Intestinal gastric cancer (IGC) carcinogenesis results from a complex interplay between environmental and molecular factors, ultimately contributing to disease development. We used integrative bioinformatic analysis to investigate IGC high-throughput molecular data to uncover interactions among differentially expressed genes, microRNAs, and proteins and their roles in IGC. An integrated network was generated based on experimentally validated microRNA-gene/protein interaction data, with three regulatory circuits involved in a complex network contributing to IGC progression. Key regulators were determined, including 23 microRNA and 15 gene/protein hubs. The regulatory circuit networks were associated with hallmarks of cancer, e.g., cell death, apoptosis and the cell cycle, the immune response, and epithelial-to-mesenchymal transition, indicating that different mechanisms of gene regulation impact similar biological functions. Altered expression of hubs was related to the clinicopathological characteristics of IGC patients and showed good performance in discriminating tumors from adjacent nontumor tissues and in relation to T stage and overall survival (OS). Interestingly, expression of upregulated hub hsa-mir-200b and its downregulated target hub gene/protein CFL2 were related not only to pathological T staging and OS but also to changes during IGC carcinogenesis. Our study suggests that regulation of CFL2 by hsa-miR-200b is a dynamic process during tumor progression and that this control plays essential roles in IGC development. Overall, the results indicate that this regulatory interaction is an important component in IGC pathogenesis. Also, we identified a novel molecular interplay between microRNAs, proteins, and genes associated with IGC in a complex biological network and the hubs closely related to IGC carcinogenesis as potential biomarkers.
肠型胃癌（IGC）的发生发展源于环境因素与分子因素之间复杂的相互作用，最终导致疾病进展。本研究采用整合生物信息学分析方法，对IGC高通量分子数据进行分析，以揭示差异表达基因、微小RNA（microRNA）和蛋白质之间的相互作用及其在IGC中的作用。基于实验验证的microRNA-基因/蛋白质相互作用数据构建了整合网络，发现三个调控回路参与构成促进IGC进展的复杂网络。研究确定了关键调控因子，包括23个microRNA枢纽和15个基因/蛋白质枢纽。这些调控回路网络与癌症特征相关，如细胞死亡、凋亡与细胞周期、免疫应答以及上皮-间质转化，表明不同的基因调控机制影响着相似的生物学功能。枢纽分子表达水平的改变与IGC患者的临床病理特征相关，并在区分肿瘤组织与癌旁组织、T分期及总生存期（OS）方面表现出良好的判别效能。值得注意的是，上调枢纽hsa-mir-200b及其下调靶向枢纽基因/蛋白质CFL2的表达不仅与病理T分期和OS相关，还与IGC癌变过程中的动态变化密切相关。本研究表明，hsa-miR-200b对CFL2的调控是肿瘤进展过程中的动态过程，该调控机制在IGC发展中起关键作用。总体而言，研究结果表明这种调控相互作用是IGC发病机制的重要组成部分。此外，我们在复杂生物网络中发现了与IGC相关的microRNA、蛋白质和基因之间新型分子相互作用网络，并鉴定出与IGC癌变密切相关的枢纽分子作为潜在生物标志物。
肿瘤(癌症)患者之家