Khalid Muhammad, Idichi Tetsuya, Seki Naohiko, Wada Masumi, Yamada Yasutaka, Fukuhisa Haruhi, Toda Hiroko, Kita Yoshiaki, Kawasaki Yota, Tanoue Kiyonori, Kurahara Hiroshi, Mataki Yuko, Maemura Kosei, Natsugoe Shoji
Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890-8580, Japan.
Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
Cancers (Basel). 2019 Mar 7;11(3):327. doi: 10.3390/cancers11030327.
Previously, we established a microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) tissues using RNA sequencing and found significantly reduced expression of . Here, we aimed to investigate the functional significance of and to identify target genes involved in PDAC pathogenesis. Cancer cell migration and invasion were significantly inhibited by ectopic expression of in PDAC cells. Comprehensive gene expression analyses and database searches revealed 25 putative targets regulated by in PDAC cells. Among these target genes, high expression levels of , , , , , and were significant predictors of a poor prognosis of patients with PDAC. In this study, we focused on (Rac guanosine triphosphatase-activating protein 1) because its expression was most significantly predictive of PDAC pathogenesis (overall survival rate: = 0.0000548; disease-free survival rate: = 0.0014). Overexpression of was detected in PDAC clinical specimens, and its expression enhanced the migration and invasion of PDAC cells. Moreover, downstream genes affected by (e.g., , , , and ) are involved in PDAC pathogenesis. Our strategy to identify antitumor miRNAs and their target genes will help elucidate the molecular pathogenesis of PDAC.
此前，我们利用RNA测序在胰腺导管腺癌（PDAC）组织中建立了一个微小RNA（miRNA）表达特征，并发现[具体miRNA名称]的表达显著降低。在此，我们旨在研究[具体miRNA名称]的功能意义，并鉴定参与PDAC发病机制的[具体miRNA名称]靶基因。在PDAC细胞中异位表达[具体miRNA名称]可显著抑制癌细胞迁移和侵袭。综合基因表达分析和数据库搜索揭示了25个在PDAC细胞中受[具体miRNA名称]调控的假定靶标。在这些靶基因中，[具体基因名称1]、[具体基因名称2]、[具体基因名称3]、[具体基因名称4]、[具体基因名称5]、[具体基因名称6]和[具体基因名称7]的高表达水平是PDAC患者预后不良的显著预测指标。在本研究中，我们重点关注[具体基因名称8]（Rac鸟苷三磷酸酶激活蛋白1），因为其表达对PDAC发病机制的预测最为显著（总生存率：P = 0.0000548；无病生存率：P = 0.0014）。在PDAC临床标本中检测到[具体基因名称8]的过表达，其表达增强了PDAC细胞的迁移和侵袭。此外，受[具体基因名称8]影响的下游基因（如[具体基因名称9]、[具体基因名称10]、[具体基因名称11]、[具体基因名称12]和[具体基因名称13]）参与了PDAC发病机制。我们鉴定抗肿瘤miRNA及其靶基因的策略将有助于阐明PDAC的分子发病机制。
