采用系统生物学方法分析乳腺癌转移中Runx2对细胞外基质重塑的调节机制

摘要细胞外基质(extracellular matrix,ECM)重塑是癌细胞迁移的关键步骤.本研究基于乳腺癌组织的基因表达谱数据,采用系统生物学方法推测乳腺癌转移中Runx2对细胞外基质重塑的调节机制.采用相关性分析程序分析49例乳腺原发癌和15例淋巴结转移癌组织的基因表达谱数据,筛选与Runx2呈相关性表达的基因,结果得到与ECM重塑相关的候选基因52个,包括ECM成分11个,ECM降解酶及其抑制剂8个,细胞信号分子33个.利用转录调节因子结合序列数据库搜索候选基因启动子区的Runx2结合模序,筛选其中Runx2转录调控的ECM重塑相关基因,并判断可能调节Runx2的上游信号分子;文献检索实验证实的与Runx2有相互调节关系的基因,并基于Runx2上游调控信号分子和下游转录调节基因的分析,构建得到以Runx2为中心的ECM重塑的生物学调控网络.WNT和TGF/BMPs是启动Runx2表达的主要信号通路,Runx2通过转录调节ECM组分、ECM降解酶及其抑制剂和信号分子调节ECM重塑,促进癌细胞完成转移的生物学过程.     

毛果杨固有无序蛋白质基因克隆及胁迫响应分析

为了解毛果杨中固有无序蛋白PtrIDP1（Potri.010G161200.1）基因的相关信息，探究该基因在毛果杨的不同组织、不同逆境胁迫下的表达特性，本研究根据Phytozome数据库中得到的基因全长序列设计引物，克隆得到该基因的目的片段。该基因完整的CDs区序列长度为423 bp，共编码140个氨基酸。构建亚细胞定位表达载体，瞬时转化洋葱表皮细胞，在激光共聚焦显微镜下观察显示，PtrIDP1定位在细胞核内。利用实时定量RT-PCR技术分析了PtrIDP1基因在毛果杨不同组织中的表达特异性和应对非生物胁迫的表达特性。结果表明：PtrIDP1基因在毛果杨的根、茎、叶中均有表达，其中在根部表达量最低，在茎和叶中相对表达量较高。PtrIDP1基因在高盐和干旱胁迫诱导时其表达量的变化模式不同，初步分析认为PtrIDP1基因参与了毛果杨非生物逆境胁迫的响应过程。     

细胞外基质硬度调控间充质干细胞分化

新近研究表叽细胞外基质（extracellularmatrix,ECM）的物理性质,特别是硬度或弹性,能对细胞的黏附、铺展、迁移、增殖、分化和凋亡等多种功能和行为产生重要影响。间充质干细胞（mesenchymalstemcells,MSCs）是组织工程和细胞治疗的理想种子细胞。ECM硬度可诱导MSCs向脂肪、软骨、神经、肌肉和骨等方向分化。该文综合论述了ECM硬度对干细胞分化的影响,涵盖了构建ECM硬度的测量、调控与表征等,不同培养条件下干细胞对硬度的响应和分化以及硬度和其他因素的联合作用;在此基础上,进一步论述了干细胞分化过程中细胞感应ECM硬度并转化为生物学信号的机制和信号通路。该文还总结了在ECM硬度调控干细胞分化行为领域最新的研究进展情况,较为系统地分析了材料学、细胞生物学、分子生物学水平的主要影响因素,并对本领域未来需要重点研究的问题进行了展望。     

NHP2调控肝癌细胞衰老机制的生物信息学分析

为了探讨核糖核蛋白NHP2在肝细胞癌（hepatocellular carcinoma, HCC）中的表达情况,了解其与疾病进展与预后的关系,通过Quick Go、GEPIA 2在线数据库筛选HCC细胞衰老的差异表达基因并确定了研究对象基因NHP2;进一步使用STRING、TIMER 2.0、UALCAN数据库等生物信息学方法分析NHP2在泛癌中的差异表达以及在肝癌和其他泛癌中病理进展过程中的相关性,并预测预后生存关系;使用miRNet数据库分析其靶向miRNAs和lncRNAs,应用Cytoscape v3.8.0绘制可能的CeRNAs调控网络图。结果显示,在线数据库检索到细胞衰老相关生物学过程相关基因113个,HCC差异表达基因2 206个,共有19个差异表达基因参与了肝癌细胞衰老的生物学过程。其中,NHP2在包括HCC的多种癌症中显著高表达,NHP2高表达的肝癌人群预后较差,具有统计学差异。NHP2基因编码的互作蛋白有10个,主要参与了1个信号通路（KEGG信号通路）、6个分子功能（molecular function,MF）、11个细胞组分（cellular component...     

