A microRNA expression signature of human solid tumors defines cancer gene targets

Small noncoding microRNAs (miRNAs) can contribute to cancer development and progression and are differentially expressed in normal tissues and cancers. From a large-scale miRnome analysis on 540 samples including lung, breast, stomach, prostate, colon, and pancreatic tumors, we identified a solid cancer miRNA signature composed by a large portion of overexpressed miRNAs. Among these miRNAs are some with well characterized cancer association, such as miR-17-5p, miR-20a, miR-21, miR-92, miR-106a, and miR-155. The predicted targets for the differentially expressed miRNAs are significantly enriched for protein-coding tumor suppressors and oncogenes (P < 0.0001). A number of the predicted targets, including the tumor suppressors RB1 (Retinoblastoma 1) and TGFBR2 (transforming growth factor, beta receptor II) genes were confirmed experimentally. Our results indicate that miRNAs are extensively involved in cancer pathogenesis of solid tumors and support their function as either dominant or recessive cancer genes.     

A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis

Epithelial ovarian cancer is the most lethal gynecologic malignancy; it is highly aggressive and causes almost 125,000 deaths yearly. Despite advances in detection and cytotoxic therapies, a low percentage of patients with advanced stage disease survive 5 y after the initial diagnosis. The high mortality of this disease is mainly caused by resistance to the available therapies. Here, we profiled microRNA (miR) expression in serous epithelial ovarian carcinomas to assess the possibility of a miR signature associated with chemoresistance. We analyzed tumor samples from 198 patients (86 patients as a training set and 112 patients as a validation set) for human miRs. A signature of 23 miRs associated with chemoresistance was generated by array analysis in the training set. Quantitative RT-PCR in the validation set confirmed that three miRs (miR-484, -642, and -217) were able to predict chemoresistance of these tumors. Additional analysis of miR-484 revealed that the sensitive phenotype is caused by a modulation of tumor vasculature through the regulation of the VEGFB and VEGFR2 pathways. We present compelling evidence that three miRs can classify the response to chemotherapy of ovarian cancer patients in a large multicenter cohort and that one of these three miRs is involved in the control of tumor angiogenesis, indicating an option in the treatment of these patients. Our results suggest, in fact, that blockage of VEGF through the use of an anti-VEGFA antibody may not be sufficient to improve survival in ovarian cancer patients unless VEGFB signaling is also blocked.Ovarian cancer is the leading cause of gynecological cancer-related death in the developed world (1). Although progress has been made in its treatment by improved debulking surgery and the introduction of platinum–taxane regimens (2), the overall 5-y survival is only 29% in advanced stage disease (1), mostly because of diagnosis at an advanced stage and intrinsic and acquired resistance to platinum-based chemotherapy. Identifying molecular markers of ovarian cancer chemoresistance is, therefore, of crucial importance. Successful translation of findings at the molecular level will lead to individualized treatment regimens, improved chemotherapeutic response rates, and avoidance of unnecessary treatments.MicroRNAs (miRs) are a class of small noncoding RNAs that modulate gene expression by causing translational repression, mRNA cleavage, or destabilization (3). They are involved in numerous physiological cellular processes (4–7). Most importantly, accumulating evidence indicates that many miRs are aberrantly expressed in human cancers (8–10), and their expression profiles can classify stage, subtype, and prognosis of some cancers (11–14).In this report, we describe an miR signature that defines chemoresistant ovarian carcinoma. We show that some miRs are deregulated in most patients with resistant ovarian carcinomas, and we show that miR-484 exerts its action through the regulation of angiogenic factors. We postulate that this miR signature of drug resistance could be used to develop strategies for targeted therapies in chemorefractive ovarian carcinoma patients.     

DNA甲基化与肿瘤

肿瘤发生、发展的分子生物学本质是细胞内遗传调控和表观遗传调控(epigenetic regulation)的紊乱。国内外对基因组所携带的遗传信息与疾病的关系已有深入的研究。相对而言,染色质所携带的表观遗传信息在疾病发生、发展中的重要作用才刚刚开始被认识。影响基因转录活性而不涉及DNA序列改变的基因表达调控方式称为表观遗传调控,其分子基础是DNA甲基化以及染色质的化学修饰和物理重塑。大量的临床和基础研究结果表明环境因素在肿瘤发生、发展中有巨大的影响,而表观遗传调控在遗传因素和环境因素的互动关系中起着桥梁的作用。     

