Bioinformatics study indicates possible microRNA-regulated pathways in the differentiation of breast cancer

microRNAs (miRNAs) have been reported to be associated with the pathogenesis and progression of breast cancer.However,little is known about the pathways through which miRNAs regulate these processes,e.g.,the interaction between miRNAs and their target genes with regard to different pathological status of breast cancer,such as histological grades.This study investigated the possible roles of miRNAs in the differentiation of histological grades of breast cancer with a computational approach.Based on a microar...     

基于功能网络信息传播预测疾病-miRNAs的关联

为了快速发现与疾病关联的miRNA, 基于功能网络信息传播,提出PMBP算法用于改进随机游走法,使用留一交叉验证评估了算法性能,最后进行案例分析.实验结果表明:对于尚未发现关联miRNA的疾病,随机游走法是失效的,而PMBP以疾病相似性作为先验信息,能够有效预测;对于已经关联miRNA的疾病,PMBP提高了预测性能,AUC值为0.866.对乳腺癌进行案例分析,预测的前50个miRNAs都被证实与乳腺癌相关,体现了PMBP算法的有效性.     

影响口腔癌发生潜在MicroRNAs的生物信息学分析

为获得口腔癌组织和正常组织之间差异表达的miRNAs,从分子水平研究相关的miRNAs在肿瘤发生发展中的作用,从GEO数据库筛选并下载口腔癌及正常组织的基因芯片,运用GEO2R工具分析筛选口腔癌与正常组织间的差异表达miRNAs. 采用FunRich软件对将所得差异miRNAs进行GO功能注释、KEGG信号通路分析. 通过对GSE124566和GSE113956两个芯片数据进行分析,分别筛选得到109、1 079个差异表达miRNAs,分别包括41、673个上调基因和68、406个下调基因,筛选得到共同差异表达miRNAs有30个,其中上调16个,参与的生物过程主要有细胞间通讯等,细胞成分主要有细胞核等,分子功能主要有转录因子活性等;下调14个,参与的生物过程主要有信号转导等,细胞成分主要有细胞质等,分子功能主要有转录因子活性等. 通过对口腔癌芯片数据的生物信息学分析,发现30个差异表达miRNAs是口腔癌发生、发展的重要miRNAs,囊泡介导的转运,核苷酸的代谢等过程. 最后预测出了13 796个靶基因,并通过PPI互作分析筛选出了联系最紧密的10个靶基因.     

A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells

Metastatic progression of cancer is a complex and clinically daunting process. We previously identified a set of human microRNAs (miRNAs) that robustly suppress breast cancer metastasis to lung and bone and which display expression levels that predict human metastasis. Although these findings revealed miRNAs as suppressors of cell-autonomous metastatic phenotypes, the roles of non-coding RNAs in non-cell-autonomous cancer progression processes remain unknown. Here we reveal that endogenous miR-126, an miRNA silenced in a variety of common human cancers, non-cell-autonomously regulates endothelial cell recruitment to metastatic breast cancer cells, in vitro and in vivo. It suppresses metastatic endothelial recruitment, metastatic angiogenesis and metastatic colonization through coordinate targeting of IGFBP2, PITPNC1 and MERTK--novel pro-angiogenic genes and biomarkers of human metastasis. Insulin-like growth factor binding protein 2 (IGFBP2) secreted by metastatic cells recruits endothelia by modulating IGF1-mediated activation of the IGF type-I receptor on endothelial cells; whereas c-Mer tyrosine kinase (MERTK) receptor cleaved from metastatic cells promotes endothelial recruitment by competitively antagonizing the binding of its ligand GAS6 to endothelial MERTK receptors. Co-injection of endothelial cells with breast cancer cells non-cell-autonomously rescues their miR-126-induced metastatic defect, revealing a novel and important role for endothelial interactions in metastatic initiation. Through loss-of-function and epistasis experiments, we delineate an miRNA regulatory network's individual components as novel and cell-extrinsic regulators of endothelial recruitment, angiogenesis and metastatic colonization. We also identify the IGFBP2/IGF1/IGF1R and GAS6/MERTK signalling pathways as regulators of cancer-mediated endothelial recruitment. Our work further reveals endothelial recruitment and endothelial interactions in the tumour microenvironment to be critical features of metastatic breast cancer.     

