微RNA通过调节上皮间质转化影响肿瘤转移

肿瘤细胞向远处转移受多因素调控, 涉及多个基因, 需要经历一系列连续的、可选择的级联事件。上皮间质转化(Epithelial-mesenchymal transition, EMT)是肿瘤细胞转移中的关键步骤, 但肿瘤发生 EMT的机制至今尚不完全明确。微RNA (MicroRNA, miRNA)是一类内源性、非编码小分子RNA, 可在转录后水平负调控EMT相关基因的表达, 在肿瘤转移中发挥重要作用。文章主要就EMT与肿瘤转移的关系、影响EMT的转录因子, 以及miRNA通过靶向EMT相关的转录因子影响肿瘤转移等方面进行了综述。     

MicroRNA对EMT的调节作用及其与肿瘤侵袭的关系

上皮间质转化（epithelial mesenchymal transition,EMT）是指上皮细胞表型由上皮向间质转换的生物学过程,可发生在生理过程中促进发育、组织愈合和修复。近年对肿瘤的研究发现,EMT与肿瘤的发生发展密切相关。肿瘤细胞发生EMT时,伴随着迁移、侵袭能力的增强,进而促进肿瘤的转移。EMT发生的程度以及相关标志分子的检测还可以用于判断肿瘤转移的危险和评估预后。MicroRNA(miRNA)作为非编码小RNA,通过与特定mRNA的3′UTR结合,在蛋白翻译水平抑制基因表达。本文主要综述目前发现的作用于EMT相关转录因子,如ZEB、SNAIL、TWIST的miRNA,以及在各种肿瘤中的表达情况和作用。其中,有些转录因子和miRNA之间,还存在相互抑制的复杂调节网络,因此,了解miRNA在肿瘤中对EMT的作用可能为肿瘤的治疗提供新的方法和策略。     

miRNA调控恶性黑色素瘤细胞上皮-间充质转化的分子网络及机制

黑色素瘤是一种极易发生转移的恶性皮肤肿瘤,具有高度的致死性。上皮-间充质细胞转化(Epithelial-mesenchymal transition, EMT)在胚胎发育过程中起到非常重要的作用,同时在肿瘤的发生和恶化过程中也扮演着重要的角色。miRNA具有广谱的调节能力,对于肿瘤发生和EMT形成都能产生不同程度的影响。本文整合黑色素瘤细胞系转录组和miRNA组测序数据,在转录组数据中筛选得到参与肿瘤EMT过程的基因,通过Mirsystem软件预测并从miRNA组数据中筛选出与之负相关的11个miRNA,包括miR-130a-3p、miR-130b-3p、miR-125a-5p、miR-30a-3p、miR-195-5p、miR-345-5p、miR-509-3-5p、miR-374a-5p、miR-509-5p、miR-148a-3p和miR-330-3p。经过生物信息学分析miRNA靶基因富集的分子网络和信号途径,发现了两个与细胞发育和细胞间相互作用密切相关的网络,以及多个参与调控EMT过程的信号通路。对11个miRNA进行分子生物学验证,发现miR-195-5p、miR-130a-3p、miR-509-5p和miR-509-3-5p共4个可以调节重要肿瘤基因的miRNA。本研究运用mRNA和miRNA两种转录组的测序数据筛选EMT相关miRNA的方法,为肿瘤多组学数据整合分析提供了新的研究思路,并以期能为肿瘤精准基因组学的发展发挥重要的推进作用。     

MicroRNA调控机制及在脂肪形成中的作用

MicroRNA(miRNA)是近几年发现的一类通过转录后调控机制对基因进行调控的非编码的短链RNA,广泛存在于真核生物。miRNAs在个体时序性发育、细胞增殖分化和凋亡、器官发育、脂肪代谢等许多生物发育过程中起着重要作用,并与肿瘤等疾病发生发展密切相关。近年来对miRNA的研究证实,大量miRNA参与脂肪组织发育相关的许多生物学过程调控。主要涉及miRNA的生物合成、调控靶基因转录后表达的机制(如降解mRNA序列、阻断翻译起始、处理小体转位及翻译激活),及其在脂肪形成中的作用,以期为更好地理解miRNA在脂肪形成中的作用,深入研究脂肪形成的分子机制提供参考。     

