循环miRNA 表达谱在肺癌早期诊断、判断预后和指导化疗中的应用

MicroRNA(miRNA)是一种高保守,长度大概21-23个核苷酸,非蛋白编码RNA,起着调节基因表达的作用。近年来有关miRNA与肺癌的关系已经得到证实,并且成为当前研究的热点。miRNA能整体调节基因表达,这使得miRNA表达谱在作为生物信号方面比蛋白编码基因更具有提示作用。最近发现miRNA以被保护的状态存在于循环血液中,这使得miRNA表达的发现具有非侵袭性、重现性以及易检测性。研究显示血浆miRNA表达谱可作为肺癌生物信号分子,在肺癌早期诊断、判断预后和指导化疗药物应用等方面具有重要作用。本文将对血浆miRNA与肺癌的研究进展,以及在肺癌早期诊断、判断预后和指导化疗药物应用等方面作一综述。     

MiRNA在乳腺癌转移中的作用

乳腺癌是女性高发的恶性肿瘤之一,远处转移是患者致死的最重要原因。目前乳腺癌转移的具体机制尚未明确。乳腺癌转移相关微RNA(microRNA,miRNA)的发现,为我们研究乳腺癌转移提供了新的思路。miRNA参与包括乳腺癌细胞的生长、凋亡、迁移、侵袭等肿瘤发生、发展过程,进而实现对乳腺癌转移的调控。有些miRNA在乳腺癌转移过程中起促进作用;有些则起抑制作用;还有一些miRNA的功能存在争议。本文将主要着眼于近年来发现的这几类miRNA在乳腺癌转移中所起的作用,并对其将来在乳腺癌诊断、预后判断及治疗中的应用做一综述。     

Circulating DNA in the blood and its application in medical diagnosis

Circulating nucleic acids were discovered more than 30 years ago, but did not attract much attention until the past decade. This review summarizes the data on the sources of extracellular DNA circulating in the blood, features of its circulation, and pathways of its removal. The possibility of using circulating DNA in medical diagnosis is discussed.     

结肠癌中核内miRNA的激活调控作用研究

为了探究增强子介导的核内miRNA在结肠癌发生中的作用,本研究筛选了结肠癌中的差异表达的miRNA数据、结肠的特异性增强子数据、结肠癌中差异表达基因数据,利用细胞核内miRNA靶向增强子预测算法,筛选miRNA调控的结肠特异性增强子;利用增强子靶基因预测数据,筛选核内miRNA调控的差异表达靶基因,并且构建核内miRNA-靶基因网络,并通过网络的分析和筛选获得结肠癌中关键的致病基因,同时对网络中的靶基因进行GO的功能注释。结果表明,我们所构建的核内miRNA-激活调控靶基因网络包含miRNA-靶基因关系对2 121个,259个节点,其中包含34个下调基因、183个上调的基因,7个下调的miRNA,35个上调的miRNA。而后我们分析了网络进行的节点度的整体分布情况,发现网络中大部分的节点的度都是小于10的,仅有少量miRNA结合和部分的差异表达基因节点的度大于10。核内miRNA主要通过激活调控了一些应激反应相关的功能和,同时,抑制调控了细胞周期、细胞凋亡、细胞死亡巨噬细胞代谢等相关功能,通过激活和抑制相关功能诱发结肠癌的发生。从核内miRNA的激活调控角度研究结肠癌的发病机制,是对原有细胞浆中miRNA抑制调控机制的补充,也为结肠癌的系统研究提供了新的视野。     

循环长链非编码RNA作为生物标志物在肿瘤分子诊断中的应用

长链非编码RNA(Long noncoding RNA,lncRNA)被发现广泛参与基因表达、表观遗传调控和X染色体失活等重要生命过程,还与肿瘤发生和发展密切相关。lncRNA可能以微泡、外泌体或蛋白质复合物形式进入人体循环系统中,形成循环lncRNA稳定而广泛存在于血液、尿液等体液中。文中简要回顾了近来关于循环lncRNA的来源,以及作为生物标志物的检测方法,着重总结分析了循环lncRNA作为潜在肿瘤生物标志物在肺癌、乳腺癌、胃癌、肝癌、结直肠癌和前列腺癌等常见恶性肿瘤中的早期诊断价值。与传统生物标志物相比,循环lncRNA具有作为新型生物标志物的独特优势和临床应用价值。     

