微小RNA-7在脑部的表达调控机制和对生理功能的影响

微小RNA-7(microRNA-7, miR-7)作为微小RNA家族成员之一,在机体脑部组织中高表达。研究发现,miR-7与机体脑部组织的发育、功能维持和病理进程密切相关,提示其可能是一个对脑部生理、病理发生过程具有重要作用的新调节分子。该文综述了近年来关于miR-7在脑部生理发育和功能中的研究进展,以期为阐明以miR-7为代表的微小RNA分子在脑部发育和生理功能发展过程中的作用机制,以及为脑部相关临床疾病的诊断、治疗新策略的开发提供帮助。     

miR-29家族及其靶基因与恶性肿瘤关系的研究进展

微小RNA-29(microRNA-29,miR-29)家族成员包括miR-29a、miR-29b和miR-29c,是一类与器官纤维化密切相关的小分子RNA。近年研究发现,多种肿瘤组织中存在miR-29s的表达紊乱。miR-29家族不但具有抑癌作用,还有促癌作用,其有望成为肿瘤早期诊断、疗效检测或复发监测的重要新靶标。现就miR-29s及其靶基因在肿瘤细胞增殖、分化、凋亡、侵袭和转移中的作用及其研究进展进行综述。     

靶向调控血管生成素miRNA的筛选和验证

血管生成素是一个重要的促血管生成因子,在细胞增殖、迁移和凋亡等过程中均发挥重要作用,但其具体的分子机制尚待阐明.miRNA是一类长约22 nt的小RNA,在转录后水平调控基因的表达,广泛参与各种生物学过程.本文探索了可直接调控血管生成素表达的miRNA,希望为阐明血管生成素的作用机制提供线索.首先,我们利用数据库预测得到8个可能靶向结合血管生成素mRNA 3′端非编码区的miRNA;然后,用实验方法验证它们与血管生成素的靶向关系,发现miR-1208、miR-196b、miR-296、miR-409-3p、miR-570和miR-641这6个miRNA可以不同程度地抑制血管生成素的mRNA和蛋白质表达水平,但只有miR-196b、miR-296、miR-409-3p和miR-641可以直接结合血管生成素mRNA的3′端非编码区;进而,在血管内皮细胞中分别过表达这4个miRNA,发现miR-196b、miR-409-3p和miR-641可以抑制血管内皮细胞的细胞增殖,而miR-196b、miR-296和miR-409-3p可以抑制血管内皮细胞的管腔形成.以上结果表明,细胞内有多个miRNA调控血管生成素的表达,它们可能协调调节血管生成,抑或在血管生成的不同阶段发挥作用.我们的工作还为“一种mRNA可被多种microRNA调节,而一种microRNA可调节多种mRNA”假说提供了部分证据.     

微小RNA与胃癌的关系

微小RNA（microRNA、miRNA）与胃癌的发生发展可通过调控其靶基因参与的信号传导通路,影响胃癌的发生、侵袭和转移等过程,发挥着类似于癌基因或抑癌基因的作用。目前,已发现多种microR—NA与胃癌关系密切,包括通过调节周期蛋白依赖性蛋白激酶（Cdk）表达影响胃癌细胞增殖的miR-106b-93～25家族、miR-222—221家族和抑制高迁移率族蛋白A2（HMGA2）基因表达抑制胃癌细胞转移的miR-129和let-一7miRNA家族等。另有研究表明,miR-d21和miR-31检测阳性率显著高于血清CEA,可能成为新的胃癌肿瘤标志物。miR-15b和miR-16与胃癌多药耐药的关系也说明microRNA可能成为胃癌治疗新的靶点。     

