Long noncoding RNAs (lncRNAs) are a relatively well-characterized class of noncoding RNA (ncRNA) molecules, involved in the regulation of various cell processes, including transcription, intracellular trafficking, and chromosome remodeling. Their deregulation has been associated with the development and progression of various cancer types, the fact which makes them suitable as biomarkers for cancer diagnosis and prognosis. In recent years, detection of cancer-associated lncRNAs in body fluids of cancer patients has proven itself as an especially valuable method to effectively diagnose cancer. Cancer diagnosis and prognosis employing circulating lncRNAs are preferential when compared to classical biopsies of tumor tissues, especially due to their noninvasiveness, and have great potential for routine usage in clinical practice. Thus, this review focuses on summarizing the perspectives of lncRNAs as biomarkers in cancer, based on evaluating their expression profiles determined in body fluids of cancer patients.
1. Introduction
Long noncoding RNAs (lncRNAs) belong to a larger group of noncoding RNAs (ncRNAs) and are generally classified as 200 nt–100 kb long transcripts, lacking the open-reading frame [1, 2]. They are usually transcribed by RNA polymerase II and controlled by the transcriptional activators of the SWI/SNF complex. Most of the generated lncRNA transcripts are usually spliced, capped, and polyadenylated in a similar manner as mRNA molecules [3]. lncRNAs represent a large (>80%) and a very heterogeneous group of ncRNAs, with their expression depending largely on the tissue and cellular context [4–7]. Following the discovery of H19 and XIST lncRNAs in 1990s [8, 9], lncRNA per se was initially regarded as a transcriptional noise with practically no or very little function [10]. However, after being identified as a class of RNA molecules in 2002 [11], studies that followed revealed lncRNA importance and indispensability in various cellular processes, including transcription, intracellular trafficking, and chromosome remodeling [3, 12]. In addition, lncRNAs functioning as regulatory factors have been determined for several complex cellular processes, such as cell death, growth, differentiation, identity establishment; controlling apoptosis, epigenetic regulation, genomic imprinting, alternative splicing, regulation of gene expression at posttranscriptional level, chromatin modification, inflammatory pathologies, and, when deregulated, also in various cancer types [13–23].
lncRNAs can be present in practically all cell compartments [24]. However, many lncRNAs with high abundance were identified especially in the nucleus and cytoplasm [25, 26]. lncRNA secondary structures, such as stem loops and hairpins, results of posttranscriptional modifications, enable their interaction with proteins and chromatin and are crucial for lncRNA’s vast set of functions [12]. Some of the main mechanisms of action that allow lncRNAs to have a crucial role in various cellular processes [27] are presented in Figure 1. In general, lncRNAs may act as scaffolds for grouping protein complexes (Figure 1(b)), guides to recruit proteins (Figure 1(c)), transcriptional enhancers by bending chromatin (Figure 1(d)), decoys to release proteins from chromatin (Figure 1(a)), or antagonists for other regulatory ncRNAs, for example, microRNAs (miRNAs) [12, 28].
Different mechanisms of long noncoding RNA (lncRNA) action. (a) The lncRNAs can act as decoys, titrating away DNA-binding proteins (e.g., transcription factors); (b) lncRNAs may act as scaffolds to bring two or more proteins to spatial proximity or into a complex; (c) lncRNAs may act as guides to recruit proteins to DNA (e.g., chromatin modification enzymes); (d) lncRNA guidance can also be exerted through chromosome looping in an enhancer-like model in cis. lncRNA (red); DNA (black); section of DNA loop (yellow); DNA-binding proteins (blue and light blue). The figure is adapted from John L. Rinn and Howard Y. Chang [12].
Decoy
Scaffold
Guide
Enhancer
Regardless of the whole human genome analyses that enabled better understanding of lncRNA expression, function, and distribution in the human genome, classification of lncRNAs remains to be unified [25, 29]. lncRNAs can be sorted according to their structure, sequence, function, localization, metabolism, and interaction with protein-coding genes or other DNA elements [29]. Recently, Wang et al. classified different types of lncRNAs according to their genomic location and context, exerted effect on DNA sequences, mechanism of functioning, and targeting mechanism [30]. In addition, lncRNAs can be classified into several categories including sense lncRNAs, antisense lncRNAs, bidirectional lncRNAs, intronic lncRNAs, intergenic lncRNAs, promoter-associated lncRNAs, and untranslated region- (UTR-) associated lncRNAs [25, 26]. Nevertheless, current classification methods remain inadequate and relatively nontransparent. The general long-term goal is to develop a unified, systematic, and comprehensive lncRNA classification and annotation framework, utilizing global system biology and genomics-driven approaches. Also, the development of improved tools is required for the integration of complex data from multiple types of experiments into this framework, revealing associations between coding and noncoding transcripts. Such lncRNA classification would be a prerequisite for an improved overview and more effective access and usage of large-scale lncRNA data in various fields and applications [29].
Association of lncRNAs in carcinogenesis was observed due to their differential expression in tumors when compared to normal tissues [31]. lncRNAs H19, MALAT1, and PCA3 are highly expressed tumor-associated lncRNAs that were characterized before the availability of next generation sequencing technologies [32–34]. It has been demonstrated that tumorigenesis mostly results from ectopic lncRNA expression [35]. lncRNAs regulate several oncogenes and tumor suppressor genes at transcriptional and posttranscriptional levels, affecting proliferation, apoptosis, angiogenesis, invasion, migration, and metastasis of tumor cells [36–39]. Also, lncRNA-mediated regulation of chromatin remodeling is essential for the integrity of nuclear structure [23]. In recent years, next-generation and high-throughput sequencing techniques have enabled a significant breakthrough in lncRNA identification and characterization. This resulted in continuously rising amounts of data elucidating deregulated lncRNAs associated with the development of various cancer types [40–42]. In this review, we primarily focus on describing circulating lncRNAs present in different body fluids which represent a promising category of biomarkers for cancer diagnosis, prognosis, and also treatment.
2. lncRNA-Mediated Epigenetic Modifications
Cancer development and progression can be mediated through multiple mechanisms involving lncRNAs [36, 43–46]. In particular, involvement of lncRNAs has been extensively studied in cancer progression, mainly through epigenetic regulation, activation of oncogenic pathways, and crosstalk with other RNA subtypes [29, 47, 48]. As mentioned before, lncRNAs can interact with chromatin remodeling complexes which usually leads to modifications in the expression of target genes, in either cis or trans [49]. In these processes, lncRNAs usually recruit chromatin modification factors, for example, DNA methyltransferase enzymes [50], resulting in gene expression variations often inherited within cell lineages [51]. One of the first reported and characterized lncRNA involved in cancer progression through genome-wide epigenetic reprogramming was HOTAIR [52–54]. HOTAIR acts through interaction with polycomb repressive complex 2 (PRC2) subunits, a key chromatin remodeling complex involved in gene silencing [55]. When deregulated, HOTAIR recruits PRC2 subunits in promoter regions of tumor suppressor genes which results in their transcriptional repression and chromatin condensation, thus, favoring tumor progression. Studies have shown that beside HOTAIR, ANRIL, and XIST, lncRNAs also recruit PRC2 in a similar fashion [52, 56, 57].