非小细胞肺癌外周血有核细胞miRNA表达特点研究

miRNA在非小细胞肺癌的发生发展中发挥重要作用,为了解非小细胞肺癌患者外周血有核细胞的miRNA表达特征及其作用,采用第二代高通量测序技术对7例非小细胞肺癌患者和7例对照的外周血有核细胞miRNA表达水平进行检测,比较非小细胞肺癌患者与对照的外周血有核细胞miRNA表达特征,分析两者miRNA表达水平差异情况,共鉴定出非小细胞肺癌患者与对照的外周血有核细胞中有显著表达差异的miRNA 209种,其中肺癌样本miRNA表达上调的有138种,表达下调的有71种.研究结果显示非小细胞肺癌患者与对照样本的外周血有核细胞中miRNA表达具有显著差异,其中部分已被证实参与肿瘤发生、发展等过程.     

乳腺癌-冠心病共享生物标志物筛选

运用生物信息学方法筛选乳腺癌-冠心病标志物,为乳腺癌诱发的冠心病治疗提供潜在的作用靶点.从基因表达数据库(gene expression omnibus,GEO)中下载乳腺癌和冠心病相关表达谱芯片数据,使用GEO2R筛选差异表达基因,依据Venn图交集获取差异共表达基因,通过DAVID网站进行基因功能注释(gene ontology,GO)及京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)生物功能富集分析,STRING网站和Cytoscape 3.7.2软件进行蛋白互作分析.GE-PIA和Kaplan-Meier Plotter进行对乳腺癌患者hub基因mRNA表达水平和预后分析.结果表明:2个数据集筛选得到差异表达基因286个,基于在乳腺癌中mRNA显著性表达水平筛选出45个基因.GO功能富集分析发现差异表达基因主要在泛素蛋白转移酶活性、糖蛋白结合、泛素蛋白连接酶结合等生物学过程发挥作用.KEGG分析显示差异基因主要参与缝隙连接、肾素分泌、5-羟色胺能突触、谷氨酸能突触、血管平滑肌收缩、血小板活化、癌细胞蛋白多糖等多条信号通路.基因mRNA表达水平和预后分析显示NLN、POSTN、MAPT、MYO6、MAP1B、FBXO31、KIT、PIK3R1等8个与冠心病相关的hub基因参与乳腺癌的发生、发展过程.NLN、POSTN、MAPT、MYO6、MAP1B、FBXO31、KIT、PIK3R1可作为检测乳腺癌诱导冠心病的潜在标志物.     

The microcosmos of cancer

The discovery of microRNAs (miRNAs) almost two decades ago established a new paradigm of gene regulation. During the past ten years these tiny non-coding RNAs have been linked to virtually all known physiological and pathological processes, including cancer. In the same way as certain key protein-coding genes, miRNAs can be deregulated in cancer, in which they can function as a group to mark differentiation states or individually as bona fide oncogenes or tumour suppressors. Importantly, miRNA biology can be harnessed experimentally to investigate cancer phenotypes or used therapeutically as a target for drugs or as the drug itself.     

血清miR-25、miR-223和miR-373作为食管鳞癌生物标志物的评价

为了探讨血清miRNA作为诊断标志物的可行性,利用茎环引物进行qRT-PCR,检测了miR-25、miR-223和miR-373在正常人血清、食管鳞癌患者术前和术后第7 d血清、癌组织和癌旁组织的相对表达量.实验结果表明:术前食管鳞癌病人的3种血清miRNA相对表达量高于正常人和手术后第7 d病人,AUC分别为0.794、0.839和0.873,癌组织的这3种miRNA相对表达量高于癌旁组织.这3种miRNA在食管癌患者癌组织的高表达导致血清的这3种miRNA含量增高,因此这3种血清miRNA可以作为候选诊断标志物.     