微RNA miR-29与人类疾病

人类微RNA miR-29包括miR-29a、miR-29b1、miR-29b2和miR-29c。miR-29在胚胎期组织不表达或低表达,而在生物体成熟组织细胞中广泛表达。实验证实的miR-29作用的靶点包括DNMT3A/3B、YY1、Mcl-1、BACE1以及HIV-1病毒等。miR-29与人类疾病密切相关,miR-29在多种肿瘤细胞、心肌梗塞与散发性阿尔茨海默病等病变组织细胞中表达受抑。本文就miR-29基因结构、基因表达与调控、生物学功能以及与疾病发生相关性作一综述。     

miR-20b-5p在肿瘤及其他疾病中的生物学功能

miRNAs是一类非编码的小RNA分子,在多种疾病的发病和治疗中发挥重要作用,可调控细胞增殖、细胞周期、凋亡和迁移等过程中关键基因的表达。miR-20b-5p属于miR-17家族,在多种肿瘤中和非肿瘤性疾病中存在异常表达。在肿瘤中,miR-20b-5p扮演着癌基因或抑癌基因的角色,可通过调控相应靶分子的表达影响肿瘤细胞的增殖、凋亡、侵袭与迁移等生物学行为,进而促进或抑制肿瘤的发生发展。该文对miR-20b-5p在肿瘤和非肿瘤性疾病中的生物学功能和机制进行简要综述。相信随着对miR-20b-5p的功能和机制的深入阐明,miR-20b-5p有望作为多种疾病的诊治靶点。     

动物microRNA-181的功能与应用前景

microRNA(miRNA)是一类短的、进化上高度保守的非蛋白编码RNA, 长度一般为17~25个核苷酸, 通过阻止靶mRNA的翻译或与之互补配对诱导靶基因降解来调控其表达。文章简要总结了microRNA-181(miR-181)在动物细胞增殖、凋亡和分化中的作用和调控机制, 探讨了miR-181对淋巴细胞的增生分化、自身免疫、炎症和抗病毒等方面的免疫调控作用, 并简要分析了miR-181在肿瘤发生发展、诊断、治疗和预后等方面的功能与价值, 最后对miR-181的应用前景进行了探讨。研究miR-181家族成员的功能对于理解生命活动机制、疾病发生发展和找到诊治相关疾病的新方法等都具有重要的意义。     

miR-26家族与肿瘤关系的研究进展

miR-26家族是由miR-26a、miR-26b、miR-1297及miR-4465等序列相似、结构相仿、种子区序列相同(UCAAGUA)的微小RNA(microRNAs,miRNAs)组成。多种组织细胞分化过程中伴有mi R-26家族表达的增加,其异常表达与特发性肺纤维化、原发性胆汁性肝硬化、多发性硬化及阿尔茨海默病等有关。近年研究报道,多种肿瘤组织亦存在mi R-26基因表达紊乱,并与肿瘤的发生发展密切相关。就miR-26家族及其调控的靶基因与肿瘤关系的研究进展进行综述。     

miR-146a/b在动脉粥样硬化疾病中的研究进展

动脉粥样硬化是冠心病等心血管疾病的病理学基础。血管内皮细胞、血管平滑肌细胞和单核/巨噬细胞是参与动脉粥样硬化发生发展的重要因素。microRNA是一类内源性、长约22个核苷酸的非编码RNA,能够参与调控众多生物学过程,与许多疾病密切相关。miR-146a/b广泛表达于血管内皮细胞、平滑肌细胞和单核/巨噬细胞中,并通过作用于不同靶基因发挥其多样化的生物学功能,参与调控动脉粥样硬化。现就miR-146a/b与动脉粥样硬化发生发展的关系作一综述。     

miR-223促进小鼠胚胎成纤维细胞复制性衰老

微小RNA（MicroRNAs（或miRNAs）是作为强大的基因表达调控子,广泛参与多种生命过程,在细胞衰老进程中的作用也日益受到关注。miR-223是一个典型的抑癌基因,可显著抑制细胞增殖能力。此外,miR-223与阿尔茨海默症、心血管疾病以及类风湿性关节炎等衰老相关疾病的发生发展密切相关。尽管如此,miR-223在细胞衰老进程中的作用及其分子机制尚未见报道。本研究通过连续传代建立了小鼠胚胎成纤维细胞（MEF细胞）的复制性衰老模型,并利用荧光定量qRT-PCR检测发现,miR-223在衰老MEF细胞中的表达水平显著上调。随后,通过转染miR-223模拟物Agomir-223在MEF细胞中过表达miR-223,结果显示过表达miR-223可显著促进MEF细胞的衰老表型并抑制其增殖能力,而抑制miR-223的表达可延缓MEF细胞的复制性衰老进程。进一步利用生物信息学方法预测获得多个miR-223的候选衰老相关靶基因,包括Rasa1、Ddit4和Smad1等。然而双萤光素酶报告系统结果显示,miR-223并不显著影响其萤光强度,表明它们很可能并不是miR-223的下游靶基因。综上所述,miR-223可显著促进MEF细胞复制性衰老,然而其调节细胞衰老进程的分子机制依然有待深入研究。     