Studies have shown that over 200 lncRNAs participate in imprinting processes where, depending on their parental origins, specific expression of nearby lncRNAs promotes suppression of neighboring genes in cis [58, 59]. Here, instead of acting through, for example, PRC2, lncRNAs recruit DNA methyltransferases directly to modify chromatin conformation and DNA methylation. Among many lncRNAs with such function, several have been characterized, including Kcnq1ot1, TARID, H19, AS1DHRS4, and DACOR1. lncRNAs may also modify nucleosome positioning through SWI/SNF complexes as it was determined for SChLAP1 [60–65]. lncRNA SChLAP1 is overexpressed in a subset of prostate cancers. SChLAP1 can bind directly to hSNF5, one of the core subunits of the SWI/SNF complexes, thus, decreasing their genomic binding. By impairing the proper SWI/SNF regulation of gene expression, SChLAP1 antagonizes tumor suppressive function of the SWI/SNF complexes and promotes tumor cell invasion and metastasis [63, 66]. In addition, NEAT1, UCA1, HIF1A-AS1, and Evf2 also interact with core subunits of SWI/SNF complexes in a similar manner in various cancer types [67]. Other lncRNAs, including Firre, bind chromatin remodelers cohesin and CTCF in order to change the chromatin of whole chromosomes in the process of X chromosome inactivation [68]. lncRNAs may also act as chromatin activators, regulating chromosome looping in their proximity to deposit activating H3K4me3 histone mark on gene promoters [69–71].
3. Circulating lncRNAs as Biomarkers in Cancer
Among the main advantages of lncRNAs that make them suitable as cancer diagnostic and prognostic biomarkers is their high stability while circulating in body fluids, especially when included in exosomes or apoptotic bodies [72]. Studies have shown that despite abundant quantities of ribonucleases in different body fluids, lncRNAs were detected in these samples which could successfully resist ribonuclease degradation activities [35]. In addition, lncRNA deregulation in primary tumor tissues is clearly mirrored in various bodily fluids, including whole blood, plasma, urine, saliva, and gastric juice [73–76]. These lncRNA characteristics present an opportunity to develop effective and convenient lncRNA-based biomarkers that are minimally invasive and may be better tolerated by patients, when compared to conventional biopsies, due to their relative noninvasiveness [77]. Detection of circulating cancer-associated lncRNAs in body fluids could be used in the assessment of cancers at distinguishing tumor patients from healthy people at early stages with both high sensitivity and specificity. In addition, predicting the prognosis of tumor patients and the risk of tumor metastasis and recurrence after surgery could be assessed, along with evaluating operation success [35]. Several individual or combined lncRNAs have demonstrated comparable or, in some cases, even higher diagnostic performance than conventional cancer biomarkers, for different cancer types. lncRNA MALAT1 has been identified, by Kaplan-Meier analysis, as an effective prognostic parameter for patient survival in stage I nonsmall cell lung cancer [78]. Also, the measurement of lncRNA PCA3 in patient urine samples has been shown to allow more sensitive and specific diagnosis of prostate cancer than the widely used prostate-specific antigen (PSA) serum levels [79–81]. CEA, CA125, CA153, and AFP are conventional biomarkers, commonly used for breast cancer diagnosis. lncRNA RP11-445H22.4 is overexpressed in breast cancer tissues and can be detected in serum samples, with a sensitivity of 92% and specificity of 74%, which is significantly better than the performance of above listed conventional biomarkers [82]. In addition, diagnostic performances of lncRNAs TINCR, CCAT2, AOC4P, BANCR, LINC00857, AA174084, and H19 were evaluated in body fluid samples (e.g., plasma and gastric juice) of gastric cancer patients. These lncRNAs had the ability to differentiate gastric cancer patients from healthy individuals and to effectively detect different stages of gastric cancer (from early to metastatic cancer forms). However, despite their overall positive diagnostic performances, similar to those obtained by several conventional cancer biomarkers, false-positive and false-negative detections were observed [19, 76, 83]. Also, similar results were obtained after characterizing lncRNAs MALAT1 and PCA3 as biomarkers in prostate cancer patients [84, 85].
Stability of lncRNAs in body fluids of tumor patients has not been thoroughly explored. Studies revealed that some lncRNAs remained stable in plasma under extreme conditions, including several freeze-thawed cycles and prolonged incubation at elevated temperatures [86]. It has also been demonstrated that lncRNAs remained their stability when using plasma and serum from EDTA vacutainer tubes or from tubes lacking the specific anticoagulant, whereas lncRNA amounts declined when using plasma from heparin vacutainer tubes [84].
Three main mechanisms for lncRNA secretion and transport to the extracellular environment have been proposed. First, extracellular RNAs may package themselves into specific membrane vesicles, such as exosomes and microvesicles, in order to be secreted and resist RNase activity. Studies revealed that exosomes most frequently protect plasma lncRNAs [87–90]. Second, extracellular RNAs can be actively released by tumor tissues and cells [84]. However, elevated values of lncRNAs in plasma may have multiple sources, including cancer-adjacent normal cells, immune cells, and other blood cells [86, 90]. Third, extracellular RNAs may encapsulate themselves into high-density lipoprotein (HDL) or apoptotic bodies or are associated with protein complexes, for example, Argonaute- (Ago-) miRNA complex [91] and nucleophosmin 1- (NPM1-) miRNA complex [92]. However, despite many performed studies, secretion and transport mechanisms of lncRNAs to the circulation system remain poorly understood, mostly because several studies tend to contradict each other. Also, thorough examinations and reports regarding biological functions of lncRNAs in cancers are still lacking [35].