乳腺癌中CyclinB1表达及临床病理意义

目的:研究细胞周期蛋白B1、癌基因C-erbB-2和雌激素受体(ER)、孕激素受体(PR)在乳腺癌中的表达情况及临床意义.方法:采用S-P免疫组化方法对65例乳腺癌组织和15例乳腺纤维瘤组织进行cy-clinB1、C-erbB-2和ER、PR表达的联合检测.结果:乳腺癌组织中CyclinB1过阳性表达率为84.62%(55/65);乳腺纤维瘤组织CyclinB1表达率为13.3%(2/15);淋巴结转移患者CyclinB1蛋白的过阳性表达率明显高于淋巴结阴性患者;CyclinB1的表达与C-erbB-2表达具有相对的一致性,CyclinB1的阳性高表达伴随ER表达降低,但与PR的表达无显著相关性.结论:CyclinB1的过表达与乳腺癌的发生、发展相关,过表达cy-clinB1可为乳腺癌早期诊断和生物学行为的判断提供帮助.CyclinB1与C-erbB-2和ER、PR的联合检测有利于指导乳腺癌的化疗和判断预后.     

The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells

Syk is a protein tyrosine kinase that is widely expressed in haematopoietic cells. It is involved in coupling activated immunoreceptors to downstream signalling events that mediate diverse cellular responses including proliferation, differentiation and phagocytosis. Syk expression has been reported in cell lines of epithelial origin, but its function in these cells remains unknown. Here we show that Syk is commonly expressed in normal human breast tissue, benign breast lesions and low-tumorigenic breast cancer cell lines. Syk messenger RNA and protein, however, are low or undetectable in invasive breast carcinoma tissue and cell lines. Transfection of wild-type Syk into a Syk-negative breast cancer cell line markedly inhibited its tumour growth and metastasis formation in athymic mice. Conversely, overexpression of a kinase-deficient Syk in a Syk-positive breast cancer cell line significantly increased its tumour incidence and growth. Suppression of tumour growth by the reintroduction of Syk appeared to be the result of aberrant mitosis and cytokinesis. We propose that Syk is a potent modulator of epithelial cell growth and a potential tumour suppressor in human breast carcinomas.     

Dynamic analysis of DNA damage induced miRNAs in colon cancer cells

It is known that microRNAs （miRNAs） expression profile shows substantial changes in cells under DNA damage. Here, we did miRNA microarray and quantitative real-time PCR to comprehensively identify the differentially expressed miRNAs in colon cancer cell lines HCT116 p53＋/＋ and HCT116 p53-/-. Cluster analysis revealed a panel of differentially expressed miRNAs which are regulated by p53 and/or UV-C induced DNA damage. These altered miRNAs tend to be located in chromosomes 13, X and 17. Moreover, pathways enrichment analysis estimated that MAPK pathway, focal adheren pathway, p53 pathway and Wnt pathway were mediated by these miRNAs to exert their functions in DNA damage response. Additionally, we found that miR- 320a, one of the UV-C induced miRNAs, play a role in protecting cells from DNA damage. Taken together, our results show that miRNAs are dynamic regulated in p53- dependent or -independent manners in different cell contexts and different situations following DNA damage.     

线粒体去乙酰化酶SIRT3与衰老疾病

线粒体去乙酰化酶SIRT3是酵母Sir2同源蛋白,通过对线粒体多种蛋白质赖氨酸的去乙酰化修饰,它可以调控多种代谢过程,如脂肪酸的β-氧化作用、TCA循环、氧化磷酸化等.SIRT3可参与氧化应激反应,降低细胞内ROS水平;也可以作为一种肿瘤抑制因子,促进细胞的凋亡.在某些乳腺癌细胞中,SIRT3表达下调.敲除SIRT3或者SIRT3表达降低,可影响与代谢相关的衰老性疾病如心脏疾病、癌症等的发生.论文总结了近年去乙酰化酶SIRT3在代谢调控及癌症细胞凋亡中的分子机制以及SIRT3与心脏疾病、癌症的相互关系,希望为衰老疾病的预防和治疗提供一定的理论基础.     