miR-15b/16-2 Regulates Factors That Promote p53 Phosphorylation and Augments the DNA Damage Response following Radiation in the Lung

MicroRNAs (miRNAs) are regulatory RNAs frequently dysregulated in disease and following cellular stress. Investigators have described changes in miR-15b expression following exposure to several stress-inducing anticancer agents, including ionizing radiation (IR), etoposide, and hydrogen peroxide. However, the role for miR-15b as a mediator of cellular injury in organs such as the lung has yet to be explored. In this study, we examined miR-15b expression patterns as well as its potential role in DNA damage and repair in the setting of IR exposure. We showed that miR-15b is up-regulated in a dose- and time-dependent manner in human bronchial epithelial cells following IR. miR-15b expression was highest after 2 h of IR and decreased gradually. Survival rates following IR were also higher in miR-15b/16-2-overexpressing cells. Cell cycle arrest in G₂/M phase and an increased DNA repair response were observed in IR-exposed miR-15b/16-2 stable cells. We observed an up-regulation of components of the ataxia telangiectasia mutated (ATM)/Chek1/p53 pathway in miR-15b/16-2-overexpressing cells after IR. Moreover, a pathway-based PCR expression array of genes demonstrated that miR-15b/16-2 overexpression significantly induced the expression of genes involved in ATM/ataxia telangiectasia and Rad-3-related (ATR) signaling, apoptosis, the cell cycle, and DNA repair pathways. Here we demonstrated a novel biological link between miR-15b and DNA damage and cellular protection in lung cells. We identified Wip1 (PPM1D) as a functional target for miR-15b and determined that miR-15b induction of the DNA damage response is partially dependent upon suppression of Wip1. Our study suggests that miR-15b/Wip1 could be a potential therapeutic target in radiation-induced lung disease.     

The MicroRNA-130/301 Family Controls Vasoconstriction in Pulmonary Hypertension

Pulmonary hypertension (PH) is a complex disorder, spanning several known vascular cell types. Recently, we identified the microRNA-130/301 (miR-130/301) family as a regulator of multiple pro-proliferative pathways in PH, but the true breadth of influence of the miR-130/301 family across cell types in PH may be even more extensive. Here, we employed targeted network theory to identify additional pathogenic pathways regulated by miR-130/301, including those involving vasomotor tone. Guided by these predictions, we demonstrated, via gain- and loss-of-function experimentation in vitro and in vivo, that miR-130/301-specific control of the peroxisome proliferator-activated receptor γ regulates a panel of vasoactive factors communicating between diseased pulmonary vascular endothelial and smooth muscle cells. Of these, the vasoconstrictive factor endothelin-1 serves as an integral point of communication between the miR-130/301-peroxisome proliferator-activated receptor γ axis in endothelial cells and contractile function in smooth muscle cells. Thus, resulting from an in silico analysis of the architecture of the PH disease gene network coupled with molecular experimentation in vivo, these findings clarify the expanded role of the miR-130/301 family in the global regulation of PH. They further emphasize the importance of molecular cross-talk among the diverse cellular populations involved in PH.     