整合受体调控基因表达信息构建细胞通信网络

目的 构建细胞通信网络有助于揭示细胞间协同工作机制、生物学过程和疾病发病机理。目前基于配体-受体相互作用构建细胞通信网络的方法大多只考虑配体和受体的表达信息，忽略了受体对其调控基因的信号传递影响，导致构建的细胞通信网络可靠性较低。鉴于此，本文提出IRRG算法，旨在构建更为准确的细胞通信网络，并挖掘具有生物学意义的细胞通信模式。方法 本文提出了一种整合受体调控基因表达信息构建细胞通信网络的方法（命名为IRRG）。该方法通过随机游走方式计算受体对下游基因的影响得分，进而与配体-受体共表达量结合构建细胞通信网络。结果 使用IRRG构建了小鼠滤泡间表皮（IFE）细胞通信网络并分析了配体-受体对的生物学意义，验证了IRRG计算受体影响得分的稳定性和细胞通信网络构建的可靠性。此外，使用IRRG构建了透明细胞肾细胞癌（ccRCC）的细胞通信网络，挖掘并分析其肿瘤微环境细胞通信模式。结论 IRRG可以构建富有生物学意义并且可靠的细胞通信网络，帮助人们从细胞通信的角度更深入地了解多种生物过程。IRRG算法代码可从GitHub获取：https://github.com/NWPU-903PR/IRRG。     

胎儿早期小鼠无疤痕愈合的数据转录组学分析

已有研究显示,胎龄小于14 d的小鼠胎儿皮肤能够实现无疤痕创伤愈合。深入研究胎儿无疤痕愈合的分子机理,对于伤口护理方法优化与创伤医学的发展至关重要。利用已有数据库进行不同胎龄的小鼠皮肤组织转录组深入挖掘是常用的研究方法之一。从基因表达综合数据库（gene expression omnibus,GEO）在线数据库中寻找适合无疤痕愈合研究的基因表达谱芯片（GSE71619）,其中包含胎龄14 d（E14）、胎龄18 d（E18）和6周龄成年鼠（W6）的皮肤组织样本。分别将无疤痕愈合（E14）与疤痕愈合皮肤组（E18+W6）对比分析,筛选差异表达基因（differential genes,DEGs）,获得了4 654个DEGs（|log2 FC|≥1,P<0.05）。通过维恩图分析和基因功能注释确定了228个候选基因,并分为4个不同的Cluster。进一步重点分析了Cluster 3中涉及的基因：对于E14组,上调基因主要与促进伤口愈合的组织重塑和细胞外基质（extracellular matrix,ECM）形成功能相关。通过蛋白互作网络分析,确定了17个属于胶原家族和成纤维细胞迁移相关基因的关键基因。研究结果揭示了ECM的重塑和成纤维细胞活化在早期妊娠胎儿无疤痕愈合模式中的重要性,并筛选出可能的关键基因,为无疤痕伤口护理和创伤、医美领域提供了重要实验依据。     

MicroRNA 122对肝癌细胞基因表达谱的影响

为研究microRNA（miR-122）对肝癌细胞Hep3B基因表达谱的影响,并探讨其在肝癌发过程中的可能作用,构建了miR-122稳定高表达的Hep3B细胞,利用基因表达谱芯片技术筛选得到和对照组细胞比较的差异表达基因.研究结果显示,2倍以上变化的差异表达基因有490个,其中上调的有345个,下调的有145个.这些基因中有16个与肿瘤发生相关,其它基因涉及细胞周期、信号转导、细胞凋亡和细胞增殖分化等众多生物学过程.这些结果提示,miR-122可能在肝癌发生的过程中发挥作用,并可能与这些差异表达基因密切相关.另外,还结合生物信息学方法,在下调表达的基因中预测了miR-122可能直接作用的靶基因.本研究初步探讨了miR-122在肝癌细胞中的生物学功能,为进一步研究miR-122在肝癌发生中的作用奠定了基础,同时也为miRNA的生物学功能及其作用机制的研究提供了一些参考.     

