Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Cancer Sci. 2013 Nov;104(11):1411-9. doi: 10.1111/cas.12240. Epub 2013 Aug 22.
Our recent studies of microRNA (miRNA) expression signatures demonstrated that microRNA-1291 (miR-1291) was significantly downregulated in renal cell carcinoma (RCC) clinical specimens and was a putative tumor-suppressive miRNA in RCC. The aim of the present study was to investigate the functional significance of miR-1291 in cancer cells and to identify novel miR-1291-mediated cancer pathways and target genes in RCC. Expression of miR-1291 was significantly downregulated in RCC tissues compared with adjacent non-cancerous tissues. Restoration of mature miR-1291 in RCC cell lines (A498 and 786-O) revealed significant inhibition of cell proliferation, migration and invasion, suggesting that miR-1291 functioned as a tumor suppressor. To identify miR-1291-mediated molecular pathways and targets, we used gene expression analysis (expression of RCC clinical specimens and miR-1291-transfected A498 cells) and in silico database analysis. Our data demonstrated that 79 signaling pathways were significantly regulated by tumor-suppressive miR-1291 in RCC cells. Moreover, solute career family 2 member 1 (SLC2A1) was a candidate target of miR-1291 regulation. The SLC2A1 gene provides instructions for producing glucose transporter protein type 1 (GLUT1). Luciferase reporter assays showed that miR-1291 directly regulated SLC2A1/GLUT1. In RCC clinical specimens, the expression of SLC2A1/GLUT1 mRNA was significantly higher in cancer tissues than in non-cancerous tissues. A significant inverse correlation was recognized between SLC2A1/GLUT1 and miR-1291 expression (r = -0.55, P < 0.0001). Loss of tumor-suppressive miR-1291 enhanced RCC cell proliferation, migration and invasion through targeting SLC2A1/GLUT1. The identification of novel tumor-suppressive miR-1291-mediated molecular pathways and targets has provided new insights into RCC oncogenesis and metastasis.
我们最近的 miRNA（miRNA）表达谱研究表明，miR-1291 在肾细胞癌（RCC）临床标本中显著下调，是 RCC 中的潜在肿瘤抑制 miRNA。本研究旨在探讨 miR-1291 在癌细胞中的功能意义，并鉴定 RCC 中新型 miR-1291 介导的癌症途径和靶基因。与相邻非癌组织相比，RCC 组织中 miR-1291 的表达显著下调。在 RCC 细胞系（A498 和 786-O）中恢复成熟 miR-1291 显示出对细胞增殖、迁移和侵袭的显著抑制，表明 miR-1291 作为肿瘤抑制因子发挥作用。为了鉴定 miR-1291 介导的分子途径和靶标，我们使用基因表达分析（RCC 临床标本和 miR-1291 转染的 A498 细胞的表达）和计算机数据库分析。我们的数据表明，在 RCC 细胞中，有 79 个信号通路被肿瘤抑制性 miR-1291 显著调节。此外，溶质载体家族 2 成员 1（SLC2A1）是 miR-1291 调节的候选靶标。SLC2A1 基因提供产生葡萄糖转运蛋白 1（GLUT1）的指令。荧光素酶报告基因检测表明，miR-1291 直接调节 SLC2A1/GLUT1。在 RCC 临床标本中，SLC2A1/GLUT1 mRNA 在癌组织中的表达明显高于非癌组织。SLC2A1/GLUT1 与 miR-1291 表达之间存在显著的负相关（r = -0.55，P < 0.0001）。肿瘤抑制性 miR-1291 的丧失通过靶向 SLC2A1/GLUT1 增强了 RCC 细胞的增殖、迁移和侵袭。新型肿瘤抑制性 miR-1291 介导的分子途径和靶标的鉴定为 RCC 发生和转移提供了新的见解。