In order to introduce circulating lncRNAs into clinical practice, further studies and improvements should be performed regarding the standardization of sample preparation protocols, endogenous controls of lncRNAs in body fluids and the extraction methods should be uniformed, standards assessing the quality of lncRNAs and the credibility of qPCR results should be more accurate and reliable, and more high-quality research studies should be performed, with selection bias reduced as much as possible [35]. In addition, several technical obstacles remain to be addressed and overcome in the future, to enable a reliable use of circulating lncRNAs as effective cancer biomarkers. Commercial kits employing columns are mostly used for lncRNA extraction from body fluids. Unfortunately, no consistent results have been obtained regarding the differences in the efficiency of column-based methods, indicating that comparison and standardization of lncRNA extraction methods are necessary [93]. Absolute concentration of lncRNAs in body fluids is usually low and frequently requires an RNA amplification step prior analysis, which is time consuming and can be problematic when results are needed promptly [94]. It has also been observed that RNA extracted from plasma and serum samples may be undetectable when using a NanoDrop spectrophotometer for quantifying circulating RNAs [93]. This makes the necessity for the development of highly sensitive methods for quantifying lncRNAs crucial. Also, since the mechanisms of lncRNA secretion are not yet fully understood, the levels of circulating lncRNAs may be affected by other concomitant disease changes, besides tumorigenesis. Thus, overrated amounts of specific lncRNAs associated with a particular disease may be determined [94]. There are also several existing obstacles regarding the techniques, commonly used for quantifying circulating lncRNAs. Quantitative RT-PCR is a well-established method for detecting and quantifying circulating RNAs. However, the cost per sample is relatively high and the throughput of the method low [93]. Recently developed assays, such as the Human Disease-Related lncRNA Profiler (System Biosciences SBI), allow the measurement of a panel of lncRNAs but can detect only annotated lncRNAs. Therefore, only a medium throughput can be attained [93]. Commercial lncRNA microarray platforms can be used to detect only previously described biomarkers already present in the lncRNA databases. Microarrays have a high throughput, but a lower dynamic range and specificity, when compared to qRT-PCR and RNA-seq [93]. RNA-seq can be used for the identification of known and new lncRNA species, with lower cost per sample than microarrays and qRT-PCR. However, a relatively large amount of starting material is required (cca. 1 μg RNA), which is difficult to extract from biological fluids, for example, plasma or serum samples. In addition, current RNA-seq methodology is expensive and complex and requires a special equipment with a trained personnel [93].
Since expression profiles of cancer-associated lncRNAs may be very specific for various cancer types, these specific lncRNAs could be efficiently used as tumor biomarkers in different body fluids in the near future, with vital significance for clinical research [35]. In the following section, we describe some of these lncRNAs.
4. lncRNAs as Cancer Biomarkers Obtained from Body Fluids
Deregulated expression of lncRNAs is strongly linked to the development of various tumors and can be relatively effectively detected in patient’s body fluids for several cancer types [77]. Regarding their involvement in malignant disease development, when comparing to normal tissues of healthy individuals, lncRNAs are generally divided into oncogenic or tumor suppressive, being upregulated or downregulated, respectively [31, 45]. Sets of a number of differentially expressed cancer-associated lncRNAs in a variety of cancers are presented in Tables 1 and 2. Among them, several lncRNAs represent promising noninvasive cancer biomarkers for detection in patient’s body fluids, including PCA3, HOTAIR, HULC, MALAT1, H19, LINC00152, RP11-160H22.5, XLOC_014172, LOC149086, AA174084, and UCA1. Moreover, for several of these lncRNAs, it has been already demonstrated that they could be effectively used as diagnostic and prognostic cancer biomarkers in clinical practice.
Upregulated cancer-associated lncRNAs when compared to normal tissues.
Name
Cancer type
Fold changea
References
Wt1-as
Acute myeloid leukemia
NAb
[111]
XIST
Glioma
NA
[112]
CRNDE
Glioma
NA
[113]
MALAT1
Glioma
2.0–5.0
[114]
Colorectal
2.0–6.0
[115]
Lung
>40.0
[116]
Prostate
NA
[84]
Hepatocellular
NA
[117]
Uterus
NA
[118]
LSINCT5
Breast
2.0–7.0
[119]
LINC00617
Breast
>1.5
[120]
RP11-445H22.4
Breast
15.0–20.0
[121]
BC200
Breast
NA
[122]
CCHE1
Cervical
NA
[123]
CCAT1-L
Colorectal
NA
[71]
POU3F3
Esophageal
NA
[124]
PCAT-1
Colorectal
NA
[125]
Prostate
NA
[126]
HOTAIR
Esophageal
NA
[127]
Lung
NA
[128]
Cervical
NA
[129]
Pancreas
NA
[130]
Breast
NA
[52]
Oral
NA
[131]
Hepatocellular
>2.0
[132]
Glioma
NA
[133, 134]
Colorectal
5.2
[101]
CCAT2
Lung
7.5
[135]
Colon
NA
[136]
Cervical
NA
[137]
LINC00152
Gastric
NA
[35, 90]
LSINCT-5
Gastric
NA
[138]
HOXA11-AS
Glioma
NA
[139]
Linc-POU3F3
Glioma
>2.6
[140]
ATB
Glioma
5.0–10.0
[141]
AB073614
Glioma
NA
[142]
RP11-160H22.5
Hepatocellular
2.5
[109]
XLOC_014172
Hepatocellular
67.7
[109]
LOC149086
Hepatocellular
4.6
[109]
BANCR
Hepatocellular
NA
[143]
SNHG3
Hepatocellular
NA
[144]
MVIH
Hepatocellular
3.75
[145]
Lung
NA
[146]
LCAL1
Lung
NA
[147]
LUADT1
Lung
NA
[148]
AFAP1-AS1
Lung
NA
[149]
Colorectal
NA
[150]
Hepatocellular
NA
[151]
Esophageal
>1.0
[152]
ANRIL
Lung
>1.5
[153]
Hepatocellular
>1.0
[154]
Bladder
>1.0
[155]
UCA1
Lung
NA
[156]
Oral
NA
[157]
Bladder
32.9
[158]
Colon
NA
[159]
Hepatocellular
NA
[160]
Breast
NA
[161]
Esophageal
>2.0
[162]
CASC15
Melanoma
NA
[163]
SPRY4-IT1
Melanoma
>2.0
[164, 165]
Glioma
NA
[166]
H19
Bladder
NA
[167]
Gastric
NA
[83]
Esophageal
NA
[168]
Colorectal
NA
[169]
Glioma
NA
[170]
HULC
Pancreas
NA
[171]
Hepatocellular
32.7
[102]
Glioma
NA
[172]
PCA3
Prostate
NA
[34, 99]
PCAT5
Prostate
NA
[173]
PCAT18
Prostate
8.8–11.1
[174]
PRNCR1
Prostate
NA
[175]
NEAT1
Glioma
NA
[176, 177]
Oral
NA
[74]
Hepatocellular
NA
[178]
Nasopharyngeal
NA
[179]
PVT1
Thyroid
NA
[180]
Gastric
NA
[181]
Colorectal
NA
[182]
SRA
Breast
NA
[183]
aFold change values, relative to normal controls; bnot available (data is presented in a graphical format in the original report).
Downregulated cancer-associated lncRNAs when compared to normal tissues.