基质金属蛋白酶家族介绍(英文)

 当细胞外基质 (ECM)组分被破坏时 ,基质金属蛋白酶 (MMPs)影响发育过程并和许多疾病如关节炎及肿瘤相关联 . ECM的正常转换是发育所需要的 . ECM的调节异常却能引起过多的损伤 ,并导致疾病如关节炎 .因此 ,更好地了解 MMP介导的 ECM的水解作用 ,有可能从机理方面为疾病诊断学与治疗学的介入提供依据 .本文介绍了 MMP生物学以及它的 ECM的相关的转换方面的最新进展 .随着新的 MMPs的发现 ,MMP家族正在迅速地扩大 .并且开始向已经确立的基因结构、潜伏期、底物专一性和功能调节方面的范例提出挑战 .即将完成的基因组测序将无容置疑地确定人类 MMPs的有限的数字 .揭示每个 MMP的功能所进行的努力可能标志我们在寻求最终了解细胞与它们的环境之间的相互作用的开始 ,这个过程对于哺乳类物种例如人类的进化是至关重要的 .     

基于生物数据挖掘分析PTX3在非小细胞肺癌中的表达及其与预后的关系

摘要 目的：探讨正五聚素蛋白 3（PTX3）在非小细胞肺癌（NSCLC）中的表达及预后意义。方法：运用 Oncomine、GEPIA分析PTX3在NSCLC组织中的表达情况，通过GEPIA分析PTX3表达与NSCLC患者生存期的相关性，利用CCLE分析 PTX3在 NSCLC细胞系中的表达水平，从CCLE下载NSCLC相关基因芯片并用 R语言筛选 PTX3共表达基因，利用基因本体（GO）和KEGG信号通路分析对 PTX3 相关共表达基因进行功能注释。结果：Oncomine和GEPIA 数据库中分析显示 PTX3 基因在NSCLC组织中显著低表达（P＜0.05）；利用GEPIA数据库生存分析功能发现，PTX3高表达与NSCLC预后呈负相关（P＜0.05）；在CCLE数据库里利用 R 软件共筛选出 105个NSCLC中与PTX3共表达的基因，GO功能富集分析表明，PTX3相关性蛋白主要定位于黏着斑、细胞-基质黏着连接及细胞间连接等，主要参与细胞外基质、细胞外结缔组织、细胞-基质粘附及上皮细胞发育等生物过程。KEGG分析显示PTX3共表达基因主要参与紧密连接、调节肌动蛋白骨架及JAK-STAT信号通路等。结论：PTX3基因在NSCLC组织中低表达，PTX3表达与NSCLC患者预后相关，可能作为NSCLC患者预后评估的分子标志物之一。     

NME1在皮肤黑色素瘤中的表达及其与临床预后的相关性分析

为探讨非转移性细胞1(NME1)基因在皮肤黑色素瘤（SKCM）中的表达及其与临床预后的相关性，通过GEPIA数据库及UALCAN数据库分析NME1在SKCM组织中的表达；通过GSCA数据库、GEPIA数据库和TIMER数据库分析NME1表达水平与SKCM患者总生存率的相关性；通过cBioPortal数据库分析SKCM患者中NME1基因的突变情况及其与患者总生存率的相关性；通过STRING数据库分析可能与NME1相互作用的蛋白，并利用Metascape数据库对其进行功能富集分析；通过TIMER数据库分析SKCM中NME1的表达水平与免疫细胞浸润水平的相关性。结果显示：NME1在SKCM组织中表达水平明显高于正常组织；NME1的高表达与转移性SKCM患者较低的总生存率显著相关；NME1基因变异与SKCM患者总生存率无明显相关性；NME1及其相互作用蛋白主要参与ARF6运输通路、嘌呤代谢、细胞发育的调节、DNA代谢等生物学过程；转移性SKCM中NME1的高表达与CD4+T细胞、CD8+T细胞、中性粒细胞、巨噬细胞和树突状细胞较低的免疫浸润水平相关。本研究表明，在转移性SKCM患者中，NME1...     

生物信息学分析筛选结直肠癌靶基因及评估预后价值

为寻找与结直肠癌发展和预后相关的潜在关键基因及信号通路.从美国国立信息中心NCBI的GEO数据库获得结直肠癌基因表达数据集GSE106582,通过PCA对样本进行分组,利用GEO2R进行综合分析,筛选结直肠癌与癌旁对照组的差异表达基因;通过DAVID在线工具对差异表达基因进行GO本体分析和KEGG通路富集分析,初步分析...     

