乳腺癌相关MicroRNAs研究进展

MicroRNAs(miRNAs)是一类广泛存在于真核细胞中长约18~23个核苷酸的小分子非编码RNA,具有转录后基因调控的功能,参与调节细胞的分化、增殖、凋亡、迁移等多种生物学进程.现今乳腺癌已成为女性常见的恶性肿瘤之一,但其发病病因尚未完全清楚.近年来,通过对分子生物学的研究,发现miRNAs是一类潜在的强有力的评估乳腺癌的发生、发展,诊断、治疗及预后的生物学指标.本文主要对miRNAs这一类新的肿瘤分子生物学标记物在乳腺癌中的作用机制作一综述.     

microRNAs与乳腺癌

microRNAs（miRNAs）是一类长约21~24个核苷酸的小分子非编码RNA,通过与位于靶基因mRNA 3' UTR区域的特异性结合位点互补配对结合,促进靶基因mRNA的降解和/或抑制翻译过程,从而行使调节基因表达的功能。miRNAs广泛存在于真核细胞内,参与了细胞的分化、增殖、凋亡、周期调控、迁移以及肿瘤的发生发展等多种生物学进程。miRNAs表达谱是一类潜在的强有力的评估肿瘤发生、发展、诊断、治疗及预后的生物学指标,在人类肿瘤的不同类型中均存在显著差异。乳腺癌是女性最常见的恶性肿瘤之一,不同类型的乳腺癌组织中miRNAs的表达谱也不同。本文对目前为止发现的一些与乳腺癌发生发展、转移及治疗反应等相关的miRNAs及其下游靶基因在乳腺癌中的表达及作用进行综述。      

Metastasis-related miRNAs,active players in breast cancer invasion,and metastasis

Breast cancer is the most common malignancy with the highest incidence among women in the world. Metastasis is the major reason for breast cancer-related deaths. The precise molecular circuitry that governs the metastasis process has not been completely understood. Discoveries of microRNAs (miRNAs) open a new avenue for cancer metastasis research. It has become clear that alterations of miRNA expression contribute to cancer pathogenesis. miRNAs control a wide array of physiological and pathological processes, including development, differentiation, cellular proliferation, programmed cell death, oncogenesis, and metastasis by modulating the expression of their cognate target genes through cleaving mRNA molecules or inhibiting their translation. Some miRNAs are associated with the invasive and metastatic phenotype of breast cancer cell lines or identified in metastatic tumor tissues and lymph nodes. Some miRNAs serve as metastasis suppressors and their expression is frequently downregulated or lost in both breast cancer cell lines and metastatic foci. Some miRNAs are considered to play key roles in the phenotype formation of breast cancer stem cells. This review will focus on recent discoveries related to the miRNAs involved in the metastasis of breast cancer and discuss the implications for the diagnosis, prognosis, and therapeutic strategies of breast cancer.     

Exosome‐encapsulated microRNAs as circulating biomarkers for breast cancer

Breast cancer is a highly prevalent disease, accounting for 29% of invasive cancers in women. Survival from this disease depends on the stage at diagnosis, with patients who are detected earlier having more favourable outcomes. It is because of this that research groups are focusing on the development of a blood‐based biomarker for breast cancer. Such biomarkers may facilitate the detection of breast cancer in its infancy before it has spread beyond the primary site. MicroRNAs (miRNAs) have shown immense potential in this setting. These short, non‐coding RNA sequences have been shown to be dysregulated in breast cancer. Despite showing immense promise, miRNAs have not been successfully implemented in the clinical setting due to a lack of a standardised approach which has resulted in conflicting results. These challenges may be addressed at least in part through the study of exosomes. The biomarker potential for exosomes holds huge promise and may revolutionise the way in which we diagnose and manage breast cancer. These nanovesicles may be isolated from a variety of bodily fluids, including serum, and their miRNA content has been shown to reflect that of the parent breast cancer cell. This review will highlight the nomenclature and defining characteristics of exosomes, and current methods of isolation of serum‐derived exosomes. Initial promising reports on the potential utility of exosomal miRNAs to be used as breast cancer biomarkers will also be addressed.     

