非编码RNA与消化系统疾病的关系

近年来随着对微小RNA及小干扰RNA等的深入研究,人们逐渐认识到非编码RNA是一大类重要的基因调控因子,并在许多疾病的诊断、治疗、预后中起独特的作用。本文总结了近年来非编码RNA（ncRNA）在消化系统疾病的研究进展,探讨值得关注的研究方向。     

外泌体长链非编码RNA在胃癌中的研究进展

外泌体为一种稳定且广泛存在于人类体液中的纳米级囊泡,特殊的结构使其能够介导一种新的细胞间通讯模式,并参与肿瘤的发生发展,是近年来的研究热点。近期研究表明,外泌体LncRNAs不仅可以作为胃癌诊断的新型生物标志物,甚至参与胃癌细胞的增殖、凋亡和肿瘤微环境的改变以及化疗耐受。因此,本文对近年来外泌体LncRNAs在胃癌中的上述研究进展进行综述,期望为进一步研究提供参考和新的思路。     

Recent advances in the molecular diagnostics of gastric cancer

Gastric cancer(GC) is the third most common cause of cancer-related death in the world,representing a major global health issue. Although the incidence of GC is declining,the outcomes for GC patients remain dismal because of the lack of effective biomarkers to detect early GC and predict both recurrence and chemosensitivity. Current tumor markers for GC,including serum carcinoembryonic antigen and carbohydrate antigen 19-9,are not ideal due to their relatively low sensitivity and specificity. Recent improvements in molecular techniques are better able to identify aberrant expression of GC-related molecules,including oncogenes,tumor suppressor genes,micro RNAs and long non-coding RNAs,and DNA methylation,as novel molecular markers,although the molecular pathogenesis of GC is complicated by tumor heterogeneity. Detection of genetic and epigenetic alterations from gastric tissue or blood samples has diagnostic value in the management of GC. There are high expectations for molecular markers that can be used as new screening tools for early detection of GC as well as for patient stratification towards personalized treatment of GC through prediction of prognosis and drug-sensitivity. In this review,the studies of potential molecular biomarkers for GC that have been reported in the publicly available literature between 2012 and 2015 are reviewed and summarized,and certain highlighted papers are examined.     

Non-coding RNAs in hepatitis C-induced hepatocellular carcinoma:Dysregulation and implications for early detection,diagnosis and therapy

Hepatitis C virus(HCV)infection is one of main causes of hepatocellular carcinoma(HCC)and the prevalence of HCV-associated HCC is on the rise worldwide.It is particularly important and helpful to identify potential markers for screening and early diagnosis of HCC among high-risk individuals with chronic hepatitis C,and to identify target molecules for the prevention and treatment of HCV-associated-HCC.Small noncoding RNAs,mainly microRNAs(miRNAs),and long non-coding RNAs(lncRNAs)with size greater than 200nucleotides,are likely to play important roles in a variety of biological processes,including development and progression of HCC.For the most part their underlying mechanisms of action remain largely unknown.In recent years,with the advance of high-resolution of microarray and application of next generation sequencing techniques,a significant number of non-coding RNAs(ncRNAs)associated with HCC,particularly caused by HCV infection,have been found to be differentially expressed and to be involved in pathogenesis of HCVassociated HCC.In this review,we focus on recent studies of ncRNAs,especially miRNAs and lncRNAs related to HCV-induced HCC.We summarize those ncRNAs aberrantly expressed in HCV-associated HCC and highlight the potential uses of ncRNAs in early detection,diagnosis and therapy of HCV-associated HCC.We also discuss the limitations of recent studies,and suggest future directions for research in the field.miRNAs,lncRNAs and their target genes may represent new candidate molecules for the prevention,diagnosis and treatment of HCC in patients with HCV infection.Studies of the potential uses of miRNAs and lncRNAs as diagnostic tools or therapies are still in their infancy.     

Noncoding RNAs in gastric cancer: Research progress and prospects

Noncoding RNAs (ncRNAs) have attracted much attention in cancer research field. They are involved in cellular development, proliferation, differentiation and apoptosis. The dysregulation of ncRNAs has been reported in tumor initiation, progression, invasion and metastasis in various cancers, including gastric cancer (GC). In the past few years, an accumulating body of evidence has deepened our understanding of ncRNAs, and several emerging ncRNAs have been identified, such as PIWI-interacting RNAs (piRNAs) and circular RNAs (circRNAs). The competing endogenous RNA (ceRNA) networks include mRNAs, microRNAs, long ncRNAs (lncRNAs) and circRNAs, which play critical roles in the tumorigenesis of GC. This review summarizes the recent hotspots of ncRNAs involved in GC pathobiology and their potential applications in GC. Finally, we briefly discuss the advances in the ceRNA network in GC.     