Urinary bladder matrix promotes site appropriate tissue formation following right ventricle outflow tract repair

The current prevalence and severity of heart defects requiring functional replacement of cardiac tissue pose a serious clinical challenge. Biologic scaffolds are an attractive tissue engineering approach to cardiac repair because they avoid sensitization associated with homograft materials and theoretically possess the potential for growth in similar patterns as surrounding native tissue. Both urinary bladder matrix (UBM) and cardiac ECM (C-ECM) have been previously investigated as scaffolds for cardiac repair with modest success, but have not been compared directly. In other tissue locations, bone marrow derived cells have been shown to play a role in the remodeling process, but this has not been investigated for UBM in the cardiac location, and has never been studied for C-ECM. The objectives of the present study were to compare the effectiveness of an organ-specific C-ECM patch with a commonly used ECM scaffold for myocardial tissue repair of the right ventricle outflow tract (RVOT), and to examine the role of bone marrow derived cells in the remodeling response. A chimeric rat model in which all bone marrow cells express green fluorescent protein (GFP) was generated and used to show the ability of ECM scaffolds derived from the heart and bladder to support cardiac function and cellular growth in the RVOT. The results from this study suggest that urinary bladder matrix may provide a more appropriate substrate for myocardial repair than cardiac derived matrices, as shown by differences in the remodeling responses following implantation, as well as the presence of site appropriate cells and the formation of immature, myocardial tissue.     

Database and interaction network of genes involved in oral cancer: Version II

The oral cancer gene database has been compiled to enable fast retrieval of updated information and role of the genes implicated in oral cancer. The first version of the database with 242 genes was published in Online Journal of Bioinformatics 8(1), 41-44, 2007. In the second version, the database has been enlarged to include 374 genes by adding 132 gene entries. The architecture and format of the database is similar to the earlier version, and includes updated information and external hyperlinks for all the genes. The functional gene interaction network for important biological processes and molecular functions has been rebuilt based on 374 genes using 'String 8.3'. The database is freely available at http://www.actrec.gov.in/OCDB/index.htm and provides the scientist information and external links for the genes involved in oral cancer, interactions between them, and their role in the biology of oral cancer along with clinical relevance.     

The chronic fatigue syndrome: a comparative pathway analysis.

In this paper, we introduce a method to detect pathological pathways of a disease. We aim to identify biological processes rather than single genes affected by the chronic fatigue syndrome (CFS). So far, CFS has neither diagnostic clinical signals nor abnormalities that could be diagnosed by laboratory examinations. It is also unclear if the CFS represents one disease or can be subdivided in different categories. We use information from clinical trials, the gene ontology (GO) database as well as gene expression data to identify undirected dependency graphs (UDGs) representing biological processes according to the GO database. The structural comparison of UDGs of sick versus non-sick patients allows us to make predictions about the modification of pathways due to pathogenesis.     

An Ensemble Method with Hybrid Features to Identify Extracellular Matrix Proteins

The extracellular matrix (ECM) is a dynamic composite of secreted proteins that play important roles in numerous biological processes such as tissue morphogenesis, differentiation and homeostasis. Furthermore, various diseases are caused by the dysfunction of ECM proteins. Therefore, identifying these important ECM proteins may assist in understanding related biological processes and drug development. In view of the serious imbalance in the training dataset, a Random Forest-based ensemble method with hybrid features is developed in this paper to identify ECM proteins. Hybrid features are employed by incorporating sequence composition, physicochemical properties, evolutionary and structural information. The Information Gain Ratio and Incremental Feature Selection (IGR-IFS) methods are adopted to select the optimal features. Finally, the resulting predictor termed IECMP (Identify ECM Proteins) achieves an balanced accuracy of 86.4% using the 10-fold cross-validation on the training dataset, which is much higher than results obtained by other methods (ECMPRED: 71.0%, ECMPP: 77.8%). Moreover, when tested on a common independent dataset, our method also achieves significantly improved performance over ECMPP and ECMPRED. These results indicate that IECMP is an effective method for ECM protein prediction, which has a more balanced prediction capability for positive and negative samples. It is anticipated that the proposed method will provide significant information to fully decipher the molecular mechanisms of ECM-related biological processes and discover candidate drug targets. For public access, we develop a user-friendly web server for ECM protein identification that is freely accessible at http://iecmp.weka.cc.     

Screening and identification of hub genes in pancreatic cancer by integrated bioinformatics analysis

