Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes

Accumulating evidence highlights the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. However, the role of lncRNA expression in human breast cancer biology, prognosis and molecular classification remains unknown. Herein, we established the lncRNA profile of 658 infiltrating ductal carcinomas of the breast from The Cancer Genome Atlas project. We found lncRNA expression to correlate with the gene expression and chromatin landscape of human mammary epithelial cells (non-transformed) and the breast cancer cell line MCF-7. Unsupervised consensus clustering of lncRNA revealed four subgroups that displayed different prognoses. Gene set enrichment analysis for cis- and trans-acting lncRNAs showed enrichment for breast cancer signatures driven by master regulators of breast carcinogenesis. Interestingly, the lncRNA HOTAIR was significantly overexpressed in the HER2-enriched subgroup, while the lncRNA HOTAIRM1 was significantly overexpressed in the basal-like subgroup. Estrogen receptor (ESR1) expression was associated with distinct lncRNA networks in lncRNA clusters III and IV. Importantly, almost two thirds of the lncRNAs were marked by enhancer chromatin modifications (i.e., H3K27ac), suggesting that expressed lncRNA in breast cancer drives carcinogenesis through increased activity of neighboring genes. In summary, our study depicts the first lncRNA subtype classification in breast cancer and provides the framework for future studies to assess the interplay between lncRNAs and the breast cancer epigenome.     

长链非编码RNA与宫颈癌的相关性研究进展

宫颈癌的发病率和死亡率均位于女性肿瘤的第二位,早期诊断与治疗是降低其死亡率的有效途径。长链非编码RNA(long non-coding RNA, lncRNA)是一类长度大于200 nt且缺乏编码蛋白能力的RNA,其通过多种途径参与基因的表达调控,在个体正常发育和疾病发生中起着重要作用。越来越多的研究表明lncRNA与肿瘤的发生、发展密切相关。本文将对lncRNAs在宫颈癌中的作用及其分子机制进行综述。     

RNA异常与肿瘤调控研究进展

肿瘤的发生是一个多因素、多步骤的过程,其根本原因是细胞稳态的失衡.近年研究发现,在肿瘤的发生、发展中除了蛋白质功能紊乱、DNA突变之外,还存在着大量RNA的异常,包括异常的microRNA(miRNA)、长链非编码RNA(long non-coding RNA,IncRNA)、循环RNA等;此外,肿瘤细胞中还存在RNA转录、加工及调控功能的异常,如RNA选择性剪接、RNA编辑、竞争性内源RNA调控等.这些非编码RNA可以在转录后水平及表观遗传学水平调控癌基因和抑癌基因的功能,影响肿瘤的发生和发展,是肿瘤诊断、治疗及预后判断的潜在靶标.竞争性内源RNA使得lncRNA与mRNA通过miRNA相互调控,以“miRNA结合位点”为媒介,形成RNA调控网络.RNA选择性剪接使得癌基因或抑癌基因产生功能异常的转录本,进而影响其生物学功能.肿瘤中究竟哪些机制导致这些RNA表达及功能的异常,RNA表达及功能的异常又如何影响肿瘤的发生和发展,有哪些表达或功能异常的RNA可以作为肿瘤诊断及预后判断的标志物,又有哪些RNA可以作为肿瘤靶向治疗的靶标?等等问题亟待深入探讨,RNA异常与肿瘤调控已成为肿瘤研究的前沿热点领域.     

Combined inhibition of EGFR and c-ABL suppresses the growth of triple-negative breast cancer growth through inhibition of HOTAIR

Triple-negative breast cancer (TNBC) does not express conventional therapeutic targets and is the only type of malignant breast cancer for which no designated FDA-approved targeted therapy is available. Although overexpression of epidermal growth factor receptor (EGFR) is frequently found in TNBC, the therapeutic effect of EGFR inhibitors in TNBC has been underwhelming. Here we show that co-treatment with clinically validated inhibitors of c-ABL (imatinib) and EGFR (lapatinib) results in synergistic growth inhibition in TNBC cells. The dual treatment leads to synergistic repression of the long non-coding RNA (lncRNA) HOTAIR (HOX Antisense Intergenic RNA). HOTAIR has been known to induce tumor growth and metastasis in breast cancer. Depleting HOTAIR alone phenocopies the dual treatment in growth suppression. We show that expression of HOTAIR is regulated by β-catenin through a LEF1/TCF4-binding site. The dual treatment blocks nuclear expression of β-catenin and prevents its recruitment to the HOTAIR promoter. Consistently, forced expression of β-catenin rescued HOTAIR expression and cell viability in the presence of both drugs. Upregulation of HOTAIR is associated with TNBC in cell lines and a cohort of primary tumors. This study elucidates a previously unidentified mechanism in TNBC linking signaling with lncRNA regulation which may be exploited for therapeutic gain.     