MicroRNA调控动物脂肪细胞分化研究进展

脂肪组织不仅在维持机体能量代谢和稳态上发挥重要作用,同时也是重要的内分泌器官。脂肪细胞分化是由间充质干细胞(Mesenchymal stem cells, MSC)向成熟脂肪细胞分化的复杂生理过程,该过程由大量转录因子、激素、信号通路分子协同调控。miRNA作为内源性非编码RNA,主要通过抑制转录后翻译等机制来调控基因表达。近年来越来越多的证据表明miRNA通过调控脂肪细胞分化相关的转录因子和重要信号分子进而影响动物脂肪细胞的分化和脂肪形成。本文对miRNA影响动物白色、棕色和米色脂肪细胞分化的作用机制及其相关调控通路和关键因子进行了归纳总结,以期为肥胖等代谢性疾病的治疗提供一定的理论指导和新的治疗思路。     

MicroRNAs在棕色脂肪细胞分化过程中的作用

MicroRNA(miRNA)是一种非编码的小分子RNA,负性调控转录后基因表达。miRNA在个体时序性发育、细胞增殖分化和凋亡、器官发育、脂肪代谢等许多生物发育过程中起着重要作用。近年来对miRNA的研究证实,miRNA直接或间接影响棕色脂肪组织发育过程中重要转录因子的表达。综述了miRNA调节棕色脂肪细胞分化的最新研究进展。     

昆虫microRNA的研究进展

MicroRNA (miRNA)是20世纪90年代发现的一类由内源基因编码的长度约21~24 nt的非编码单链RNA分子, 广泛存在于真核生物中, 对基因的转录后调控起着非常重要的作用。本文简要介绍了miRNA的产生与调控机制, 同时从昆虫miRNA的发现鉴定、 靶基因预测与功能验证, 昆虫miRNA的序列特征与进化, 果蝇和非果蝇类昆虫miRNA生物学功能以及供昆虫miRNA研究的网络平台等方面对昆虫miRNA的最新进展进行了综述, 旨在为进一步研究昆虫miRNA提供借鉴和参考。对昆虫miRNA的研究表明其参与调控细胞分化、 增殖及凋亡、 胚胎发育、 器官发生、 形态构建、 生理代谢、 环境协调、 行为认知、 免疫防御等几乎所有的生物过程。因此, 深入研究其生物功能、 调控网络和开发应用等可能成为今后一段时间昆虫miRNA研究的重要内容。     

microRNA调控紧密连接功能的研究进展

紧密连接(tight junction,TJ)是构成机体上皮和内皮屏障的重要结构,在维持细胞极性,调控物质扩散,防止毒素、过敏原以及病原体入侵中发挥重要作用。微小RNA(microRNA,miRNA)长度约19～25个核苷酸,是能在转录后水平调控基因表达的内源性非编码RNA。研究表明,miRNA可以调节编码TJ蛋白基因的稳定性和翻译过程,调控TJ功能,影响肠道、呼吸道、脑和视网膜等众多组织器官的屏障功能,从而参与全身多种疾病的发生发展过程。本文就miRNA对TJ的调节作用以及与相关疾病发生发展的关系进行综述,为防治与TJ改变相关的疾病提供新的思路。     

MicroRNA对胚胎干细胞的多能性网络调控

胚胎干细胞(Embryonic stem cells, ESCs)是一类能够无限增殖和诱导分化为多种类型细胞的干细胞。MicroRNA(miRNA)是一类内源性具有调控基因表达功能的非编码RNA, 在ESCs增殖和分化过程中起重要作用。MiRNA可以通过对ESCs多能性网络中的转录因子、细胞周期、表观遗传学、信号转导等方面调控, 促使ESCs维持多能性状态。文章重点综述了miRNA的生成过程、调控ESCs多能性的主要miRNA家族以及miRNA对ESCs多能性网络调控作用等内容。     

上皮间质转化和细胞衰老在肿瘤发生中的共同调节分子

上皮间质转化(epithelial-mesenchymal transition,EMT)和细胞衰老是与肿瘤发生密切相关的两个重要事件。在肿瘤发展过程中,上皮间质转化是促进迁移和侵袭的重要机制。细胞衰老作为一个重要的细胞自主的肿瘤预防机制,可以抑制细胞转化和肿瘤发生。虽然EMT和细胞衰老发生在肿瘤发展过程中的不同时间段,但众多研究发现,多种介导EMT发生的关键信号通路和转录因子能调节细胞衰老过程;同时,参与细胞衰老的经典信号通路也影响着EMT进程。就联系这两种细胞生物学事件的调控因素作一综述。     