Circulating microRNA breast cancer biomarker detection in patient sera with surface plasmon resonance imaging biosensor

In this article, we report for the first time, the detection of circulating miRNA as a breast cancer biomarker in patient sera using surface plasmon resonance imaging biosensor. The advantage of this approach lies in the rapid, label-free and sensitive detection. The sensor excites plasmonic resonance on the gold sensor surface and specific DNA-miRNA molecular bindings elucidate responses in the plasmonic resonance image. Experiments of detecting synthetic miRNA molecules (miR-1249) were performed and the sensor resolution was found to be 63.5 nM. The sensor was further applied to screen 17 patient serum samples from National Cancer Centre Singapore and Tan Tock Seng Hospital. Sensor intensity response was found to differ by 20% between malignant and benign cases and thus forms, a potential and an important metric in distinguishing benignity and malignancy.     

microRNAs in breast cancer: regulatory roles governing the hallmarks of cancer

A large number of etiological factors and the complexity of breast cancers present challenges for prevention and treatment. Recently, the emergence of microRNAs (miRNAs) as cancer biomarkers has added an extra dimension to the ‘molecular signatures’ of breast cancer. Bioinformatic analyses indicate that each miRNA can regulate hundreds of target genes and could serve functionally as ‘oncogenes’ or ‘tumour suppressor’ genes, and co‐ordinate multiple cellular processes relevant to cancer progression. A number of studies have shown that miRNAs play important roles in breast tumorigenesis, metastasis, proliferation and differentiation of breast cancer cells. This review provides a comprehensive overview of miRNAs with established functional relevance in breast cancer, their established target genes and resulting cellular phenotype. The role and application of circulating miRNAs in breast cancer is also discussed. Furthermore, we summarize the role of miRNAs in the hallmarks of breast cancer, as well as the possibility of using miRNAs as potential biomarkers for detection of breast cancer.     

miRNA在白血病中的研究进展

microRNA(miRNA)是一种小分子非编码RNA,在细胞增殖、分化和凋亡等多种生理过程中发挥着重要作用.白血病相关miRNA研究进展迅速,并呈现了miRNA介导白血病瘤细胞增殖、分化和凋亡的调控网络.深入了解相关miRNA与白血病的发生、发展关系将为白血病的治疗开辟新途径.     

冠心病相关循环miRNA

冠心病诊断中最主要的挑战就是从常规的血液样本中鉴定出可靠的临床生物标志物.循环miRNA是一种可以稳定存在于体液中的小分子RNA,具有较高的组织、疾病特异性及敏感性,具有作为新的冠心病非侵入性生物标志物的潜力.通过综述血液样本（全血、血浆、血清、外周血单核细胞（PBMC）、内皮祖细胞（EPC）及血小板）中冠心病相关循环miRNA,及探讨循环miRNA研究中存在的一些问题,为未来筛选出真正具有临床应用价值的循环miRNA生物标志物奠定基础.     

A genome‐scale screen reveals context‐dependent ovarian cancer sensitivity to miRNA overexpression

Large‐scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease. Thus, restoration of miRNA activity may represent a common vulnerability among diverse EOC oncogenotypes. To test this, we employed genome‐scale, gain‐of‐function, miRNA mimic toxicity screens in a large, diverse spectrum of EOC cell lines. We found that all cell lines responded to at least some miRNA mimics, but that the nature of the miRNA mimics provoking a response was highly selective within the panel. These selective toxicity profiles were leveraged to define modes of action and molecular response indicators for miRNA mimics with tumor‐suppressive characteristics in vivo. A mechanistic principle emerging from this analysis was sensitivity of EOC to miRNA‐mediated release of cell fate specification programs, loss of which may be a prerequisite for development of this disease.     

