal-regulated kinase, in PDAC cells. Our in silico database analyses and luciferase reporter assays showed that two cell-surface matrix receptors, integrin &alpha;3 ( ITGA3 ) and integrin &beta;1 ( ITGB1 ), were directly regulated by miR-124-3p in PDAC cells. Overexpression of ITGA3 and ITGB1 was confirmed in PDAC clinical specimens. Interestingly, a large number of cohort analyses from TCGA database showed that high expressions of ITGA3 and ITGB1 were significantly associated with poor prognosis of patients with PDAC. Knockdown of ITGA3 and ITGB1 by siRNAs markedly suppressed the migration and invasion abilities of PDAC cells. Moreover, downstream oncogenic signaling was inhibited by ectopic expression of miR-124-3p 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.