PDF(Pubmed)
Abstract：
Toll-like receptors (TLRs) are critical components to stimulate immune responses against various infections. Recently, TLR agonists have emerged as a promising way to activate anti-tumor immunity. L-pampo, a TLR1/2 and TLR3 agonist, induces humoral and cellular immune responses and also causes cancer cell death. In this study, we investigated the L-pampo-induced signals and delineated their interactions with molecular signaling pathways using RNA-seq in immune cells and colon and prostate cancer cells. We first constructed a template network with differentially expressed genes and influential genes from network propagation using the weighted gene co-expression network analysis. Next, we obtained perturbed modules using the above method and extracted core submodules from them by conducting Walktrap. Finally, we reconstructed the subnetworks of major molecular signals utilizing a shortest path-finding algorithm, TOPAS. Our analysis suggests that TLR signaling activated by L-pampo is transmitted to oxidative phosphorylation (OXPHOS) with reactive oxygen species (ROS) through PI3K-AKT and JAK-STAT only in immune and prostate cancer cells that highly express TLRs. This signal flow may further sensitize prostate cancer to L-pampo due to its high basal expression level of OXPHOS and ROS. Our computational approaches can be applied for inferring underlying molecular mechanisms from complex gene expression profiles.
摘要：
Toll样受体(TLR)是刺激针对各种感染的免疫应答的关键组分。最近,TLR激动剂已成为激活抗肿瘤免疫的有希望的方法。L-Pampo,TLR1/2和TLR3激动剂，诱导体液和细胞免疫反应，也导致癌细胞死亡。在这项研究中,我们在免疫细胞,结肠癌和前列腺癌细胞中使用RNA-seq研究了L-pampo诱导的信号,并描述了它们与分子信号通路的相互作用.我们首先使用加权基因共表达网络分析构建了一个具有差异表达基因和网络传播影响基因的模板网络。接下来,我们使用上述方法获得了扰动模块，并通过进行Walktrap从其中提取了核心子模块。最后,我们利用最短路径查找算法重建了主要分子信号的子网络，TOPAS.我们的分析表明，L-pampo激活的TLR信号仅在高度表达TLR的免疫和前列腺癌细胞中通过PI3K-AKT和JAK-STAT传递给活性氧（ROS）的氧化磷酸化（OXPHOS）。由于其OXPHOS和ROS的高基础表达水平,该信号流可以进一步使前列腺癌对L-pampo敏感。我们的计算方法可用于从复杂的基因表达谱推断潜在的分子机制。
