Dissection of miRNA-miRNA Interaction in Esophageal Squamous Cell Carcinoma

The relationships between miRNAs and their regulatory influences in esophageal carcinoma remain largely unknown. Accumulated evidence suggests that delineation of subpathways within an entire pathway can underlie complex diseases. To analyze the regulation of differentially expressed miRNAs in subpathways of esophageal squamous cell carcinoma (ESCC), we constructed bipartite miRNA and subpathway networks to determine miRNA regulatory influences on subpathways. The miRNA-subpathway network indicated that miRNAs regulate numerous subpathways. Two principal biological networks were derived from the miRNA-subpathway network by the hypergeometric test. This miRNA-miRNA network revealed the co-regulation of subpathways between the upregulated and downregulated miRNAs. Subpathway-subpathway networks characterized scale free, small world, and modular architecture. K-clique analysis revealed co-regulation of subpathways between certain downregulated and upregulated miRNAs. When ESCC patients were grouped according to their expression levels of paired upregulation of miR-31 and downregulation of miR-338-3p, survival time analysis revealed a significant difference based on miR-31-miR-338-3p interaction. These findings can facilitate the understanding of the biological meaning of miRNA-miRNA interactions with either the same or opposite expression trend.食管癌中微RNA（miRNAs）与其调控作用之间的关联仍未被充分阐明。已有大量研究证据表明，解析完整通路中的亚通路（subpathway）可为复杂疾病的机制研究提供基础。为分析食管鳞状细胞癌（esophageal squamous cell carcinoma, ESCC）亚通路中差异表达miRNAs的调控情况，本研究构建了miRNA与亚通路的二分网络，以明确miRNAs对亚通路的调控作用。该miRNA-亚通路网络显示，miRNAs可调控大量亚通路。通过超几何检验从miRNA-亚通路网络中提取得到两个核心生物网络。该miRNA-miRNA网络揭示了上调与下调miRNAs之间对亚通路的共调控关系。亚通路-亚通路网络具有无标度、小世界及模块化的结构特征。K团分析显示，部分下调与上调miRNAs之间存在对亚通路的共调控现象。当根据miR-31上调与miR-338-3p下调的配对表达水平对ESCC患者进行分组时，生存分析显示，基于miR-31-miR-338-3p相互作用的患者生存时间存在显著差异。本研究结果有助于深入理解表达趋势相同或相反的miRNA之间相互作用的生物学意义。