人肝转移结直肠癌微小核糖核酸表达谱的初步研究

目的 研究人肝转移结直肠癌、无肝转移结直肠癌中微小核糖核酸(miRNA)的表达谱,筛选与结直肠癌肝转移相关的miRNA.方法 收集25例手术切除结直肠癌标本液氮储存.分别选取3例无肝转移和3例肝转移结直肠癌组织,提取组织总RNA,采用illumina miRNA芯片技术检测两种组织中miRNA的表达,筛选两种不同组织中差异表达miRNA,采用实时定量PCR技术在全部结直肠癌组织中对芯片检测结果进行验证.结果 肝转移结直肠癌组织与无肝转移结直肠癌组织中miRNA表达有明显差异,与无肝转移结直肠癌组织相比,在肝转移结直肠癌组织中差异表达的miRNA有28个,其中4个上调,24个下调.肝转移结直肠癌组织中miR-139-3p表达量为1.75±0.40,较无肝转移上调(0.69±0.58,P<0.05),而miR-19a在肝转移中的表达量为0.39±0.20,较无肝转移下调(1.38±0.98,P<0.05),miRNA芯片结果与定量RT-PCR结果一致.结论 miRNA的异常表达可能与结直肠癌的肝转移有关,特异的miRNA表达谱可以为结直肠癌的肝转移提供新的诊断和治疗靶点.     

DNA甲基化与结肠癌

DNA异常甲基化是肿瘤常见的表观遗传学改变.广泛的低甲基化和区域性高甲基化是基因异常表达的常见机制.某些基因异常甲基化与结肠癌发生密切相关,且常见于结肠癌发病早期.     

DNA methylation and microRNAs in cancer

DNA methylation is a type of epigenetic modification in the human genome, which means that gene expression is regulated without altering the DNA sequence. Methylation and the relationship between methylation and cancer have been the focus of molecular biology researches. Methylation represses gene expression and can influence embryogenesis and tumorigenesis. In different tissues and at different stages of life, the level of methylation of DNA varies, implying a fundamental but distinct role for methylation. When genes are repressed by abnormal methylation, the resulting effects can include instability of that gene and inactivation of a tumor suppressor gene. MicroRNAs have some aspects in common with this regulation of gene expression. Here we reviewed the influence of gene methylation on cancer and analyzed the methods used to profile methylation. We also assessed the correlation between methylation and other epigenetic modifications and microRNAs. About 55,845 research papers have been published about methylation, and one-fifth of these are about the appearance of methylation in cancer. We conclude that methylation does play a role in some cancer types.     

DNA methylation in aging and cancer

DNA methylation processes appear to be disturbed in senescing mice and also in some tumor cells. Although it is possible that age-related demethylation of DNA could predispose cells to carcinogenic transformation, present evidence does not favor this hypothesis.     

DNA甲基化与胃癌的关系研究

基因的表观遗传学修饰是一种不依赖DNA序列改变的可逆的基因表达调控过程。主要包括DNA甲基化与去甲基化,这些可逆的表观遗传学修饰可以方便地关闭和开放某些特定基因,有选择性表达基因组的信息,在维持染色体结构的稳定、基因组的完整、组织特异性基因的表达调节、细胞分化和个体成长等过程中发挥着至关重要的作用,而DNA的甲基化与胃癌的关系日益受到重视,为胃癌的诊断和治疗提供了新的途径。这些分子病理基础研究的不断深入使我们更好地理解发病机制,进而能够为临床治疗提供更好的借鉴价值。     

DNA甲基化与胃癌的研究进展

表观遗传学主要涉及DNA甲基化作用的改变和染色质组蛋白的修饰作用、基因印记等,表现遗传调控机制维持着细胞的特性,以保证其发展、分化.表观遗传学调控机制在肿瘤发生、发展过程中扮演着重要的角色,其中DNA甲基化的研究对于胃癌早期诊断、靶向治疗以及明确胃癌的发病机制等方面具有十分重要的意义.现将DNA甲基化与胃癌的研究进展作...     

Genomic landscape of human allele-specific DNA methylation

DNA methylation mediates imprinted gene expression by passing an epigenomic state across generations and differentially marking specific regulatory regions on maternal and paternal alleles. Imprinting has been tied to the evolution of the placenta in mammals and defects of imprinting have been associated with human diseases. Although recent advances in genome sequencing have revolutionized the study of DNA methylation, existing methylome data remain largely untapped in the study of imprinting. We present a statistical model to describe allele-specific methylation (ASM) in data from high-throughput short-read bisulfite sequencing. Simulation results indicate technical specifications of existing methylome data, such as read length and coverage, are sufficient for full-genome ASM profiling based on our model. We used our model to analyze methylomes for a diverse set of human cell types, including cultured and uncultured differentiated cells, embryonic stem cells and induced pluripotent stem cells. Regions of ASM identified most consistently across methylomes are tightly connected with known imprinted genes and precisely delineate the boundaries of several known imprinting control regions. Predicted regions of ASM common to multiple cell types frequently mark noncoding RNA promoters and represent promising starting points for targeted validation. More generally, our model provides the analytical complement to cutting-edge experimental technologies for surveying ASM in specific cell types and across species.     