MicroRNA在乳腺癌中作用的研究进展

MicroRNA（miRNA,miRNAs)是广泛存在于生物中,长度约为20-24个核苷酸的非编码微小RNA分子。目前研究发现,miRNA与肿瘤的发生、进展有紧密联系,且逐渐成为癌症研究的热点。近年来,miRNA在乳腺癌发生与进展中起到的重要作用逐渐被揭示,已迅速发展为乳腺癌等癌症的重要生物标记物。本综述将就微小RNA在乳腺癌的发生、进展、远处转移、早期诊断以及化学治疗耐药性方面的作用进行论述。     

乳腺癌miRNA的研究进展

研究显示微小RNA(miRNA)与乳腺癌的发生发展过程关系密切.多种miRNA参与了乳腺癌的发病进展,并能评估预后,指导临床用药及探索其耐药机制.     

MicroRNA profiling as a tool to understand prognosis,therapy response and resistance in breast cancer

Despite advances in detection and therapies, breast cancer is still the leading cause of cancer death in women worldwide. The etiology of this neoplasm is complex, and both genetic and environmental factors contribute to the complicated scenario.Gene profiling studies have been extensively used over the past decades as a powerful tool in defining the signature of different cancers and in predicting outcome and response to therapies.More recently, a new class of small non-coding RNAs, microRNAs (miRNAs), able to regulate gene expression binding seed sequences on the 3′UTR of mRNA targets, has been linked to several human diseases, including cancer. An increasing amount of experimental evidence shows that miRNAs are aberrantly expressed in different tumour types, and that they can have a causal role in tumourigenesis.Here, we describe and discuss the evidence supporting the association between miRNAs and breast cancer, underlining their role in the development of this neoplasia, and the impact on putative innovative therapeutical approaches.     

Dysregulation of microRNAs in breast cancer and their potential role as prognostic and predictive biomarkers in patient management

MicroRNAs (miRNAs) are an emerging class of gene expression modulators with relevant roles in several biological processes, including cell differentiation, development, apoptosis, and regulation of the cell cycle. Deregulation of those tiny RNA molecules has been described frequently as a major determinant for the initiation and progression of diseases, including cancer. Not only miRNAs but also the enzymes responsible for miRNA processing could be deregulated in cancer. In this review, we address the role of miRNAs in the pathogenesis of breast cancer, since there are oncogenic, tumor-suppressive, and metastatic-influencing miRNAs. Additionally, the different detection platforms and normalization strategies for miRNAs will be discussed. The major part of this review, however, will focus on the capability of miRNAs to act as diagnostic, predictive, or prognostic biomarkers. We will give an overview of their potential to correlate with response to or benefit from a given treatment and we will consider their ability to give information on prognosis in breast cancer. We will focus on miRNAs validated by more than one study or verified in independent cohorts or where results rely on preclinical as well as clinical evidence. As such, we will discuss their potential use in the personalized management of breast cancer.     

MicroRNA在三阴性乳腺癌发生发展中的作用

microRNA（miRNA）是近年来发现的一种可以调控基因表达的单链小分子RNA,其表达异常或突变被认为与多种肿瘤的发生、发展有关。有研究表明,miRNA在三阴性乳腺癌中扮演着重要角色,这将为后者的治疗提供新思路。本文就miRNA作为一种新的分子标志物在三阴性乳腺癌中的研究进展作一综述。【关键词】miRNA;三阴性乳腺癌;分子标志物     

MicroRNA-mediated breast cancer metastasis: from primary site to distant organs

The recent upsurge of interest in microRNA (miRNA) is partly attributed to the discovery of the novel roles of miRNAs in many physiological and pathological processes, including tumor development. Research on breast cancer metastasis has also focused on the concept of miRNA, which can act either as promoters or as suppressors of metastases. This review will focus on a series of recent studies that demonstrate the involvement of miRNAs in breast cancer metastasis and will briefly describe various pathways of miRNA-regulated metastasis. Finally, future prospects will be discussed for the potential role of miRNAs as predictive markers and therapeutic agents for patients with breast cancer metastases.     

microRNA在乳腺癌诊断及预后判断中的作用

乳腺癌是全球女性患病率最高的恶性肿瘤,严重危害广大女性的健康。微小RNA(microRNA,miRNA)是一类小的内源性非编码RNA,通过与mRNA 3’端非翻译区部分互补配对,在翻译后水平调节靶基因的表达。miRNA在乳腺的发育过程中发挥多种作用,其表达异常可能导致乳腺癌的发生。乳腺癌中miRNA的异常表达,以及miRNA在血清中的稳定存在,使miRNA有望成为新的生物标志物用于乳腺癌的诊断及预后判断。     