MicroRNA expression profiles classify human cancers

Recent work has revealed the existence of a class of small non-coding RNA species, known as microRNAs (miRNAs), which have critical functions across various biological processes. Here we use a new, bead-based flow cytometric miRNA expression profiling method to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers. The miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours. We observe a general downregulation of miRNAs in tumours compared with normal tissues. Furthermore, we were able to successfully classify poorly differentiated tumours using miRNA expression profiles, whereas messenger RNA profiles were highly inaccurate when applied to the same samples. These findings highlight the potential of miRNA profiling in cancer diagnosis.     

基于随机矩阵理论分析乳腺癌基因网络

利用随机矩阵理论分析乳腺癌基因微阵列数据,得到乳腺癌基因共表达网络,找出乳腺癌基因共表达网络中重要的增殖模块和免疫模块,并预测基因PMSCL1与乳腺癌细胞的增殖、侵袭及迁移有关,基因CCAN2与乳腺癌细胞的有丝分裂有关,基因SCYA5与乳腺癌细胞的免疫应答有关,基因PRC1、RAB31、INHBA可作为乳腺癌的靶向基因.     

Serum microRNA-155 as a potential biomarker for breast cancer screening

MicroRNAs(miRs) have been shown to be differentially expressed in the serum of cancer patients and controls,and can thus be used as biomarkers for cancer screening.We detected the expression level of miR-155 in the serum of female breast cancer patients and healthy controls to investigate whether serum miR-155 could discriminate patients with early-stage breast cancer.Serum samples were collected from 20 female patients with newly diagnosed breast cancer and 10 healthy controls.Real-time quantitative PCR was used to detect the expression level of miR-155.The expression level of miR-155 was significantly increased in the serum of breast cancer patients compared with in the serum of normal controls.MiR-155 may be useful as a blood-based biomarker for breast cancer screening.     

乳腺癌患者细胞免疫指标的检测及意义

目的检测乳腺癌患者外周血T淋巴细胞总数及CD4~+T细胞、CD8~+T细胞、CD45RA~+T细胞、CD45RO~+T细胞等T淋巴细胞亚群的百分率,用以评价患者的免疫状态.方法选择女性原发性乳腺肿瘤患者50例为病例组,并以病理检查的TNM分期结果做进一步分组,其中乳腺癌Ⅰ期27例,乳腺癌Ⅱ+Ⅲ期23例;选择女性健康体检者40例为健康对照组.应用流式细胞仪,分别检测各组外周血T淋巴细胞亚群的数量,统计分析各组检测结果的差异性.结果乳腺癌Ⅱ+Ⅲ期组CD3~+T细胞和CD4~+T细胞百分率明显低于正常对照组和乳腺癌Ⅰ期组,差异具有统计学意义(P0.05);乳腺癌Ⅰ期组CD45RA~+T细胞明显低于正常对照组,乳腺癌Ⅱ+Ⅲ期组CD45RA~+T细胞明显低于乳腺癌Ⅰ期组,差异具有统计学意义(P0.05);乳腺癌Ⅰ期组CD45RO~+T细胞明显高于正常对照组,乳腺癌Ⅱ+Ⅲ期组CD45RO~+T细胞明显高于乳腺癌Ⅰ期组,差异具有统计学意义(P0.05).结论T细胞亚群检测是评价肿瘤患者细胞免疫功能的重要指标,具有重要的临床应用价值.乳腺癌患者免疫功能与肿瘤恶变的发生、发展、临床分期有一定相关性,随着病情的进展,机体免疫功能呈现下降趋势.     

人类乳腺癌的分子遗传学研究进展

乳腺癌发病机制非常复杂，其中涉及多种基因异常，包括易感基因、癌基因、抑癌基因等，对乳腺癌发生发展中这些基因异常的认识，是乳腺癌防治的关键。我们对近年来乳腺癌发病过程中分子遗传学的研究进展及乳腺癌相关基因的研究现状进行综述。