Emerging roles of non-coding RNAs in gastric cancer: Pathogenesis and clinical implications

Gastric cancer is a leading cause of cancer-related deaths. However, the mechanisms underlying gastric carcinogenesis remain largely unclear. The association of non-coding RNAs(nc RNAs) with cancer has been widely studied during the past decade. In general, nc RNAs have been classified as small nc RNAs, including micro RNAs(mi RNAs), and long non-coding RNAs(lnc RNAs). Emerging evidence shows that mi RNAs and lnc RNAs play key roles in the formation and progression of many cancers. In this review, we focus on the regulation of mi RNAs and lnc RNAs in gastric cancer. mi RNAs and lnc RNAs appear to be involved in gastric tumor growth, invasion, and metastasis and in establishment of the gastric tumor microenvironment through various mechanisms. Furthermore, we also discuss the possibilities of establishing mi RNAs and lnc RNAs as potential biomarkers and therapeutic targets for gastric cancer. Taken together, we summarize the emerging roles of nc RNAs in gastric cancer development and their possible clinical significance.     

Non-coding landscapes of colorectal cancer

For two decades Vogelstein's model has been theparadigm for describing the sequence of molecular changes within protein-coding genes that would lead to overt colorectal cancer(CRC). This model is now too simplistic in the light of recent studies, which have shown that our genome is pervasively transcribed in RNAs other than m RNAs, denominated non-coding RNAs(nc RNAs). The discovery that mutations in genes encoding these RNAs [i.e., micro RNAs(mi RNAs), long non-coding RNAs, and circular RNAs] are causally involved in cancer phenotypes has profoundly modified our vision of tumour molecular genetics and pathobiology. By exploiting a wide range of different mechanisms, nc RNAs control fundamental cellular processes, such as proliferation, differentiation, migration, angiogenesis and apoptosis: these data have also confirmed their role as oncogenes or tumor suppressors in cancer development and progression. The existence of a sophisticated RNA-based regulatory system, which dictates the correct functioning of protein-coding networks, has relevant biological and biomedical consequences. Different mi RNAs involved in neoplastic and degenerative diseases exhibit potential predictive and prognostic properties. Furthermore, the key roles of nc RNAs make them very attractive targets for innovative therapeutic approaches. Several recent reports have shown that nc RNAs can be secreted by cells into the extracellular environment(i.e., blood and other body fluids): this suggests the existence of extracellular signalling mechanisms, which may be exploited by cells in physiology and pathology. In this review, we will summarize the most relevant issues on the involvement of cellular and extracellular nc RNAs in disease. We will then specifically describe their involvement in CRC pathobiology and their translational applications to CRC diagnosis, prognosis and therapy.     

Analysis of long non-coding RNA expression profiles in gastric cancer

AIM: To investigate the expression patterns of long non-coding RNAs (lncRNAs) in gastric cancer. METHODS: Two publicly available human exon arrays for gastric cancer and data for the corresponding normal tissue were downloaded from the Gene Expression Omnibus (GEO). We re-annotated the probes of the human exon arrays and retained the probes uniquely mapping to lncRNAs at the gene level. LncRNA expression profiles were generated by using robust multi-array average method in affymetrix power tools. The normalized data were then analyzed with a Bioconductor package linear models for microarray data and genes with adjusted P -values below 0.01 were considered differentially expressed. An independent data set was used to validate the results. RESULTS: With the computational pipeline established to re-annotate over 6.5 million probes of the Affymetrix Human Exon 1.0 ST array, we identified 136053 probes uniquely mapping to lncRNAs at the gene level. These probes correspond to 9294 lncRNAs, covering nearly 76% of the GENCODE lncRNA data set. By analyzing GSE27342 consisting of 80 paired gastric cancer and normal adjacent tissue samples, we identified 88 lncRNAs that were differentially expressed in gastric cancer, some of which have been reported to play a role in cancer, such as LINC00152, taurine upregulated 1, urothelial cancer associated 1, Pvt1 oncogene, small nucleolar RNA host gene 1 and LINC00261. In the validation data set GSE33335, 59% of these differentially expressed lncRNAs showed significant expression changes (adjusted P -value < 0.01) with the same direction. CONCLUSION: We identified a set of lncRNAs differentially expressed in gastric cancer, providing useful information for discovery of new biomarkers and therapeutic targets in gastric cancer.     