基于数据库中肺纤维化miRNA及肺癌mRNA芯片资料分析筛查肺癌的潜在治疗靶点

肺癌严重危害人类健康,患者预后较差。肺纤维化是肺癌的危险因素之一,与肺癌的发病机制存在一定关系。肺纤维化中失调的微小RNA(microRNA, miRNA)在肺癌发生发展过程中发挥着重要作用。本研究使用基因表达综合数据库(Gene Expression Omnibus, GEO)中肺纤维化miRNA及肺癌mRNA的芯片数据,利用GEO2R筛选肺纤维化差异miRNA与肺癌差异基因、miRWalk预测miRNA靶基因、STRING分析互作关系、WebGestalt进行GO与KEGG分析、GEPIA分析基因对患者生存的影响,最终获得SNRPE、PIK3R1、ARHGEF6等潜在的肺癌治疗靶点。通过对这些潜在靶点的认识进一步了解肺癌的发生发展机制,为肺癌的临床治疗贡献新的思路。     

MicroRNA与膀胱癌

MicroRNA(miRNA)是一类21～23个核苷酸长度的单链非编码小分子RNA,在转录后水平调节基因表达,从而实现对组织发生、个体发育及肿瘤发生等生理病理过程的调节作用。膀胱癌是国人泌尿系统中最常见的肿瘤。研究表明,miRNA参与了膀胱癌的发生、发展,一些差异表达miRNA有望成为膀胱癌诊断、治疗的靶点。该文就miRNA在膀胱癌发病机理、诊断、治疗等方面的研究进展作一综述。     

Expression profile of lncRNAs and miRNAs in esophageal cancer: Implications in diagnosis,prognosis, and therapeutic response

Esophageal cancer is the seventh most common cancer worldwide. Although a number of environmental and lifestyle-related risk factors have been identified for this kind of cancer, the exact molecular mechanisms of tumor evolution have not been clarified yet. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) as important regulators of gene expression and chromatin configuration have essential roles in the pathogenesis of esophageal cancer. They have been shown to alter the function of cancer-related signaling pathways such as phosphoinositide 3-kinase/protein kinase B and Wnt pathway, thus they might modulate the response of patients to pathway-targeted therapies. Moreover, a number of lncRNAs, such as AFAP1-AS1, UCA1, HOTAIR, LOC285194, and TUSC7, are involved in conferring chemoresistant/radioresistant in esophageal cancer cells. A complex network of interaction exists between lncRNAs and miRNAs in the context of esophageal cancer. Finally, various panels of lncRNAs and miRNAs have been introduced that can predict the survival of esophageal cancer patients. In this review article, we summarize the recent findings regarding the role of miRNAs and lncRNAs in the pathogenesis of esophageal cancer with the special focus on their regulatory roles on signaling pathways, their potential as diagnostic/prognostic markers, and their relevance with therapeutic response.     

miRNA expression profiling for identification of potential breast cancer biomarkers

To identify micro RNA (miRNA) biomarker candidates for early detection of breast cancer and detection of minimal residual breast cancer, we performed miRNA expression profiling in pooled RNA samples from breast tumors, and from bone marrow mononuclear cells, peripheral blood mononuclear cells and plasma from healthy controls. We found substantially higher levels of five miRNAs in the breast tumors compared to the normal samples. However, validation of these miRNA levels, and seven other candidates selected from the literature, in individual samples from healthy controls and patients with non-metastatic breast cancer did not suggest further examination of their biomarker potential.     

