Involvement of anti-tumor miR-124-3p and its targets in the pathogenesis of pancreatic ductal adenocarcinoma: direct regulation of ITGA3 and ITGB1 by miR-124-3p.
Involvement of anti-tumor miR-124-3p and its targets in the pathogenesis of pancreatic ductal adenocarcinoma: direct regulation of ITGA3 and ITGB1 by miR-124-3p.
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DOI：
10.18632/oncotarget.25599
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发表时间：
2018-06-22
期刊：
影响因子：
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通讯作者：
Natsugoe S
中科院分区：
文献类型：
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作者：
Idichi T;Seki N;Kurahara H;Fukuhisa H;Toda H;Shimonosono M;Yamada Y;Arai T;Kita Y;Kijima Y;Mataki Y;Maemura K;Natsugoe S
MicroRNA (miRNA) 的独特之处在于单个 miRNA 分子可调节大量 RNA 转录本。因此，异常表达的 miRNA 会破坏癌细胞中严格控制的 RNA 网络。我们的功能筛选显示，胰腺导管腺癌 (PDAC) 组织中 miR-124-3p 的表达下调。在这里，我们的目的是研究 miR-124-3p 在 PDAC 细胞中的抗肿瘤作用，并鉴定 miR-124-3p 介导的致癌信号传导。 miR-124-3p 的异位表达抑制 PDAC 细胞中的癌细胞迁移和侵袭。此外，PDAC 细胞中粘着斑激酶、AKT 和细胞外信号调节激酶的磷酸化降低表明，miR-124-3p 的恢复抑制了致癌信号传导。我们的计算机数据库分析和荧光素酶报告基因检测表明，PDAC 细胞中两种细胞表面基质受体整合素 α3 (ITGA3) 和整合素 β1 (ITGB1) 直接受 miR-124-3p 调节。 PDAC 临床标本中证实了 ITGA3 和 ITGB1 的过度表达。有趣的是，TCGA数据库的大量队列分析表明，ITGA3和ITGB1的高表达与PDAC患者的不良预后显着相关。 siRNA 敲低 ITGA3 和 ITGB1 显着抑制 PDAC 细胞的迁移和侵袭能力。此外，miR-124-3p 的异位表达或两个整合素的敲低可抑制下游致癌信号传导。抗肿瘤 miRNA 和 miRNA 介导的致癌信号传导的发现可能为 PDAC 的治疗提供新的治疗靶点。
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 α3 (ITGA3) and integrin β1 (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.