去泛素化酶在肿瘤上皮间质转化中的作用

肿瘤的侵袭和转移是加剧肿瘤恶化的主要原因,也是导致患者预后不良的根本原因。近年来大量研究发现,大部分肿瘤的转移都依赖于上皮间质转化(epithelial-mesenchymal transition, EMT)的发生,此外EMT也与肿瘤干性和肿瘤耐药等诸多肿瘤恶性行为密切相关,因此有效的抑制EMT的发生将可能极大的有利于肿瘤的治疗。去泛素化酶(deubiquitinating enzymes, DUBs)的主要功能之一就是通过移除底物蛋白质上泛素链,避免其通过泛素蛋白酶体途径降解,来维持细胞内蛋白质水平的动态平衡。去泛素化酶作为调节蛋白质泛素化修饰的一类重要酶类,其异常表达或酶活性的改变通常都会导致疾病的发生。众多研究发现,部分去泛素化酶在肿瘤侵袭和转移过程中表达失衡,在肿瘤转移的过程中扮演着重要的角色。EMT是指由上皮型细胞转变为间质型细胞的动态细胞生物学过程,在该过程中涉及到例如Snial1、Slug、ZEB1等EMT相关转录因子和细胞表面的例如E-钙黏着蛋白、N-钙黏着蛋白等分子标志物表达水平的变化。这些蛋白质通常具有不稳定性,易被降解等特征。EMT过程的发生,涉及到许多蛋白质稳定性的调节,而去泛素化酶作为一类维持蛋白质稳定的重要酶类,在调节这些蛋白质的稳定性方面发挥着重要的作用。EMT的发生也与TGF-β通路、Wnt通路等细胞内众多信号通路的异常活化密不可分,去泛素化酶通过介导这些信号通路的活化,从而间接的调节EMT发生发展。去泛素化酶通过调节EMT相关分子或EMT相关信号通路等多种方式直接或间接影响EMT进展,因此,通过靶向于去泛素化酶抑制肿瘤的侵袭和转移,将为肿瘤治疗提供新的治疗手段和方案,从而有效的推动肿瘤的治疗。本文主要就去泛素化酶在调节EMT相关分子以及信号通路等方面,阐述去泛素化酶在EMT过程中所发挥的重要作用及其作为肿瘤治疗靶点的可能性。     

Effects and mechanism of miR-23b on glucose-mediated epithelial-to-mesenchymal transition in diabetic nephropathy

MicroRNAs (miRNAs) play important roles in epithelial-to-mesenchymal transition (EMT). Moreover, hyperglycaemia induces damage to renal tubular epithelial cells, which may lead to EMT in diabetic nephropathy. However, the effects of miRNAs on EMT in diabetic nephropathy are poorly understood. In the present study, we found that the level of microRNA-23b (miR-23b) was significantly decreased in high glucose (HG)-induced human kidney proximal tubular epithelial cells (HK2) and in kidney tissues of db/db mice. Overexpression of miR-23b attenuated HG-induced EMT, whereas knockdown of miR-23b induced normal glucose (NG)-mediated EMT in HK2 cells. Mechanistically, miR-23b suppressed EMT in diabetic nephropathy by targeting high mobility group A2 (HMGA2), thereby repressing PI3K-AKT signalling pathway activation. Additionally, HMGA2 knockdown or inhibition of the PI3K-AKT signalling pathway with LY294002 mimicked the effects of miR-23b overexpression on HG-mediated EMT, whereas HMGA2 overexpression or activation of the PI3K-AKT signalling pathway with BpV prevented the effects of miR-23b on HG-mediated EMT. We also confirmed that overexpression of miR-23b alleviated EMT, decreased the expression levels of EMT-related genes, ameliorated renal morphology, glycogen accumulation, fibrotic responses and improved renal functions in db/db mice. Taken together, we showed for the first time that miR-23b acts as a suppressor of EMT in diabetic nephropathy through repressing PI3K-AKT signalling pathway activation by targeting HMGA2, which maybe a potential therapeutic target for diabetes-induced renal dysfunction.     