miRNA在肿瘤分子诊断和治疗中的研究进展

微小RNA(miRNA)是一类真核生物内源性、长18~25个核苷酸的小分子单链RNA,能够通过与靶mRNA特异性的碱基互补配对引起靶mRNA的降解或者翻译抑制,miRNA调节的紊乱将对细胞产生重要的影响。在肿瘤中,抑癌性miRNA的缺失会增加其靶向致癌基因的表达,而致癌miRNA(被称为oncomirs)的升高能够降低其靶向肿瘤抑制基因的表达。这一认识使得应用靶向致癌性miRNA与恢复抑癌性miRNA的功能来治疗肿瘤成为可能。随着临床研究的不断深入,miRNA不断为肿瘤分子诊断和治疗提供新的思路和治疗手段。     

The use of miRNA microarrays for the analysis of cancer samples with global miRNA decrease

Recent studies have established that mutations or deletions in microRNA (miRNA) processing enzymes resulting in a global decrease of miRNA expression are frequent across cancers and can be associated with a poorer prognosis. While very popular in miRNA profiling studies, it remains unclear whether miRNA microarrays are suited or not to accurately detecting global miRNA decreases seen in cancers. In this work, we analyzed the miRNA profiles of samples with global miRNA decreases using Affymetrix miRNA microarrays following the inducible genetic deletion of Dicer1. Surprisingly, up to a third of deregulated miRNAs identified upon Dicer1 depletion were found to be up-regulated following standard robust multichip average (RMA) background correction and quantile normalization, indicative of normalization bias. Our comparisons of five preprocess steps performed at the probe level demonstrated that the use of cyclic loess relying on non-miRNA small RNAs present on the Affymetrix platform significantly improved specificity and sensitivity of detection of decreased miRNAs. These findings were validated in samples from patients with prostate cancer, where conjugation of robust normal-exponential background correction with cyclic loess normalization and array weights correctly identified the greatest number of decreased miRNAs, and the lowest amount of false-positive up-regulated miRNAs. These findings highlight the importance of miRNA microarray normalization for the detection of miRNAs that are truly differentially expressed and suggest that the use of cyclic loess based on non-miRNA small RNAs can help to improve the sensitivity and specificity of miRNA profiling in cancer samples with global miRNA decrease.     

Role of miRNA and miRNA processing factors in development and disease

Mature microRNAs (miRNAs) are single-stranded RNA molecules of 17-24 nucleotides (nt) in length that are encoded in the genomes of plants and animals. The seminal discoveries of miRNA made in C. elegans have led the way to the rampant discoveries being made today in this field. Since each miRNA is predicted and in some cases confirmed to regulate multiple genes, the potential regulatory circuitry afforded by miRNAs is thought to be enormous and could amount to regulation of >30% of all human genes. Due to the sequences of many of the miRNAs being highly homologous among organisms, the huge potential of miRNAs to regulate gene expression, and the hints of miRNAs being useful in both diagnostics and therapeutics, it is no wonder these small RNAs are gaining such popularity in both the academic and industrial settings. It is now becoming clear that the miRNA gene class represents a very important gene regulatory network. This article reviews the initial discoveries of miRNA that began in the nematode C. elegans, and extends into what is known about miRNAs and miRNA processing factors in mouse development and human disease.     

Novel miRNA markers for the diagnosis and prognosis of endometrial cancer

As endometrial cancer (EC) is a major threat to female health worldwide, the ability to provide an accurate diagnosis and prognosis of EC is promising to improve its treatment guidance. Since the discovery of miRNAs, it has been realized that miRNAs are associated with every cell function, including malignant transformation and metastasis. This study aimed to explore diagnostic and prognostic miRNA markers of EC. In this study, differential analysis and machine learning were performed, followed by correlation analysis of miRNA‐mRNA based on the miRNA and mRNA expression data. Nine miRNAs were identified as diagnostic markers, and a diagnostic classifier was established to distinguish between EC and normal endometrium tissue with overall correct rates >95%. Five specific prognostic miRNA markers were selected to construct a prognostic model, which was confirmed more effective in identifying EC patients at high risk of mortality compared with the FIGO staging system. This study demonstrates that the expression patterns of miRNAs may hold promise for becoming diagnostic and prognostic biomarkers and novel therapeutic targets for EC.