Tseng Chien-Wei, Lin Chen-Ching, Chen Chiung-Nien, Huang Hsuan-Cheng, Juan Hsueh-Fen
Institute of Molecular and Cellular Biology and Department of Life Science, National Taiwan University, Taipei 106, Taiwan.
BMC Syst Biol. 2011 Jun 26;5:99. doi: 10.1186/1752-0509-5-99.
MicroRNAs (miRNAs) are a class of endogenous, small and highly conserved noncoding RNAs that control gene expression either by degradation of target mRNAs or by inhibition of protein translation. They play important roles in cancer progression. A single miRNA can provoke a chain reaction and further affect protein interaction network (PIN). Therefore, we developed a novel integrative approach to identify the functional roles and the regulated PIN of oncomirs.
We integrated the expression profiles of miRNA and mRNA with the human PIN to reveal miRNA-regulated PIN in specific biological conditions. The potential functions of miRNAs were determined by functional enrichment analysis and the activities of miRNA-regulated PINs were evaluated by the co-expression of protein-protein interactions (PPIs). The function of a specific miRNA, miR-148a, was further examined by clinical data analysis and cell-based experiments. We uncovered several miRNA-regulated networks which were enriched with functions related to cancer progression. One miRNA, miR-148a, was identified and its function is to decrease tumor proliferation and metastasis through its regulated PIN. Furthermore, we found that miR-148a could reduce the invasiveness, migratory and adhesive activities of gastric tumor cells. Most importantly, elevated miR-148a level in gastric cancer tissues was strongly correlated with distant metastasis, organ and peritoneal invasion and reduced survival rate.
This study provides a novel method to identify active oncomirs and their potential functions in gastric cancer progression. The present data suggest that miR-148a could be a potential prognostic biomarker of gastric cancer and function as a tumor suppressor through repressing the activity of its regulated PIN.
微小RNA（miRNA）是一类内源性、短小且高度保守的非编码RNA，其通过降解靶标mRNA或抑制蛋白质翻译来控制基因表达。它们在癌症进展中发挥重要作用。单个miRNA可引发连锁反应并进一步影响蛋白质相互作用网络（PIN）。因此，我们开发了一种新的综合方法来鉴定癌基因miRNA的功能作用及其调控的PIN。
我们将miRNA和mRNA的表达谱与人类PIN整合，以揭示特定生物学条件下miRNA调控的PIN。通过功能富集分析确定miRNA的潜在功能，并通过蛋白质-蛋白质相互作用（PPI）的共表达评估miRNA调控的PIN的活性。通过临床数据分析和基于细胞的实验进一步研究了特定miRNA miR-148a的功能。我们发现了几个富含与癌症进展相关功能的miRNA调控网络。鉴定出一种miRNA miR-148a，其功能是通过其调控的PIN降低肿瘤增殖和转移。此外，我们发现miR-148a可降低胃癌细胞的侵袭性、迁移和粘附活性。最重要的是，胃癌组织中miR-148a水平升高与远处转移、器官和腹膜侵犯以及生存率降低密切相关。
本研究提供了一种鉴定活跃癌基因miRNA及其在胃癌进展中潜在功能的新方法。目前的数据表明，miR-148a可能是胃癌的潜在预后生物标志物，并通过抑制其调控的PIN的活性发挥肿瘤抑制作用。
