Functional modules by relating protein interaction networks and gene expression

Genes and proteins are organized on the basis of their particular mutual relations or according to their interactions in cellular and genetic networks. These include metabolic or signaling pathways and protein interaction, regulatory or co-expression networks. Integrating the information from the different types of networks may lead to the notion of a functional network and functional modules. To find these modules, we propose a new technique which is based on collective, multi-body correlations in a genetic network. We calculated the correlation strength of a group of genes (e.g. in the co-expression network) which were identified as members of a module in a different network (e.g. in the protein interaction network) and estimated the probability that this correlation strength was found by chance. Groups of genes with a significant correlation strength in different networks have a high probability that they perform the same function. Here, we propose evaluating the multi-body correlations by applying the superparamagnetic approach. We compare our method to the presently applied mean Pearson correlations and show that our method is more sensitive in revealing functional relationships.     

Identification of novel TGF-β regulated genes with pro-migratory roles

Transforming growth factor-β (TGF-β) signaling plays fundamental roles in the development and homeostasis of somatic cells. Dysregulated TGF-β signaling contributes to cancer progression and relapse to therapies by inducing epithelial-to-mesenchymal transition (EMT), enriching cancer stem cells, and promoting immunosuppression. Although many TGF-β-regulated genes have been identified, only a few datasets were obtained by next-generation sequencing. In this study, we performed RNA-sequencing analysis of MCF10A cells and identified 1166 genes that were upregulated and 861 genes that were downregulated by TGF-β. Gene set enrichment analysis revealed that focal adhesion and metabolic pathways were the top enriched pathways of the up- and downregulated genes, respectively. Genes in these pathways also possess significant predictive value for renal cancers. Moreover, we confirmed that TGF-β induced expression of MICAL1 and 2, and the histone demethylase, KDM7A, and revealed their regulatory roles on TGF-β-induced cell migration. We also show a critical effect of KDM7A in regulating the acetylation of H3K27 on TGF-β-induced genes. In sum, this study identified novel effectors that mediate the pro-migratory role of TGF-β signaling, paving the way for future studies that investigate the function of MICAL family members in cancer and the novel epigenetic mechanisms downstream TGF-β signaling.     

三棱内酯B调控人冠状动脉内皮细胞基因表达谱的生物信息学分析

目的:分析三棱内酯B在人冠状动脉内皮细胞中的表达谱数据集,寻找三棱内酯B调控血管内皮功能的关键作用靶点。方法:基于GEO公共数据库,下载原始表达谱数据集(GSE44598),经过差异基因筛选,功能注释,通路富集,信号通路网络以及基因互作网络分析,找出三棱内酯B对人冠状动脉内皮细胞基因表达谱产生影响的关键基因和信号通路。结果:同对照组相比,三棱内酯B给药组共有5224个基因有显著性差异,包括2628个上调基因和2596个下调基因。基因功能注释和信号通路富集分析表明,差异基因主要参与了细胞周期过程。网络分析显示,MAPK信号通路、细胞周期通路以及PLCG2,PRKACA和ADCY4等为关键信号通路和基因。结论:三棱内酯B通过影响PLCG2,PRKACA,ADCY4等基因的表达,参与MAPK和细胞周期等信号通路,从而调节人冠状内皮细胞的功能。这些关键基因和信号通路是三棱内酯B在心血管疾病治疗应用中潜在的作用靶点。     

Stratification of clear cell renal cell carcinoma by signaling pathway analysis

Investigation of cell signaling pathways in 16 clear cell renal cell carcinomas to identify groups based on commonly shared phosphorylation-driven signaling networks. Using laser capture microdissection and reverse-phase protein arrays, we profiled 75 key nodes spanning signaling pathways important in tumorigenesis. Analysis revealed significantly different (P < 0.05) signaling levels for 27 nodes between two groups of samples, designated A (4 samples; high EGFR, RET, and RASGFR1 levels, converging to activate AKT/mTOR) and B (12 samples; high ERK1/2 and STAT phosphorylation). Group B was further partitioned into groups C (7 samples; elevated expression of LC3B) and D (5 samples; activation of Src and STAT). Network analysis indicated that group A was characterized by signaling pathways related to cell cycle and proliferation, and group B by pathways related to cell death and survival. Homogeneous clear cell renal cell carcinomas could be stratified into at least two major functional groups.     

Bioinformatics role of the WGCNA analysis and co-expression network identifies of prognostic marker in lung cancer

Lung cancer is the most talked about cancer in the world. It is also one of the cancers that currently has a high mortality rate. The aim of our research is to find more effective therapeutic targets and prognostic markers for human lung cancer. First, we download gene expression data from the GEO database. We performed weighted co-expression network analysis on the selected genes, we then constructed scale-free networks and topological overlap matrices, and performed correlation modular analysis with the cancer group. We screened the 200 genes with the highest correlation in the cyan module for functional enrichment analysis and protein interaction network construction, found that most of them focused on cell division, tumor necrosis factor-mediated signaling pathways, cellular redox homeostasis, reactive oxygen species biosynthesis, and other processes, and were related to the cell cycle, apoptosis, HIF-1 signaling pathway, p53 signaling pathway, NF-κB signaling pathway, and several cancer disease pathways are involved. Finally, we used the GEPIA website data to perform survival analysis on some of the genes with GS > 0.6 in the cyan module. CBX3, AHCY, MRPL12, TPGB, TUBG1, KIF11, LRRC59, MRPL17, TMEM106B, ZWINT, TRIP13, and HMMR was identified as an important prognostic factor for lung cancer patients. In summary, we identified 12 mRNAs associated with lung cancer prognosis. Our study contributes to a deeper understanding of the molecular mechanisms of lung cancer and provides new insights into drug use and prognosis.     

Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks

Crosstalk and complexity within signaling pathways and their perturbation by oncogenes limit component-by-component approaches to understanding human disease. Network analysis of how normal and oncogenic signaling can be rewired by drugs may provide opportunities to target tumors with high specificity and efficacy. Using targeted inhibition of oncogenic signaling pathways, combined with DNA-damaging chemotherapy, we report that time-staggered EGFR inhibition, but not simultaneous coadministration, dramatically sensitizes a subset of triple-negative breast cancer cells to genotoxic drugs. Systems-level analysis-using high-density time-dependent measurements of signaling networks, gene expression profiles, and cell phenotypic responses in combination with mathematical modeling-revealed an approach for altering the intrinsic state of the cell through dynamic rewiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death by reactivation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state.     

Role of Src family kinases and N-Myc in spermatogonial stem cell proliferation

Spermatogonial stem cells are required for the initiation of spermatogenesis and the continuous production of sperm. In addition, they can acquire pluripotency and differentiate into derivatives of the three embryonic germ layers when cultured in the appropriate conditions. Therefore, understanding the signaling pathways that lead to self-renewal or differentiation of these cells is of paramount importance for the treatment of infertility, the development of male contraceptives, the treatment of testicular cancers, and ultimately for tissue regeneration. In this report, we studied some of the signaling pathways triggered by glial cell line-derived neurotrophic factor (GDNF), a component of the spermatogonial stem cell niche produced by the somatic Sertoli cells. As model systems, we used primary cultures of mouse spermatogonial stem cells, a mouse spermatogonial stem cell line and freshly isolated testicular tubules. We report here that GDNF promotes spermatogonial stem cell proliferation through activation of members of the Src kinase family, and that these kinases exert their action through a PI3K/Akt-dependent pathway to up-regulate N-myc expression. Thus, to proliferate, spermatogonial stem cells activate mechanisms that are similar to the processes observed in brain stem cells and lung progenitors.     

Interleukin-6 up-regulates the expression of interleukin-15 is associated with MAPKs and PI3-K signaling pathways in the human keratinocyte cell line,HaCaT

Interleukin (IL)-15 is an important inflammatory cytokine and plays a key role in autoimmune disease. At present, IL-15 gene expression and regulation related to many innate immunity trigger signals have been clarified in some specific cell types, but the relationship of IL-6 and IL-15 in the human keratinocyte cell line (HaCaT) is unknown. In this study, we investigated the effect of IL-6 on the expression of IL-15 and selected signaling pathways in HaCaT cells. Results demonstrated that IL-6 up-regulated the expression of IL-15 both at the mRNA and protein levels. Meanwhile, IL-6 was able to activate MAPKs-ERK1/2 and PI3K-AKT signaling pathways. Furthermore, the high expression of IL-15 induced by IL-6 was down-regulated while MAPKs-ERK1/2 and PI3K-AKT signaling pathways were, respectively, blocked by PD98059 and LY294002. These findings indicate that the expression of IL-15 up-regulated by IL-6 is associated with MAPKs-ERK1/2 and PI3K-AKT signaling pathways in HaCaT cells.     

Whole Genome Expression Profiling Reveals a Significant Role for the Cell Junction and Apoptosis Pathways in Breast Cancer Stem Cells

Side population (SP) cells in primary tumors and cell lines are a small cell population, but they are known to enrich cancer stem cells (CSCs). In this study, we isolated SP cells from the human breast cancer cell line MCF7 as a model for studying CSCs. Compared with non-SP cells, MCF7 SP cells had higher mammosphere-formation efficiency (MFE) in vitro and greater tumorigenicity in vivo, suggesting that MCF7 SP cells enrich CSCs. We first directly compared the gene expression profile of SP and non-SP cells from MCF7 cell line. Comparing the expression signature of SP to non-SP cells, we identified 753 differentially expressed genes (DEGs). Using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we identified multiple pathways that were aberrantly regulated in SP compared with non-SP cells. Several pathways, including cell junction and apoptosis, play important roles in breast CSC function. This study demonstrates that combining global gene expression analysis with detailed annotated pathway resources can enhance our understanding of the critical pathways that regulate breast CSCs.     

Cell death pathways in Parkinson’s disease: proximal triggers, distal effectors, and final steps

Parkinson’s disease (PD) is a common neurodegenerative disorder. Neuronal cell death in PD is still poorly understood, despite a wealth of potential pathogenic mechanisms and pathways. Defects in several cellular systems have been implicated as early triggers that start cells down the road toward neuronal death. These include abnormal protein accumulation, particularly of alpha-synuclein; altered protein degradation via multiple pathways; mitochondrial dysfunction; oxidative stress; neuroinflammation; and dysregulated kinase signaling. As dysfunction in these systems mounts, pathways that are more explicitly involved in cell death become recruited. These include JNK signaling, p53 activation, cell cycle re-activation, and signaling through bcl-2 family proteins. Eventually, neurons become overwhelmed and degenerate; however, even the mechanism of final cell death in PD is still unsettled. In this review, we will discuss cell death triggers and effectors that are relevant to PD, highlighting important unresolved issues and implications for the development of neuroprotective therapies.