Name
Cancer type
Fold changea
References
MEG3
Glioma
NAb
[184, 185]
ZFAS1
Breast
2.0
[186]
GAS5
Breast
<1.0
[187]
Glioma
NA
[188]
LOC554202
Colorectal
NA
[189]
CUDR
Gastric
NA
[190]
PTENP1
Gastric
NA
[191]
Prostate
NA
[191]
AA174084
Gastric
3.2
[76]
LINC00982
Gastric
7.7
[192]
TSLC1-AS1
Glioma
NA
[193]
ADAMTS9-AS2
Glioma
NA
[194]
MDC1-AS
Glioma
NA
[195]
TUG1
Glioma
NA
[196]
ROR
Glioma
NA
[197]
CACS2
Glioma
NA
[198]
PRAL
Hepatocellular
NA
[199]
MALAT1
Lung
3.3
[106]
AK023948
Papillary thyroid carcinoma
5.0
[200]
aFold change values, relative to normal controls; bnot available (data is presented in a graphical format in the original report).
PCA3 has been recently approved as a urine biomarker for prostate cancer by the US Food and Drug Administration [73]. This lncRNA allows better sensitivity and specificity when compared to the widely used PSA blood test, mainly because of its significantly higher expression in prostate cancer patients [79–81, 95–97]. A meta-analysis of several studies has determined the validity of PCA3 levels in urine samples for prostate cancer diagnosis, with a summary sensitivity of 62% and specificity of 75%. In the receiver operating characteristic (ROC) curve analysis, this translated to an area under the ROC curve (AUC) of 0.75 [98]. PCA3 has also a prognostic value for prostate cancer, since its expression levels correlate well with tumor aggressiveness [99, 100].
HOTAIR was found to be highly expressed in saliva samples of oral squamous cell carcinoma (OSCC) patients. Since higher expression levels of HOTAIR were determined for metastatic patients, this lncRNA represents a strong candidate for metastatic oral cancer diagnosis [74]. In addition, the association between increased blood levels of HOTAIR and poor prognosis with higher mortality in colorectal cancer patients has been determined. Expression levels of HOTAIR could also predict the survival time of patients. Evaluated diagnostic performance of HOTAIR in peripheral blood cells has shown its sensitivity of 67%, specificity of 92.5%, and AUC of 0.87. Thus, HOTAIR represents an effective negative prognostic biomarker for colorectal cancer in blood samples [101].
HULC can be effectively detected in plasma and peripheral blood cells and is significantly overexpressed in hepatocellular carcinoma patients, thus, representing a prominent novel biomarker for liver cancer. However, no data regarding HULC diagnostic performance are available at this time [102, 103]. HULC detected in blood has also been recently proposed as a diagnostic biomarker for gastric cancer [104].
MALAT1 represents a promising diagnostic biomarker detectable in blood, to effectively screen lung cancer. One study has shown downregulation of MALAT1 in blood samples of lung cancer patients which was contrary to MALAT1 levels in lung cancer tissues, where it was significantly upregulated. Conversely, MALAT1 showed elevated expression levels in whole blood of metastatic lung cancer patients [105]. Due to its relatively low expression and low detection sensitivity (sensitivity 56%; specificity 96%; AUC 0.79) in diagnosis of non-small-cell lung cancer (NSCLC), MALAT1 is not regarded suitable as an independent biomarker to diagnose lung cancer but should be rather used as a complementary biomarker [106]. In addition to lung cancer, MALAT1 has proven itself as a prominent biomarker with its elevated expression detected in plasma and urine of prostate cancer patients, with a sensitivity and specificity of 58.6% and 84.8%, respectively (AUC 0.836). MALAT1 also helped to predict the outcome of prostate biopsies [84, 107].
Elevated expression profiles of H19 have been determined in plasma samples of gastric cancer patients. H19 has great potential as a promising biomarker due to its high diagnostic value for the detection of gastric cancer (sensitivity 82.9%; specificity 72.9%; AUC 0.838). It has also been more effective in early stage gastric cancer diagnosis than the conventional biomarkers, such as CEA and CA199, with a sensitivity of 85.5%, specificity of 80.1%, and AUC of 0.877 [83].
Expression levels of LINC00152 in plasma were found to be significantly increased in early and advanced gastric cancer patients. This lncRNA had also significantly higher expression profiles in postoperative plasma samples. The diagnostic value of LINC00152 (sensitivity 48.1%; specificity 85.2%; AUC 0.675) was better than those of CEA and CA199 biomarkers, which makes LINC00152 a good candidate as a novel blood-based biomarker for gastric cancer diagnosis [90]. In addition, LINC00152 could also be detected in the gastric juice of patients with gastric cancer [108].
Among the less commonly studied lncRNAs belong RP11-160H22.5, XLOC_014172, and LOC149086 which have been proposed as biomarkers for the diagnosis of hepatocellular carcinoma in patient plasma samples. These three lncRNAs had better scores for hepatocellular carcinoma diagnosis when used in combination, in comparison to each individual lncRNA, with a merged AUC of 0.896, sensitivity of 82%, and specificity of 73% [109]. In addition, XLOC_014172 and LOC149086 lncRNAs had also a good prognostic value for metastasis prediction (sensitivity 91%; specificity 90%; AUC for the combined lncRNAs 0.675) [109].
AA174084 represents a relatively robust but specific biomarker, suitable for the diagnosis of gastric cancer in gastric juice samples (sensitivity 46%; specificity 93%; AUC 0.848). Levels of AA174084 in patient’s gastric juices were found to be significantly upregulated when compared to those of healthy individuals. Interestingly, this lncRNA was not suitable for the diagnosis of gastric cancer from plasma samples [76].
UCA1 lncRNA has been identified as a potential biomarker for bladder cancer. Due to its relatively high overall specificity, it has a high potential to discriminate between the bladder/urothelial cancer and other cancer types, or other diseases related to the urinary tract (sensitivity 80.9%; specificity 91.8%; AUC 0.882). UCA1 can be detected in urine samples of bladder cancer patients, mostly in the cellular sediments [110].
Additional, continuously increasing amounts of information regarding cancer-associated lncRNAs, including those detected in body fluids, can be obtained from many existing databases, several of which are presented in Table 3.
lncRNAs represent a relatively large and heterogeneous group of ncRNAs and are considered as suitable diagnostic and prognostic biomarkers in cancer. In recent years, circulating lncRNAs have proven themselves extremely valuable for the detection of various cancer types. Their usage as biomarkers is convenient not only because samples containing circulating lncRNAs can be easily and noninvasively obtained from cancer patients but also because these lncRNAs remain relatively stable in body fluids. They can be quite easily detected in whole blood, plasma, serum, urine, saliva, and gastric juice samples, by using a variety of common molecular biology techniques, such as qRT-PCR, microarray hybridization, and sequencing (e.g., RNA-seq). Because lncRNAs are usually differentially abundant in different body fluids, mainly depending on the cancer type, effective cancer diagnosis and prognosis currently depend on combining different candidate lncRNAs, together with previously established biomarkers. Some circulating lncRNAs have already been proven as promising and sensitive biomarkers, and there are likely more to come.