Construction and analysis of lncRNA-lncRNA synergistic networks to reveal clinically relevant lncRNAs in cancer

Long non-coding RNAs (lncRNAs) play key roles in diverse biological processes. Moreover, the development and progression of cancer often involves the combined actions of several lncRNAs. Here we propose a multi-step method for constructing lncRNA-lncRNA functional synergistic networks (LFSNs) through co-regulation of functional modules having three features: common coexpressed genes of lncRNA pairs, enrichment in the same functional category and close proximity within protein interaction networks. Applied to three cancers, we constructed cancer-specific LFSNs and found that they exhibit a scale free and modular architecture. In addition, cancer-associated lncRNAs tend to be hubs and are enriched within modules. Although there is little synergistic pairing of lncRNAs across cancers, lncRNA pairs involved in the same cancer hallmarks by regulating same or different biological processes. Finally, we identify prognostic biomarkers within cancer lncRNA expression datasets using modules derived from LFSNs. In summary, this proof-of-principle study indicates synergistic lncRNA pairs can be identified through integrative analysis of genome-wide expression data sets and functional information.     

长链非编码RNA在舌癌细胞上皮间质转化过程中的调节作用

舌癌恶性程度高,浸润性较强,易早期发生淋巴结转移。上皮间质转化(epithelial-mesenchymal transformation,EMT)是生物胚胎发育中的基础过程,在肿瘤细胞的迁移与侵袭过程中发挥关键作用。长链非编码RNA(Long non-coding RNA,lncRNA)是一类参与多种生物学进程的非编码RNA,部分lncRNA在恶性肿瘤的发生发展过程中异常表达,并通过多种方式参与调节肿瘤细胞的EMT。全文就近年来lncRNA在舌癌细胞EMT过程中的调节作用作一综述。     

The functional roles of exosomes-derived long non-coding RNA in human cancer

Cancer is one of the most pervasive causes of morbidity and mortality worldwide regardless of the fact that a majority of therapeutic strategies have been constantly invented. The survival rate of cancer patients remains unsatisfactory due to the late diagnosis, frequent metastasis and poor response to chemotherapeutics. Therefore, novel methods with high specificity and susceptibility for prompt diagnosis and precise treatment of cancer are imperative. Circulating RNA is located in bodily fluids, including urine, saliva, breast milk and naturally present in blood. Recently, long non-coding RNAs (lncRNAs), a subset of non-coding RNAs are discovered to be differentially expressed in a variety of cancers. LncRNAs have been broadly recognized as emerging mediators for cancer behavior. Presence of lncRNA in circulation can be cell-free or encapsulated in extracellular vesicles (EVs) released by cancer cells. The release of EVs, especially exosomes, with 40–120 nm diameter in size, has been implicated in the regulation of malignancies as carriers for nucleic acid cargo through intercellular transfer. Therefore, systematic understanding of the role of exosomal lncRNAs in carcinogenesis may offer ideal diagnostic and prognostic biomarker or even therapeutic targets for malignancies. Herein, the underlying functional roles of exosomal lncRNAs in regulating tumor progression, immunomodulation as well as drug resistance will be elaborated. Lastly, the importance of exosomal lncRNAs in cancer study will also be discussed.     

Long non-coding RNAs in cancer简

Long non-coding RNAs （IncRNAs）, gradually being paid attention to, have been found playing a critical role in regulation of cellular processes such as cell growth and apoptosis, what is more, accumulating evidence indicates that IncRNAs also play a critical role in regulation of carcinogenesis and cancer progression. Here, we will summarize the recent researches about some IncRNAs in the development of cancers, hoping to give a new view about the study in the mechanisms involved in carcinogenesis and tumor progression.     

Progress and assessment of lncRNA DGCR5 in malignant phenotype and immune infiltration of human cancers

As a special type of noncoding RNA, long noncoding RNAs (lncRNAs) have vital roles during the development of human cancers and may be novel predictors or therapeutic targets for improving the management of patients with cancer. DiGeorge syndrome critical region gene 5 (DGCR5) is a prominent tumor-associated lncRNA, exerting tumor suppressor or oncogenic roles in various cancers. Previous studies have reported that DGCR5 has low expression in most types of cancers but high expression in triple-negative breast cancer, gallbladder cancer, and lung cancer. And DGCR5 expression is related to many hallmarks of cancer types, including cell proliferation, invasion, migration, apoptosis, stemness, and therapeutic responsiveness. Additionally, the pivotal molecules involved in DGCR5 regulation of signaling pathways are attributed to cancer hallmarks related to the pathogenesis of different types of malignant tumors. Herein, we discuss the DGCR5 expression pattern in various types of tumor tissues and relationships between DGCR5 expression and immune cell infiltration and immune purity. We also review our current understanding of DGCR5 in carcinogenesis and its potential application as a prognostic biomarker or therapeutic target in human cancers.     