Circulating RNAs as new biomarkers for detecting pancreatic cancer

Pancreatic cancer remains difficult to treat and has a high mortality rate. It is difficult to diagnose early, mainly due to the lack of screening imaging modalities and specific biomarkers. Consequently, it is important to develop biomarkers that enable the detection of early stage tumors. Emerging evidence is accumulating that tumor cells release substantial amounts of RNA into the bloodstream that strongly resist RNases in the blood and are present at sufficient levels for quantitative analyses. These circulating RNAs are upregulated in the serum and plasma of cancer patients, including those with pancreatic cancer, compared with healthy controls. The majority of RNA biomarker studies have assessed circulating microRNAs (miRs), which are often tissue-specific. There are few reports of the tumor-specific upregulation of other types of small non-coding RNAs (ncRNAs), such as small nucleolar RNAs and Piwi-interacting RNAs. Long ncRNAs (lncRNAs), such as HOTAIR and MALAT1, in the serum/plasma of pancreatic cancer patients have also been reported as diagnostic and prognostic markers. Among tissue-derived RNAs, some miRs show increased expression even in pre-cancerous tissues, and their expression profiles may allow for the discrimination between a chronic inflammatory state and carcinoma. Additionally, some miRs and lncRNAs have been reported with significant alterations in expression according to disease progression, and they may thus represent potential candidate diagnostic or prognostic biomarkers that may be used to evaluate patients once detection methods in peripheral blood are well established. Furthermore, recent innovations in high-throughput sequencing techniques have enabled the discovery of unannotated tumor-associated ncRNAs and tumor-specific alternative splicing as novel and specific biomarkers of cancers. Although much work is required to clarify the release mechanism, origin of tumor-specific circulating RNAs, and selectivity of carrier complexes, and technical advances must also be achieved, such as creating a consensus normalization protocol for quantitative data analysis, circulating RNAs are largely unexplored and might represent novel clinical biomarkers.     

长链非编码RNA作为ceRNA在结直肠癌中的作用

结直肠癌(colorectal cancer,CRC)是全球第三大恶性肿瘤,恶性程度高,具有很高的转移和复发率.长链非编码RNA(lncRNA)在CRC发生发展过程中发挥重要作用.最近的研究表明,lncRNA可通过与微小RNA(miRNA)的反应元件(MRE)结合,充当竞争性内源RNA(ceRNA),从而间接调控miR...     

Prognostic thirteen-long non-coding RNAs (IncRNAs) could improve the survival prediction of gastric cancer

ObjectiveAccumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) play important regulatory roles in the tumorigenesis and progression of gastric cancer (GC). The aim of this study was to construct the prognostic predictive model of lncRNAs signature and improve the survival prediction of GC.Patients and methodsThe expression profiling of lncRNAs in large GC cohorts was performed from The Cancer Genome Atlas (TCGA) databases using the lncRNAs-mining approach, including training data set (N = 160) and testing data set (N = 159). A 13-lncRNAs signature significantly associated with overall survival (OS) in the training data set was selected. The prognostic value of this 13-lncRNAs signature was then confirmed in the test validation set and the entire validation set, respectively.ResultsBased on lncRNA expression profiling of 319 patients with stomach adenocarcinoma (STAD), prognostic 13-lncRNAs signature was found to be significantly associated with the prognosis of GC. Compared to patients with low-risk scores, patients with high-risk scores had a significantly shorter survival time. Moreover, functional enrichment analysis indicated that this 13-lncRNAs signature was potentially involved in multiple biological processes, such as DNA replication and cell cycle signaling pathway.ConclusionsThe prognostic model of the 13-lncRNAs signature established by our study could improve the survival prediction of GC to a greater extent.     

Functional role of long non-coding RNA CASC19/miR-140-5p/CEMIP axis in colorectal cancer progression in vitro

BACKGROUND Long non-coding RNAs(lncRNAs) are widely involved in tumor regulation.Nevertheless, the role of the lncRNA cancer susceptibility 19(CASC19) in colorectal cancer(CRC) has yet to be fully clarified.AIM To explore the effect of CASC19 on proliferation and metastasizing ability of CRC cells.METHODS CASC19 expression in human CRC tissues, pair-matched adjacent normal colon tissues, and CRC cells was detected using quantitative real-time PCR(qRT-PCR).CASC19 expression, as well as its relation to overall survival, was extrapolated by Kaplan-Meier survival analysis together with multivariable Cox regression assay.In vitro experiments were performed to confirm whether CASC19 regulates CRC cell invasion, migration, proliferation, and apoptosis.RESULTS CASC19 expression was markedly upregulated in CRC tissues and CRC cell lines(P < 0.05). qRT-PCR revealed that CASC19 expression was higher in 25 tissue samples from patients with aggressive CRC compared with the 27 tissue samples from patients with nonaggressive CRC(P < 0.05). Higher CASC19 expression was associated with poorer patient prognoses. Furthermore, in vitro experiments demonstrated that CASC19 overexpression enhanced CRC cell invasion,migration, and proliferation. CASC19 overexpression enhanced the expression of cell migration inducing hyaluronidase 1(CEMIP) and epithelial-mesenchymal transition markers. MiR-140-5 p was found to be able to bind directly to CASC19 and CEMIP. Overexpression of miR-140-5 p reversed the effect of CASC19 on cellproliferation and tumor migration, as well as suppressed CASC19-induced CEMIP expression.CONCLUSION CASC19 positively regulates CEMIP expression through targeting miR-140-5 p.CASC19 may possess an oncogenic function in CRC progression, highlighting its potential as an essential biomarker in CRC diagnosis and therapy.     