Conflicts of Interest
The authors declare that they have no competing interests.
Acknowledgments
The authors would like to thank Nina Hauptman, PhD (Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Slovenia), for designing the figure in this review.
MattickJ. S.Non-coding RNAs: the architects of eukaryotic complexity200121198699110.1093/embo-reports/kve2302-s2.0-0035195942117131890035195942LeeC.KikyoN.Strategies to identify long noncoding RNAs involved in gene regulation201221372312668010.1186/2045-3701-2-372-s2.0-84869144550QuinnJ. J.ChangH. Y.Unique features of long non-coding RNA biogenesis and function2016171476210.1038/nrg.2015.102-s2.0-8494995209926666209HarrowJ.FrankishA.GonzalezJ. M.TapanariE.DiekhansM.KokocinskiF.AkenB. L.BarrellD.ZadissaA.SearleS.BarnesI.BignellA.BoychenkoV.HuntT.KayM.MukherjeeG.RajanJ.Despacio-ReyesG.SaundersG.StewardC.HarteR.LinM.HowaldC.TanzerA.DerrienT.ChrastJ.WaltersN.BalasubramanianS.PeiB.TressM.RodriguezJ. M.EzkurdiaI.van BarenJ.BrentM.HausslerD.KellisM.ValenciaA.ReymondA.GersteinM.GuigóR.HubbardT. J.GENCODE: the reference human genome annotation for the ENCODE project20122291760177410.1101/gr.135350.1112-s2.0-848657603952295598784865760395AlamT.MedvedevaY. A.JiaH.BrownJ. B.LipovichL.BajicV. B.Promoter analysis reveals globally differential regulation of human long non-coding RNA and protein-coding genes2014910, article e10944310.1371/journal.pone.01094432-s2.0-849075369732527532084907536973WapinskiO.ChangH. Y.Long noncoding RNAs and human disease201121635436110.1016/j.tcb.2011.04.0012-s2.0-799578403562155024479957840356BrosnanC. A.VoinnetO.The long and the short of noncoding RNAs200921341642510.1016/j.ceb.2009.04.0012-s2.0-660491385871944759466049138587BrannanC. I.DeesE. C.IngramR. S.TilghmanS. M.The product of the H19 gene may function as an RNA1990101283610.1128/MCB.10.1.2816884650025012640BrockdorffN.AshworthA.KayG. F.McCabeV. M.NorrisD. P.CooperP. J.SwiftS.RastanS.The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus199271351552610.1016/0092-8674(92)90519-I2-s2.0-002648990614236100026489906van BakelH.HughesT. R.Establishing legitimacy and function in the new transcriptome2009864244361983369810.1093/bfgp/elp0372-s2.0-70449723389OkazakiY.FurunoM.KasukawaT.AdachiJ.BonoH.KondoS.NikaidoI.OsatoN.SaitoR.SuzukiH.YamanakaI.KiyosawaH.YagiK.TomaruY.HasegawaY.NogamiA.SchönbachC.GojoboriT.BaldarelliR.HillD. P.BultC.HumeD. A.QuackenbushJ.SchrimlL. M.KanapinA.MatsudaH.BatalovS.BeiselK. W.BlakeJ. A.BradtD.BrusicV.ChothiaC.CorbaniL. E.CousinsS.DallaE.DraganiT. A.FletcherC. F.ForrestA.FrazerK. S.GaasterlandT.GariboldiM.GissiC.GodzikA.GoughJ.GrimmondS.GustincichS.HirokawaN.JacksonI. J.JarvisE. D.KanaiA.KawajiH.KawasawaY.KedzierskiR. M.KingB. L.KonagayaA.KurochkinI. V.LeeY.LenhardB.LyonsP. A.MaglottD. R.MaltaisL.MarchionniL.McKenzieL.MikiH.NagashimaT.NumataK.OkidoT.PavanW. J.PerteaG.PesoleG.PetrovskyN.PillaiR.PontiusJ. U.QiD.RamachandranS.RavasiT.ReedJ. C.ReedD. J.ReidJ.RingB. Z.RingwaldM.SandelinA.SchneiderC.SempleC. A.SetouM.ShimadaK.SultanaR.TakenakaY.TaylorM. S.TeasdaleR. D.TomitaM.VerardoR.WagnerL.WahlestedtC.WangY.WatanabeY.WellsC.WilmingL. G.Wynshaw-BorisA.YanagisawaM.YangI.YangL.YuanZ.ZavolanM.ZhuY.ZimmerA.CarninciP.HayatsuN.Hirozane-KishikawaT.KonnoH.NakamuraM.SakazumeN.SatoK.ShirakiT.WakiK.KawaiJ.AizawaK.ArakawaT.FukudaS.HaraA.HashizumeW.ImotaniK.IshiiY.ItohM.KagawaI.MiyazakiA.SakaiK.SasakiD.ShibataK.ShinagawaA.YasunishiA.YoshinoM.WaterstonR.LanderE. S.RogersJ.BirneyE.HayashizakiY.FANTOM ConsortiumRIKEN Genome Exploration Research Group Phase I & II TeamAnalysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs2002420691556357310.1038/nature012662-s2.0-0142104045124668510142104045RinnJ. L.ChangH. Y.Genome regulation by long noncoding RNAs20128114516610.1146/annurev-biochem-051410-0929022-s2.0-848619041782266307884861904178HuW.Alvarez-DominguezJ. R.LodishH. F.Regulation of mammalian cell differentiation by long non-coding RNAs2012131197198310.1038/embor.2012.1452-s2.0-848686830512307036684868683051FlynnR. A.ChangH. Y.Long noncoding RNAs in cell-fate programming and reprogramming201414675276110.1016/j.stem.2014.05.0142-s2.0-849021418002490516584902141800RossiM. N.AntonangeliF.LncRNAs: new players in apoptosis control20142014747385710.1155/2014/4738572-s2.0-8489682326024627686HarriesL. W.Long non-coding RNAs and human disease201240490290610.1042/BST201200202-s2.0-848643951012281775684864395101QianK.LiuG.TangZ.HuY.FangY.ChenZ.XuX.The long non-coding RNA NEAT1 interacted with miR-101 modulates breast cancer growth by targeting EZH220176151910.1016/j.abb.2016.12.0112803464385008224833LiuB.PanC. F.HeZ. C.WangJ.WangP. L.MaT.XiaY.ChenY. J.Long noncoding RNA-LET suppresses tumor growth and EMT in lung adenocarcinoma201620169469347110.1155/2016/46934712-s2.0-8499902953627896272ZhangK.ShiH.XiH.WuX.CuiJ.GaoY.LiangW.HuC.LiuY.LiJ.WangN.WeiB.ChenL.Genome-wide lncRNA microarray profiling identifies novel circulating lncRNAs for detection of gastric cancer20177121322710.7150/thno.160442804232984999861030YangZ. Y.YangF.ZhangY. L.LiuB.WangM.HongX.YuY.ZhouY. H.ZengH.LncRNA-ANCR down-regulation suppresses