SNHG1在肿瘤中的表达和作用

长链非编码RNA（long non-coding RNA,lncRNA）是一类转录本长度大于200 nt的不编码蛋白质的RNA分子。近年来研究发现长链非编码RNA在诸多肿瘤的发生发展过程中发挥重要作用。小核糖体管家基因RNA 1（small nucleolar RNA host gene 1,SNHG1）是由11号染色体上作为18s核糖体RNA重要组成部分的UHG基因转录而来的lncRNA。随研究不断深入,SNHG1在多种肿瘤中（胶质瘤、食管癌、胃癌等）的异常表达以及其对肿瘤恶性生物学行为的调控作用逐渐被揭示。SNHG1功能较为复杂并在肿瘤中通过多种机制发挥致癌作用,并且SNHG1的高表达预示着患者不良预后。本文结合国内外最新报道,对SNHG1在肿瘤中的表达水平及作用进行简要综述。     

microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer

The human genome is replete with long non-coding RNAs (lncRNA), many of which are transcribed and likely to have a functional role. Microarray analysis of >23,000 lncRNAs revealed downregulation of 712 (~3%) lncRNA in malignant hepatocytes, among which maternally expressed gene 3 (MEG3) was downregulated by 210-fold relative to expression in non-malignant hepatocytes. MEG3 expression was markedly reduced in four human hepatocellular cancer (HCC) cell lines compared with normal hepatocytes by real-time PCR. RNA in situ hybridization showed intense cytoplasmic expression of MEG3 in non-neoplastic liver with absent or very weak expression in HCC tissues. Enforced expression of MEG3 in HCC cells significantly decreased both anchorage-dependent and -independent cell growth, and induced apoptosis. MEG3 promoter hypermethylation was identified by methylation-specific PCR and MEG3 expression was increased with inhibition of methylation with either 5-Aza-2-Deoxycytidine, or siRNA to DNA Methyltransferase (DNMT) 1 and 3b in HCC cells. MiRNA-dependent regulation of MEG3 expression was studied by evaluating the involvement of miR-29, which can modulate DNMT 1 and 3. Overexpression of mir-29a increased expression of MEG3. GTL2, the murine homolog of MEG3, was reduced in liver tissues from hepatocyte-specific miR-29a/b1 knock-out mice compared with wild-type controls. These data show that methylation-dependent tissue-specific regulation of the lncRNA MEG3 by miR-29a may contribute to HCC growth and highlight the inter-relationship between two classes of non-coding RNA, miRNAs and lncRNAs, and epigenetic regulation of gene expression.     

人类癌症中长链非编码RNA与miRNA相互作用的研究进展

人类基因组中大部分为非编码区,转录产生非编码RNA（ncRNA）。这些ncRNA可以在表观遗传学水平及转录后水平调控癌基因和抑癌基因的表达,影响肿瘤的发生和发展,是肿瘤诊断、治疗及预后判断的潜在靶标。微小RNA（miRNA） 和长链非编码RNA（lncRNA） 是ncRNA的两个重要分类。其中,lncRNA通过多种机制在不同水平进行基因表达调控,发挥其生物学功能,这些机制包括基因印迹、染色质重塑、细胞周期调控、选择性剪接、mRNA降解和翻译调控等。近年来,miRNA和lncRNA在癌症发生发展中相互作用的分子机制引起了人们的注意。本文主要就这两者在癌症发生发展过程中的相互作用机制及研究方法进行综述。     

长链非编码RNA及其在非小细胞肺癌中的表达和作用

长链非编码RNA(long non-coding RNAs,lncRNAs)是一类转录本长度超过200个核苷酸的非编码RNA(non-coding RNAs,ncRNAs),它们不编码蛋白质,而是以RNA的形式通过转录,转录后和表观遗传等多种调控机制发挥生物学功能,包括生长发育、骨髓造血、细胞凋亡和细胞增殖等生命进程中的一系列重要过程。肺癌是全球癌症死亡的主要原因,它是由不同病因引起的一系列疾病,可分为小细胞肺癌(small-cell lung cancer,SCLC)和非小细胞肺癌(non-small cell lung cancer,NSCLC)两种类型。肺癌的基本特征是基因组遗传和表观遗传发生改变;然而,肺癌发生的具体机制目前仍不明确。近年来的研究资料表明,lncRNAs的异常表达与包括肺癌在内的多种癌症的发生发展有关。本文着重研究lncRNAs在NSCLC中的表达和作用,并讨论其作为早期诊断,指导预后的生物标志物以及治疗靶点的潜在临床应用。