Circulating micro RNAs and long non-coding RNAs in gastric cancer diagnosis:An update and review

Gastric cancer(GC) is the fourth most common cancer and the third leading cause of cancer mortality worldwide. Micro RNAs(mi RNAs) and long non-coding RNAs(lnc RNAs) are the most popular non-coding RNAs in cancer research. To date,the roles of mi RNAs and lnc RNAs have been extensively studied in GC,suggesting that mi RNAs and lnc RNAs represent a vital component of tumor biology. Furthermore,circulating mi RNAs and lnc RNAs are found to be dysregulated in patients with GC compared with healthy individuals. Circulating mi RNAs and lnc RNAs may function as promising biomarkers to improve the early detection of GC. Multiple possibilities for mi RNA secretion have been elucidated,including active secretion by microvesicles,exosomes,apoptotic bodies,highdensity lipoproteins and protein complexes as well as passive leakage from cells. However,the mechanism underlying lnc RNA secretion and the functions of circulating mi RNAs and lnc RNAs have not been fully illuminated. Concurrently,to standardize results of global investigations of circulating mi RNAs and lnc RNAs biomarker studies,several recommendations for preanalytic considerations are put forward. In this review,we summarize the known circulating mi RNAs and lnc RNAs for GC diagnosis. The possible mechanism of mi RNA and lnc RNA secretion as well as methodologies for identification of circulating mi RNAs and lnc RNAs are also discussed. The topics covered here highlight new insights into GC diagnosis and screening.     

Epigenetic aspects of rheumatoid arthritis: contribution of non-coding RNAs

Since microRNA was discovered in the late 1990s the role of non-coding RNAs in the regulation of cellular processes has been confirmed. Intensive researches have revealed a number of subtypes of non-coding RNA. It has been proved that these molecules can influence each step of the development of cells and tissues. Moreover, researchers have found their expression change during disease development.In this article, we gathered the current results on the contribution of microRNA and long non-coding RNA in rheumatoid arthritis pathogenesis and their potential use in rheumatoid arthritis treatment. Although the present stage of studies on this matter is still very early, many studies have confirmed non-coding RNAs’ involvement in rheumatoid arthritis development. We showed ncRNAs changes in various tissues or cell lines of RA in humans or in animal models of RA. We tried to present possible mechanisms causing respective modifications of ncRNAs expression. There are some propositions to use some of them as markers of rheumatoid arthritis. Moreover, very advanced techniques of drug preparation are proposed to influence the microRNA or lncRNA pathways to inhibit inflammation in RA patients. None of them are now at the trial stage, but some are very promising.     

长链非编码RNA GIHCG对非小细胞肺癌恶性表型的影响

目的探讨长链非编码RNA GIHCG(lncRNA GIHCG)对非小细胞肺癌(NSCLC)恶性表型的影响。 方法使用qRT-PCR法分别检测50例NSCLC的肿瘤组织及其癌旁组织中lncRNA GIHCG及正常人支气管上皮细胞系E16HB,NSCLC细胞系A549、H1299、H1650、H2087中lncRNA GIHCG的表达。分别使用小干扰RNA(siRNA-1、siRNA-2)及对照转染A549和H1299细胞,实验设siRNA-1转染组、siRNA-2转染组、阴性对照组和空白对照组。各组转染48 h后采用CCK-8实验检测细胞增殖活性,Transwell实验检测细胞侵袭能力,流式细胞术检测各组细胞周期变化。 结果qRT-PCR结果显示,lncRNA GIHCG在肺癌组织中的表达水平明显高于癌旁组织,同时非小细胞肺癌细胞系A549、H1299、H1650、H2087中lncRNA GIHCG的表达均高于16HBE细胞,差异有统计学意义(P<0.05)。转染48 h后,与空白对照组和阴性对照相比,siRNA-1组和siRNA-2组细胞存活率明显下降,穿膜细胞数明显减少,G0/G1期细胞比例明显增加,S期细胞减少,差异均有统计学意义,而阴性对照组和空白对照组上述指标差异均无统计学意义。 结论lncRNA GIHCG高表达于NSCLC组织及细胞系中,沉默lncRNA GIHCG表达可明显抑制NSCLC恶性生物学表型。