Pancreatic cancer (Pa) is a malignant tumor of the digestive tract with high degree of malignancy, this study aimed to obtain the hub genes in the tumorigenesis of Pa. Microarray datasets GSE15471, GSE16515, and GSE62452 were downloaded from Gene Expression Omnibus (GEO) database, GEO2R was conducted to screen the differentially expressed genes (DEGs), and functional enrichment analyses were carried out by Database for Annotation, Visualization and Integrated Discovery (DAVID). The protein-protein interaction (PPI) network was constructed with the Search Tool for the Retrieval of Interacting Genes (STRING), and the hub genes were identified by Cytoscape. Totally 205 DEGs were identified, consisting of 51 downregulated genes and 154 upregulated genes enriched in Gene Ontology terms including extracellular matrix (ECM) organization, collagen binding, cell adhesion, and pathways associated with ECM-receptor interaction, focal adhesion, and protein digestion. Two modules in the PPI were chosen and biological process analyses showed that the module genes were mainly enriched in ECM and cell adhesion. Twenty-four hub genes were confirmed, the survival analyses from the cBioPortal online platform revealed that topoisomerase (DNA) II α (TOP2A), periostin (POSTN), plasminogen activator, urokinase (PLAU), and versican (VCAN) may be involved in the carcinogenesis and progression of Pa, and the receiver-operating characteristic curves indicated their diagnostic value for Pa. Among them, TOP2A, POSTN, and PLAU have been previously reported as biomarkers for Pa, and far too little attention has been paid to VCAN. Analysis from R2 online platform showed that Pa patients with high VCAN expression were more sensitive to gemcitabine than those with low level, suggesting that VCAN may be an indicator to guide the use of the chemotherapeutic drug. In vitro experiments also showed that the sensitivity of the VCAN siRNA group to gemcitabine was lower than that of the control group. In conclusion, this study discerned hub genes and pathways related to the development of Pa, and VCAN was identified as a novel biomarker for the diagnose and therapy of Pa.     

Biological and functional analysis of statistically significant pathways deregulated in colon cancer by using gene expression profiles

Gene expression profiling offers a great opportunity for studying multi-factor diseases and for understanding the key role of genes in mechanisms which drive a normal cell to a cancer state. Single gene analysis is insufficient to describe the complex perturbations responsible for cancer onset, progression and invasion. A deeper understanding of the mechanisms of tumorigenesis can be reached focusing on deregulation of gene sets or pathways rather than on individual genes. We apply two known and statistically well founded methods for finding pathways and biological processes deregulated in pathological conditions by analyzing gene expression profiles. In particular, we measure the amount of deregulation and assess the statistical significance of predefined pathways belonging to a curated collection (Molecular Signature Database) in a colon cancer data set. We find that pathways strongly involved in different tumors are strictly connected with colon cancer. Moreover, our experimental results show that the study of complex diseases through pathway analysis is able to highlight genes weakly connected to the phenotype which may be difficult to detect by using classical univariate statistics. Our study shows the importance of using gene sets rather than single genes for understanding the main biological processes and pathways involved in colorectal cancer. Our analysis evidences that many of the genes involved in these pathways are strongly associated to colorectal tumorigenesis. In this new perspective, the focus shifts from finding differentially expressed genes to identifying biological processes, cellular functions and pathways perturbed in the phenotypic conditions by analyzing genes co-expressed in a given pathway as a whole, taking into account the possible interactions among them and, more importantly, the correlation of their expression with the phenotypical conditions.     

The KEGG databases at GenomeNet

The Kyoto Encyclopedia of Genes and Genomes (KEGG) is the primary database resource of the Japanese GenomeNet service (http://www.genome.ad.jp/) for understanding higher order functional meanings and utilities of the cell or the organism from its genome information. KEGG consists of the PATHWAY database for the computerized knowledge on molecular interaction networks such as pathways and complexes, the GENES database for the information about genes and proteins generated by genome sequencing projects, and the LIGAND database for the information about chemical compounds and chemical reactions that are relevant to cellular processes. In addition to these three main databases, limited amounts of experimental data for microarray gene expression profiles and yeast two-hybrid systems are stored in the EXPRESSION and BRITE databases, respectively. Furthermore, a new database, named SSDB, is available for exploring the universe of all protein coding genes in the complete genomes and for identifying functional links and ortholog groups. The data objects in the KEGG databases are all represented as graphs and various computational methods are developed to detect graph features that can be related to biological functions. For example, the correlated clusters are graph similarities which can be used to predict a set of genes coding for a pathway or a complex, as summarized in the ortholog group tables, and the cliques in the SSDB graph are used to annotate genes. The KEGG databases are updated daily and made freely available (http://www.genome.ad.jp/kegg/).     

The matrix reorganized: extracellular matrix remodeling and integrin signaling

Via integrins, cells can sense dimensionality and other physical and biochemical properties of the extracellular matrix (ECM). Cells respond differently to two-dimensional substrates and three-dimensional environments, activating distinct signaling pathways for each. Direct integrin signaling and indirect integrin modulation of growth factor and other intracellular signaling pathways regulate ECM remodeling and control subsequent cell behavior and tissue organization. ECM remodeling is critical for many developmental processes, and remodeled ECM contributes to tumorigenesis. These recent advances in the field provide new insights and raise new questions about the mechanisms of ECM synthesis and proteolytic degradation, as well as the roles of integrins and tension in ECM remodeling.