Yamada Yasutaka, Arai Takayuki, Sugawara Sho, Okato Atsushi, Kato Mayuko, Kojima Satoko, Yamazaki Kazuto, Naya Yukio, Ichikawa Tomohiko, Seki Naohiko
Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan.
Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.
Cancer Sci. 2018 Apr;109(4):1239-1253. doi: 10.1111/cas.13526. Epub 2018 Mar 9.
Recent analyses of our microRNA (miRNA) expression signatures obtained from several types of cancer have provided novel information on their molecular pathology. In renal cell carcinoma (RCC), expression of microRNA-451a (miR-451a) was significantly downregulated in patient specimens and low expression of miR-451a was significantly associated with poor prognosis of RCC patients (P = .00305) based on data in The Cancer Genome Atlas. The aims of the present study were to investigate the antitumor roles of miR-451a and to identify novel oncogenic networks it regulated in RCC cells. Ectopic expression of miR-451a significantly inhibited cancer cell migration and invasion by RCC cell lines, suggesting that miR-451a had antitumor roles. To identify oncogenes regulated by miR-451a in RCC cells, we analyzed genome-wide gene expression data and examined information in in silico databases. A total of 16 oncogenes and were found to be possible targets of miR-451a regulation. Interestingly, high expression of 9 genes (PMM2, CRELD2, CLEC2D, SPC25, BST2, EVL, TBX15, DPYSL3, and NAMPT) was significantly associated with poor prognosis. In this study, we focused on phosphomannomutase 2 (PMM2), which was the most strongly associated with prognosis. Overexpression of PMM2 was detected in clinical specimens and Spearman's rank test indicated a negative correlation between the expression levels of miR-451a and PMM2 (P = .0409). Knockdown of PMM2 in RCC cells inhibited cancer cell migration and invasion, indicating overexpression of PMM2 could promote malignancy. Analytic strategies based on antitumor miRNAs is an effective tool for identification of novel pathways of cancer.
最近对我们从几种癌症类型中获得的微小RNA（miRNA）表达特征进行的分析，为其分子病理学提供了新信息。在肾细胞癌（RCC）中，根据癌症基因组图谱中的数据，患者标本中微小RNA - 451a（miR - 451a）的表达显著下调，且miR - 451a的低表达与RCC患者的不良预后显著相关（P = 0.00305）。本研究的目的是探讨miR - 451a的抗肿瘤作用，并确定其在RCC细胞中调控的新致癌网络。miR - 451a的异位表达显著抑制了RCC细胞系的癌细胞迁移和侵袭，表明miR - 451a具有抗肿瘤作用。为了鉴定RCC细胞中受miR - 451a调控的癌基因，我们分析了全基因组基因表达数据并检查了计算机数据库中的信息。共发现16个癌基因可能是miR - 451a调控的靶标。有趣的是，9个基因（PMM2、CRELD2、CLEC2D、SPC25、BST2、EVL、TBX15、DPYSL3和NAMPT）的高表达与不良预后显著相关。在本研究中，我们重点关注与预后关联最密切的磷酸甘露糖变位酶2（PMM2）。在临床标本中检测到PMM2的过表达，Spearman秩检验表明miR - 451a和PMM2的表达水平之间呈负相关（P = 0.0409）。RCC细胞中PMM2的敲低抑制了癌细胞的迁移和侵袭，表明PMM2的过表达可促进恶性肿瘤。基于抗肿瘤miRNA的分析策略是鉴定癌症新途径的有效工具。