The role of microRNA in myelodysplastic syndromes: beyond DNA methylation and histone modification

Myelodysplastic syndromes (MDS) are heterogeneous group of hematologic disorders of mostly elderly and based on distinct clinical phenotypes. Current paradigm of their pathogenesis relies on somatic gene mutations combined with the predisposing defective osteohematopoietic niche, but due to the breakout in epigenetic research scientific focus has steered toward two most common epigenetic modifications: methylation mechanisms and histone modification. At the same time, relatively few studies have been undertaken regarding the third epigenetic pathway – microRNAs – in MDS. The main aim of this review is to provide the basics of microRNA biology and function in oncogenesis, showing the complexity of mechanisms behind this single‐stranded 22 nucleotides long RNA molecule, with further focus on its implication in MDS pathology and clinical context. By extensive literature search, we have shown enough evidence for their deregulation in MDS. However, few studies have addressed the issue on pathogenic events in MDS and its association with specific microRNAs. Preliminary research in clinical setting has shown the possible utility of microRNAs in terms of prognosis and therapy, although we are only beginning to understand various implications of microRNAs in MDS and further extensive research is warranted to answer multiple questions arising from interconnection of this epigenetic mechanism in MDS.     

结直肠癌肝转移相关microRNA的研究现状

肿瘤的转移是一个多步骤复杂的过程,肝转移是结直肠癌最常见的转移方式之一,对转移机制的理解和深入研究有助于寻求解决结直肠癌肝转移的方法,当前研究认为microRNA参与了肿瘤的转移与复发,通过对结直肠癌肝转移相关microRNA的研究,为疾病的发生发展、诊断治疗及预后等方面的研究提供了新的思路。归纳了结直肠癌肝转移相关microRNA的研究进展,回顾了microRNA的生物学功能以及分子机制,表明microRNA在肿瘤转移领域具有重要的意义,尤其在结直肠癌肝转移方面发挥着重要的作用。     

microRNA与结直肠癌转移的相关性研究进展

结直肠癌是我国最常见的消化道恶性肿瘤,严重危害人们的健康和生活质量。结直肠癌的发生发展是一个多因素、多步骤的过程。microRNA(miRNA)是一类近年发现的内源性、非编码单链小分子RNA,它在细胞增殖、分化、凋亡以及肿瘤发生发展等过程中发挥着重要作用。目前许多miRNA已被证实在结直肠癌进程中起着至关重要的作用。该文就miRNA在结直肠癌转移中所起的作用作一综述。     

Relationship of plasma folic acid and status of DNA methylation in human gastric cancer

To evaluate the anti-cancer effects of folic acid at the molecular level, we determined plasma folic acid concentration by radioimmuno-assay and the degree of total genomic DNA methylation by incubating DNA with³H-S-adenosylmethionine (³H-SAM) in the presence of a methylase, and analyzed the methylation status of the c-myc and c-Ha-ras oncogenes by Southern blotting in 21 patients with advanced gastric cancer. The degree of total genomic DNA methylation of cancerous tissues was significantly lower than that of paracancerous and non-cancerous tissues; c-myc and c-Ha-ras oncogenes from cancerous (10/21, 5/10) and paracancerous (13/21, 4/10) tissues were hypomethylated. The plasma folic acid concentration in patients who showed hypomethylation was lower than that patients showing normal methylation. These findings suggest that a decrease in folic acid, and the subsequent DNA hypomethylation, may be involved in human gastric carcinogenesis.     

Identification of a DNA methylation signature in blood cells from persons with Down Syndrome

Down Syndrome (DS) is characterized by a wide spectrum of clinical signs, which include segmental premature aging of central nervous and immune systems. Although it is well established that the causative defect of DS is the trisomy of chromosome 21, the molecular bases of its phenotype are still largely unknown. We used the Infinium HumanMethylation450 BeadChip to investigate DNA methylation patterns in whole blood from 29 DS persons, using their relatives (mothers and unaffected siblings) as controls. This family-based model allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental factors. Although differentially methylated regions (DMRs) displayed a genome-wide distribution, they were enriched on chromosome 21. DMRs mapped in genes involved in developmental functions, including embryonic development (HOXA family) and haematological (RUNX1 and EBF4) and neuronal (NCAM1) development. Moreover, genes involved in the regulation of chromatin structure (PRMD8, KDM2B, TET1) showed altered methylation. The data also showed that several pathways are affected in DS, including PI3K-Akt signaling. In conclusion, we identified an epigenetic signature of DS that sustains a link between developmental defects and disease phenotype, including segmental premature aging.