Subcellular proteomics revealed the epithelial-mesenchymal transition phenotype in lung cancer

Subcellular proteomics was used to compare the protein profiles between human lung adenocarcinoma A549 cells and human bronchial epithelial (HBE) cells. In total, 106 differential proteins were identified and the altered expression levels of partial identified proteins were confirmed by Western blot analysis. Importantly, pathway analysis and biological validation revealed epithelial-mesenchymal transition (EMT) phenotype shift in A549 cells as compared with HBE cells. The EMT phenotype of A549 cells can be increased by self-producing TGF-β1 and significantly decreased by silencing heterogeneous nuclear ribonucleoprotein (hnRNPK) expression. As EMT has been considered as an important event during malignant tumor progression and metastasis, investigating EMT and deciphering the related pathways may lead to more efficient strategies to fight lung cancer progression. By integrating the subcellular proteomic data with EMT-related functional studies, we revealed new insights into the EMT progress of lung carcinogenesis, providing clues for further investigations on the discovery of potential therapeutic targets.     

上皮间质转化在肿瘤侵袭转移中的研究进展

上皮-间质转化（epithelial-mesenchymal transitions,EMT）是上皮细胞向间质细胞转化的现象,不仅参与胚胎发育和正常生理,还参与许多病理过程。同样EMT也参与肿瘤的发生与发展,尤其在促进肿瘤侵袭转移中发挥着重要作用。研究表明,肿瘤细胞借助EMT方式增强肿瘤细胞迁移和运动能力,促进肿瘤的侵袭与转移。在肿瘤侵袭转移历程中,关于EMT发生的分子调控机制研究已取得了良好的进展,但其详细机制仍然不是十分清楚。本文主要介绍生长因子、转录因子、miRNAs、甲基化及其他调控因子在肿瘤EMT中的调控功能,进一步综述EMT在肿瘤侵袭转移中的作用。     

A novel network profiling analysis reveals system changes in epithelial-mesenchymal transition

Patient-specific analysis of molecular networks is a promising strategy for making individual risk predictions and treatment decisions in cancer therapy. Although systems biology allows the gene network of a cell to be reconstructed from clinical gene expression data, traditional methods, such as bayesian networks, only provide an averaged network for all samples. Therefore, these methods cannot reveal patient-specific differences in molecular networks during cancer progression. In this study, we developed a novel statistical method called NetworkProfiler, which infers patient-specific gene regulatory networks for a specific clinical characteristic, such as cancer progression, from gene expression data of cancer patients. We applied NetworkProfiler to microarray gene expression data from 762 cancer cell lines and extracted the system changes that were related to the epithelial-mesenchymal transition (EMT). Out of 1732 possible regulators of E-cadherin, a cell adhesion molecule that modulates the EMT, NetworkProfiler, identified 25 candidate regulators, of which about half have been experimentally verified in the literature. In addition, we used NetworkProfiler to predict EMT-dependent master regulators that enhanced cell adhesion, migration, invasion, and metastasis. In order to further evaluate the performance of NetworkProfiler, we selected Krueppel-like factor 5 (KLF5) from a list of the remaining candidate regulators of E-cadherin and conducted in vitro validation experiments. As a result, we found that knockdown of KLF5 by siRNA significantly decreased E-cadherin expression and induced morphological changes characteristic of EMT. In addition, in vitro experiments of a novel candidate EMT-related microRNA, miR-100, confirmed the involvement of miR-100 in several EMT-related aspects, which was consistent with the predictions obtained by NetworkProfiler.     

Integrated analyses identify the involvement of microRNA-26a in epithelial–mesenchymal transition during idiopathic pulmonary fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and highly lethal fibrotic lung disease with poor treatment and unknown etiology. Emerging evidence suggests that epithelial–mesenchymal transition (EMT) has an important role in repair and scar formation following epithelial injury during pulmonary fibrosis. Although some miRNAs have been shown to be dysregulated in the pathophysiological processes of IPF, limited studies have payed attention on the participation of miRNAs in EMT in lung fibrosis. In our study, we identified and constructed a regulation network of differentially expressed IPF miRNAs and EMT genes. Additionally, we found the downregulation of miR-26a in mice with experimental pulmonary fibrosis. Further studies showed that miR-26a regulated HMGA2, which is a key factor in the process of EMT and had the maximum number of regulating miRNAs in the regulation network. More importantly, inhibition of miR-26a resulted in lung epithelial cells transforming into myofibroblasts in vitro and in vivo, whereas forced expression of miR-26a alleviated TGF-β1- and BLM-induced EMT in A549 cells and in mice, respectively. Taken together, our study deciphered the essential role of miR-26a in the pathogenesis of EMT in pulmonary fibrosis, and suggests that miR-26a may be a potential therapeutic target for IPF.