MicroRNA gene expression deregulation in human breast cancer

MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. Indeed, miRNA aberrant expression has been previously found in human chronic lymphocytic leukemias, where miRNA signatures were associated with specific clinicobiological features. Here, we show that, compared with normal breast tissue, miRNAs are also aberrantly expressed in human breast cancer. The overall miRNA expression could clearly separate normal versus cancer tissues, with the most significantly deregulated miRNAs being mir-125b, mir-145, mir-21, and mir-155. Results were confirmed by microarray and Northern blot analyses. We could identify miRNAs whose expression was correlated with specific breast cancer biopathologic features, such as estrogen and progesterone receptor expression, tumor stage, vascular invasion, or proliferation index.     

Involvement of microRNAs in HER2 signaling and trastuzumab treatment

The prognostic value of HER2 has been demonstrated in many human cancer types such us breast cancer, gastric cancer and ovarian cancer. Trastuzumab is the first anti-HER2 monoclonal antibody that has remarkably improved outcomes of patients with HER2-positive breast cancer. For HER2-positive metastatic gastric cancers, the addition of trastuzumab to traditional chemotherapy also significantly prolonged overall survival. However, intrinsic and acquired resistance to trastuzumab is common and results in disease progression. HER2 signaling network and mechanisms underlying the resistance have been broadly investigated in order to develop strategy to overcome the dilemma. Increasing evidence indicates that microRNAs (miRNA), a group of small non-coding RNAs, are involved in HER2 signaling and trastuzumab treatment. This review summarizes all the miRNAs that target HER2 and describes their activity on biological processes. Moreover, miRNAs that regulate trastuzumab resistance and relevant molecular mechanisms are highlighted. MiRNA signatures associated with HER2, miRNAs that mediate trastuzumab activity, and potential miRNA biomarkers of trastuzumab sensitivity are also discussed.     

Role of miR-10b in breast cancer metastasis

Ninety percent of cancer-related mortality is caused by metastasis. Current cancer treatments can control many primary tumors but rarely stop the metastatic spread. Accumulating evidence demonstrates that miRNAs are involved in cancer initiation and progression. Furthermore, several miRNAs have been found to regulate metastasis. In particular, recent studies provide the first functional evidence that overexpression of a specific miRNA, miR-10b, can contribute to the development of metastasis, which can be exploited therapeutically in treating breast cancer metastasis in mice. Further in-depth analysis should provide more precise evaluation of the roles, mechanisms, and therapeutic utility of this miRNA in breast cancer.     

乳腺癌细胞与乳腺上皮细胞MicroRNAs表达谱的差异性分析

背景与目的：已有研究表明,MicroRNAs（miRNAs）的异常表达参与了乳腺癌的发生和发展,常起到抑癌基因或癌基因作用。本研究旨在探讨乳腺癌细胞与乳腺上皮细胞miRNAs的差异性表达,并预测异常表达的miRNAs可能调控的靶基因。方法：培养乳腺癌细胞株MCF-7和正常乳腺上皮细胞株HBL-100．分别提取细胞总RNA,并进行质检;利用miRNAs芯片技术,检测乳腺癌细胞和正常乳腺上皮细胞miRNAs的表达,对其表达谱进行差异性分析：采用实时定量RT—PCR进行验证：运用MiRanda、TargetScan、PicTar、DIANA—microT软件预测miRNAs可能调控的靶基因。结果：从MCF-7细胞与HBL-100细胞提取到的总RNA纯度较高,其A260／A280为1．90,A260/A230为2．0;琼脂糖凝胶实验结果显示总RNA完整性好。通过miRNAs表达谱的差异性分析,获得173个与乳腺癌相关的miRNAs,其中113个表达上调,60个表达下调：实时定量PCR检测到mir-18a和mir-195在MCF-7细胞中高表达;对乳腺癌细胞显著异常表达的mir-200b进行信息学分析,共筛选出68个靶基因。结论：获得了乳腺癌细胞与乳腺上皮细胞miRNAs的差异表达谱,其中部分miRNAs可能通过调控其靶基因而参与乳腺癌的发病机制。