MicroRNA-147b Regulates Vascular Endothelial Barrier Function by Targeting ADAM15 Expression

A disintegrin and metalloproteinase15 (ADAM15) has been shown to be upregulated and mediate endothelial hyperpermeability during inflammation and sepsis. This molecule contains multiple functional domains with the ability to modulate diverse cellular processes including cell adhesion, extracellular matrix degradation, and ectodomain shedding of transmembrane proteins. These characteristics make ADAM15 an attractive therapeutic target in various diseases. The lack of pharmacological inhibitors specific to ADAM15 prompted our efforts to identify biological or molecular tools to alter its expression for further studying its function and therapeutic implications. The goal of this study was to determine if ADAM15-targeting microRNAs altered ADAM15-induced endothelial barrier dysfunction during septic challenge by bacterial lipopolysaccharide (LPS). An in silico analysis followed by luciferase reporter assay in human vascular endothelial cells identified miR-147b with the ability to target the 3′ UTR of ADAM15. Transfection with a miR-147b mimic led to decreased total, as well as cell surface expression of ADAM15 in endothelial cells, while miR-147b antagomir produced an opposite effect. Functionally, LPS-induced endothelial barrier dysfunction, evidenced by a reduction in transendothelial electric resistance and increase in albumin flux across endothelial monolayers, was attenuated in cells treated with miR-147b mimics. In contrast, miR-147b antagomir exerted a permeability-increasing effect in vascular endothelial cells similar to that caused by LPS. Taken together, these data suggest the potential role of miR147b in regulating endothelial barrier function by targeting ADAM15 expression.     

miR-20a and miR-290, multi-faceted players with a role in tumourigenesis and senescence

Expression of microRNAs changes markedly in tumours and evidence indicates that they are causatively related to tumourigenesis, behaving as tumour suppressor microRNAs or onco microRNAs; in some cases they can behave as both depending on the type of cancer. Some tumour suppressor microRNAs appear to be an integral part of the p53 and Retinoblastoma (RB) network, the main regulatory pathways controlling senescence, a major tumour suppressor mechanism. The INK4a/ARF locus which codifies for two proteins, p19ARF and p16INK4a, plays a central role in senescence by controlling both p53 and RB. Recent evidence shows that the proto-oncogene leukaemia/lymphoma related factor, a p19ARF specific repressor, is controlled by miRNAs and that miRNAs, in particular miR-20a and miR-290, are causatively involved in mouse embryo fibroblasts (MEF) senescence in culture. Intriguingly, both miR-20a, member of the oncogenic miR-17-92 cluster, and miR-290, belonging to the miR-290-295 cluster, are highly expressed in embryonic stem (ES) cells. The pro-senescence role of miR-20a and miR-290 in MEF is apparently in contrast with their proliferative role in tumour and ES cells. We propose that miRNAs may exert opposing functions depending on the miRNAs repertoire as well as target/s level/s present in different cellular contexts, suggesting the importance of evaluating miRNAs activity in diverse genetic settings before their therapeutic use as tumour suppressors.     

MicroRNA miR-21 regulates the metastatic behavior of B16 melanoma cells

MicroRNA-21 (miR-21) is overexpressed in many human tumors and has been linked to various cellular processes altered in cancer. miR-21 is also up-regulated by a number of inflammatory agents, including IFN, which is of particular interest considering the close relationship between inflammation and cancer. Because miR-21 appears to be overexpressed in human melanoma, we examined the role of miR-21 in cancer development and metastasis in B16 mouse melanoma cells. We found that miR-21 is a member of an IFN-induced miRNA subset that requires STAT3 activation. To characterize the role of miR-21 in melanoma behavior, we transduced B16 cells with lentivirus encoding a miR-21 antagomir and isolated miR-21 knockdown B16 cells. miR-21 knockdown or IFN treatment alone inhibited B16 cell proliferation and migration in vitro, and in combination they had an enhanced effect. Moreover, miR-21 knockdown sensitized B16 cells to IFN-induced apoptosis. In B16 cells miR-21 targeted tumor suppressor (PTEN and PDCD4) and antiproliferative (BTG2) proteins. To characterize the role of miR-21 in vivo, empty vector- and antagomiR-21-transduced B16 melanoma cells were injected via tail vein into syngeneic C57BL/6 mice. Although empty vector-transduced B16 cells produced large lung metastases, miR-21 knockdown cells only formed small lung lesions. Importantly, miR-21 knockdown tumor-bearing mice exhibited prolonged survival compared with empty vector tumor-bearing mice. Thus, miR-21 regulates the metastatic behavior of B16 melanoma cells by promoting cell proliferation, survival, and migration/invasion as well as by suppressing IFN action, providing important new insights into the role of miR-21 in melanoma.