invasion and migration of colorectal cancer cells by regulating EZH2 expression2017181951042798353910.3233/CBM-161715KapranovP.ChengJ.DikeS.NixD. A.DuttaguptaR.WillinghamA. T.StadlerP. F.HertelJ.HackermüllerJ.HofackerI. L.BellI.CheungE.DrenkowJ.DumaisE.PatelS.HeltG.GaneshM.GhoshS.PiccolboniA.SementchenkoV.TammanaH.GingerasT. R.RNA maps reveal new RNA classes and a possible function for pervasive transcription20073165830148414881751032510.1126/science.11383412-s2.0-34250160256SpizzoR.AlmeidaM. I.ColombattiA.CalinG. A.Long non-coding RNAs and cancer: a new frontier of translational research?201231434577458710.1038/onc.2011.6212-s2.0-848679006382226687384867900638WiluszJ. E.SunwooH.SpectorD. L.Long noncoding RNAs: functional surprises from the RNA world20092313149415041957117910.1101/gad.18009092-s2.0-67649671961FlippotR.MaloufG. G.SuX.MouawadR.SpanoJ. P.KhayatD.Cancer subtypes classification using long non-coding RNA2016733540825409310.18632/oncotarget.102132-s2.0-8498228169427340923DerrienT.JohnsonR.BussottiG.TanzerA.DjebaliS.TilgnerH.GuernecG.MartinD.MerkelA.KnowlesD. G.LagardeJ.VeeravalliL.RuanX.RuanY.LassmannT.CarninciP.BrownJ. B.LipovichL.GonzalezJ. M.ThomasM.DavisC. A.ShiekhattarR.GingerasT. R.HubbardT. J.NotredameC.HarrowJ.GuigóR.The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression20122291775178910.1101/gr.132159.1112-s2.0-848657273932295598884865727393PontingC. P.OliverP. L.ReikW.Evolution and functions of long noncoding RNAs2009136462964110.1016/j.cell.2009.02.0062-s2.0-601490993851923988560149099385GuttmanM.RinnJ. L.Modular regulatory principles of large non-coding RNAs2012482738533934610.1038/nature108872-s2.0-848570667862233705384857066786MercerT. R.DingerM. E.MattickJ. S.Long non-coding RNAs: insights into functions200910315515910.1038/nrg25212-s2.0-603491209141918892260349120914St LaurentG.WahlestedtC.KapranovP.The landscape of long non-coding RNA classification20153152392512586999910.1016/j.tig.2015.03.0072-s2.0-84928761213WangQ.GaoS.LiH.LvM.LuC.Long noncoding RNAs (lncRNAs) in triple negative breast cancer20179999182813899210.1002/jcp.25830BartonicekN.MaagJ. L. V.DingerM. E.Long noncoding RNAs in cancer: mechanisms of action and technological advancements20161514310.1186/s12943-016-0530-62-s2.0-849733595372723361884973359537ZhangY.ShieldsT.CrenshawT.HaoY.MoultonT.TyckoB.Imprinting of human H19: allele-specific CpG methylation, loss of the active allele in Wilms tumor, and potential for somatic allele switching19935311131248391213LuoJ. H.RenB.KeryanovS.TsengG. C.RaoU. N.MongaS. P.StromS.DemetrisA. J.NalesnikM.YuY. P.RanganathanS.MichalopoulosG. K.Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas2006444101210241700693210.1002/hep.213282-s2.0-33750613935de KokJ. B.VerhaeghG. W.RoelofsR. W.HesselsD.KiemeneyL. A.AaldersT. W.SwinkelsD. W.SchalkenJ. A.DD3(PCA3), a very sensitive and specific marker to detect prostate tumors20026292695269811980670ShiT.GaoG.CaoY.Long noncoding RNAs as novel biomarkers have a promising future in cancer diagnostics2016201610908519510.1155/2016/90851952-s2.0-8496917484527143813ZhangH.ChenZ.WangX.HuangZ.HeZ.ChenY.Long non-coding RNA: a new player in cancer2013613710.1186/1756-8722-6-372-s2.0-8487837640023725405QiuM. T.HuJ. W.YinR.XuL.Long noncoding RNA: an emerging paradigm of cancer research20133426136202335927310.1007/s13277-013-0658-62-s2.0-84877147615XuS.SuiS.ZhangJ.BaiN.ShiQ.ZhangG.GaoS.YouZ.ZhanC.LiuF.PangD.Downregulation of long noncoding RNA MALAT1 induces epithelial-to-mesenchymal transition via the PI3K-AKT pathway in breast cancer2015854881489126191181JiQ.LiuX.FuX.ZhangL.SuiH.ZhouL.SunJ.CaiJ.QinJ.RenJ.LiQ.Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/beta-catenin signal pathway2013811, article e7870010.1371/journal.pone.00787002-s2.0-848929299802424434384892929980IyerM. K.NiknafsY. S.MalikR.SinghalU.SahuA.HosonoY.BarretteT. R.PrensnerJ. R.EvansJ. R.ZhaoS.PoliakovA.CaoX.DhanasekaranS. M.WuY. M.RobinsonD. R.BeerD. G.FengF. Y.IyerH. K.ChinnaiyanA. M.The landscape of long noncoding RNAs in the human transcriptome201547319920810.1038/ng.31922-s2.0-849240633552559940384924063355YanX.HuZ.FengY.HuX.YuanJ.ZhaoS. D.ZhangY.YangL.ShanW.HeQ.FanL.KandalaftL. E.TanyiJ. L.LiC.YuanC. X.ZhangD.YuanH.HuaK.LuY.KatsarosD.HuangQ.MontoneK.FanY.CoukosG.BoydJ.SoodA. K.RebbeckT.MillsG. B.DangC. V.ZhangL.Comprehensive genomic characterization of long non-coding RNAs across human cancers201528452954010.1016/j.ccell.2015.09.0062-s2.0-849440773582646109584944077358ClarkM. B.MercerT. R.BussottiG.LeonardiT.HaynesK. R.CrawfordJ.BrunckM. E.CaoK. A.ThomasG. P.ChenW. Y.TaftR. J.NielsenL. K.EnrightA. J.MattickJ. S.DingerM. E.Quantitative gene profiling of long noncoding RNAs with targeted RNA sequencing201512433934210.1038/nmeth.33212-s2.0-849265248932575114384926524893CheethamS. W.GruhlF.MattickJ. S.DingerM. E.Long noncoding RNAs and the genetics of cancer2013108122419242510.1038/bjc.2013.2332-s2.0-848796847912366094284879684791GibbE. A.BrownC. J.LamW. L.The functional role of long non-coding RNA in human carcinomas20111013810.1186/1476-4598-10-382-s2.0-799538884602148928979953888460HauptmanN.GlavacD.Long non-coding RNA in cancer20131434655466910.3390/ijms140346552-s2.0-848750577362344316484875057736MitraS. A.MitraA. P.TricheT. J.A central role for long non-coding RNA in cancer20123177010.3389/fgene.2012.000172-s2.0-8486866468022363342CalinG. A.LiuC. G.FerracinM.HyslopT.SpizzoR.SevignaniC.FabbriM.CimminoA.LeeE. J.WojcikS. E.ShimizuM.TiliE.RossiS.TaccioliC.PichiorriF.LiuX.ZupoS.HerleaV.GramantieriL.LanzaG.AlderH.RassentiL.VoliniaS.SchmittgenT. D.KippsT. J.NegriniM.CroceC. M.Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas200712321522910.1016/j.ccr.2007.07.0272-s2.0-345482308851778520334548230885GaoY. F.WangZ. B.ZhuT.MaoC. X.MaoX. Y.LiL.YinJ. Y.ZhouH. H.LiuZ. Q.A critical overview of long non-coding RNA in glioma etiology 2016: an update2016371114403144132762929010.1007/s13277-016-5307-42-s2.0-84988416367FaticaA.BozzoniI.Long non-coding RNAs: new players in cell differentiation and development20141517212429653510.1038/nrg36062-s2.0-84890559595LaiF.ShiekhattarR.Where long noncoding RNAs meet DNA methylation201424326326410.1038/cr.2014.132-s2.0-848976065402448153084897606540MartinC.ZhangY.Mechanisms of epigenetic inheritance200719326627210.1016/j.ceb.2007.04.0022-s2.0-342501925371746650234250192537GuptaR. A.ShahN.WangK. C.KimJ.HorlingsH. M.WongD. J.TsaiM. C.HungT.ArganiP.RinnJ. L.WangY.BrzoskaP.KongB.LiR.WestR. B.van de VijverM. J.SukumarS.ChangH. Y.Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis201046472911071107610.1038/nature089752-s2.0-779511189362039356677951118936LuL.ZhuG.ZhangC.DengQ.KatsarosD.MayneS. T.RischH. A.MuL.CanutoE. M.GregoriG.BenedettoC.YuH.Association of large noncoding RNA HOTAIR expression and its downstream intergenic CpG island methylation with survival in breast cancer2012136387588310.1007/s10549-012-2314-z2-s2.0-848787670582312441784878767058SorensenK. P.ThomassenM.TanQ.BakM.ColdS.BurtonM.LarsenM. J.KruseT. A.Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer2013142352953610.1007/s10549-013-2776-72-s2.0-848903101892425826084890310189BeckedorffF. C.AmaralM. S.Deocesano-PereiraC.Verjovski-AlmeidaS.Long non-coding RNAs and their implications in cancer epigenetics2013334, article e0006110.1042/BSR201300542-s2.0-848848347212387568784884834721RinnJ. L.KerteszM.WangJ. K.SquazzoS. L.XuX.BrugmannS. A.GoodnoughL. H.HelmsJ. A.FarnhamP. J.SegalE.ChangH. Y.Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs200712971311132310.1016/j.cell.2007.05.0222-s2.0-342507291381760472034250729138KanduriC.WhiteheadJ.MohammadF.The long and the short of it: RNA-directed chromatin asymmetry in mammalian X-chromosome inactivation2009583585786410.1016/j.febslet.2009.02.0042-s2.0-613491931051930278361349193105CaoJ.The functional role of long non-coding RNAs and epigenetics20141611110.1186/1480-9222-16-112-s2.0-849079111722527609884907911172HeY.MengX. M.HuangC.WuB. M.ZhangL.LvX. W.LiJ.Long noncoding RNAs: novel insights into hepatocelluar carcinoma20143441202710.1016/j.canlet.2013.10.0212-s2.0-848937009112418385184893700911MohammadF.MondalT.GusevaN.PandeyG. K.KanduriC.Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1201013715249324992057369810.1242/dev.0481812-s2.0-77955757309LiQ.SuZ.XuX.LiuG.SongX.WangR.SuiX.LiuT.ChangX.HuangD.AS1DHRS4, a head-to-head natural antisense transcript, silences the DHRS4 gene cluster in cis and trans201210935141101411510.1073/pnas.11165971092-s2.0-848655535752289133484865553575MerryC. R.ForrestM. E.SabersJ. N.BeardL.GaoX. H.HatzoglouM.JacksonM. W.WangZ.MarkowitzS. D.KhalilA. M.DNMT1-associated long non-coding RNAs regulate global gene expression and DNA methylation in colon cancer201524216240625310.1093/hmg/ddv3432-s2.0-849460208072630708884946020807LeeR. S.RobertsC. W.Linking the SWI/SNF complex to prostate cancer201345111268126910.1038/ng.28052-s2.0-848917000302416572684891700030ArabK.ParkY. J.LindrothA. M.SchäferA.OakesC.WeichenhanD.LukanovaA.LundinE.RischA.MeisterM.DienemannH.DyckhoffG.Herold-MendeC.GrummtI.NiehrsC.PlassC.Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A201455460461410.1016/j.molcel.2014.06.0312-s2.0-849067910432508787284906791043MonnierP.MartinetC.PontisJ.StanchevaI.Ait-Si-AliS.DandoloL.H19 lncRNA controls gene expression of the imprinted gene network by recruiting MBD1201311051206932069810.1073/pnas.13102011102-s2.0-848908282362429792184890828236PrensnerJ. R.IyerM. K.SahuA.AsanganiI. A.CaoQ.PatelL.VergaraI. A.DavicioniE.ErhoN.GhadessiM.JenkinsR. B.TricheT. J.MalikR.BedenisR.McGregorN.MaT.ChenW.HanS.JingX.CaoX.WangX.ChandlerB.YanW.SiddiquiJ.KunjuL. P.DhanasekaranS. M.PientaK. J.FengF. Y.ChinnaiyanA. M.The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex201345111392139810.1038/ng.27712-s2.0-848871224612407660184887122461TangY.WangJ.LianY.FanC.ZhangP.WuY.LiX.XiongF.LiX.LiG.XiongW.ZengZ.Linking long non-coding RNAs and SWI/SNF complexes to chromatin remodeling in cancer2017161422821264610.1186/s12943-017-0612-0YangF.DengX.MaW.BerletchJ. B.RabaiaN.WeiG.MooreJ. M.FilippovaG. N.XuJ.LiuY.NobleW. S.ShendureJ.DistecheC. M.The lncRNA Firre anchors the inactive X chromosome to the nucleolus by binding CTCF and maintains H3K27me3 methylation2015161522588744710.1186/s13059-015-0618-02-s2.0-84938412430WangK. C.YangY. W.LiuB.SanyalA.Corces-ZimmermanR.ChenY.LajoieB. R.ProtacioA.FlynnR. A.GuptaR. A.WysockaJ.LeiM.DekkerJ.HelmsJ. A.ChangH. Y.A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression2011472734112012410.1038/nature098192-s2.0-799537486732142316879953748673LaiF.OromU. A.CesaroniM.BeringerM.TaatjesD. J.BlobelG. A.ShiekhattarR.Activating RNAs associate with mediator to enhance chromatin architecture and transcription2013494743849750110.1038/nature118842-s2.0-848743683492341706884874368349XiangJ. F.YinQ. F.ChenT.ZhangY.ZhangX. O.WuZ.ZhangS.WangH. B.GeJ.LuX.YangL.ChenL. L.Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus201424551353110.1038/cr.2014.352-s2.0-848999390742466248484899939074AkersJ. C.GondaD.KimR.CarterB. S.ChenC. C.Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies2013113111110.1007/s11060-013-1084-82-s2.0-848743550762345666184874355076SartoriD. A.ChanD. W.Biomarkers in prostate cancer: what’s new?201426325926410.1097/CCO.00000000000000652-s2.0-848994900622462612884899490062TangH.WuZ.ZhangJ.SuB.Salivary lncRNA as a potential marker for oral squamous cell carcinoma diagnosis20137376176610.3892/mmr.2012.12542-s2.0-8487320612023292713ReisE. M.Verjovski-AlmeidaS.Perspectives of long non-coding RNAs in cancer diagnostics20123323210.3389/fgene.2012.000322-s2.0-8487101892322408643ShaoY.YeM.JiangX.SunW.DingX.LiuZ.YeG.ZhangX.XiaoB.GuoJ.Gastric juice long noncoding RNA used as a tumor marker for screening gastric cancer2014120213320332810.1002/cncr.288822-s2.0-849194543122498604184919454312SilvaA.BullockM.CalinG.The clinical relevance of long non-coding RNAs in cancer2015742169218210.3390/cancers70408842-s2.0-849459347202651691884945934720JiP.DiederichsS.WangW.BöingS.MetzgerR.SchneiderP. M.TidowN.BrandtB.BuergerH.BulkE.ThomasM.BerdelW. E.ServeH.Müller-TidowC.MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer200322398031804110.1038/sj.onc.12069282-s2.0-0344429906129707510344429906FradetY.SaadF.AprikianA.DessureaultJ.ElhilaliM.TrudelC.MâsseB.PichéL.ChypreC.uPM3, a new molecular urine test for the detection of prostate cancer2004642311315discussion 315-31610.1016/j.urology.2004.03.0522-s2.0-2342452144153024852342452144TinzlM.MarbergerM.HorvathS.ChypreC.DD3PCA3 RNA analysis in urine—a new perspective for detecting prostate cancer2004462182186discussion 18710.1016/j.eururo.2004.06.0042-s2.0-3142540904152458113142540904ShappellS. B.Clinical utility of prostate carcinoma molecular diagnostic tests2008101446918470278RasoolM.MalikA.ZahidS.AshrafM. A.QaziM. H.AsifM.ZaheerA.ArshadM.RazaA.JamalM. S.Non-coding RNAs in cancer diagnosis and therapy201611697610.1016/j.ncrna.2016.11.001ZhouX.YinC.DangY.YeF.ZhangG.Identification of the long non-coding RNA H19 in plasma as a novel biomarker for diagnosis of gastric cancer20155, article 115162609607310.1038/srep115162-s2.0-84934985556RenS.WangF.ShenJ.SunY.XuW.LuJ.WeiM.XuC.WuC.ZhangZ.GaoX.LiuZ.HouJ.HuangJ.SunY.Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 derived miniRNA as a novel plasma-based biomarker for diagnosing prostate cancer20134913294929592372626610.1016/j.ejca.2013.04.0262-s2.0-84881092106HuB.YangH.YangH.Diagnostic value of urine prostate cancer antigen 3 test using a cutoff value of 35 mug/L in patients with prostate cancer2014359857385802486394510.1007/s13277-014-2109-42-s2.0-84919836153AritaT.IchikawaD.KonishiH.KomatsuS.ShiozakiA.ShodaK.KawaguchiT.HirajimaS.NagataH.KubotaT.FujiwaraH.OkamotoK.OtsujiE.Circulating long non-coding RNAs in plasma of patients with gastric cancer20133383185319323898077TrajkovicK.HsuC.ChiantiaS.RajendranL.WenzelD.WielandF.SchwilleP.BrüggerB.SimonsM.Ceramide triggers budding of exosome vesicles into multivesicular endosomes20083195867124412471830908310.1126/science.11531242-s2.0-40049112564JohnstoneR. M.Exosomes biological significance: a concise review20063623153211648773110.1016/j.bcmd.2005.12.0012-s2.0-33645314949HuangX.YuanT.TschannenM.SunZ.JacobH.DuM.LiangM.DittmarR. L.LiuY.LiangM.KohliM.ThibodeauS. N.BoardmanL.WangL.Characterization of human plasma-derived exosomal RNAs by deep sequencing20131413192366336010.1186/1471-2164-14-3192-s2.0-84877298502LiQ.ShaoY.ZhangX.ZhengT.MiaoM.QinL.WangB.YeG.XiaoB.GuoJ.Plasma long noncoding RNA protected by exosomes as a potential stable biomarker for gastric cancer2015363200720122539142410.1007/s13277-014-2807-y2-s2.0-84930889309ArroyoJ. D.ChevilletJ. R.KrohE. M.RufI. K.PritchardC. C.GibsonD. F.MitchellP. S.BennettC. F.Pogosova-AgadjanyanE. L.StirewaltD. L.TaitJ. F.TewariM.Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma2011108125003500810.1073/pnas.10190551082-s2.0-799532022002138319479953202200WangK.ZhangS.WeberJ.BaxterD.GalasD. J.Export of microRNAs and microRNA-protective protein by mammalian cells201038207248725910.1093/nar/gkq6012-s2.0-781494093162061590178149409316QiP.ZhouX.DuX.Circulating long non-coding RNAs in cancer: current status and future perspectives20161513910.1186/s12943-016-0524-42-s2.0-849695146082718922484969514608HuangJ. L.ZhengL.HuY. W.WangQ.Characteristics of long non-coding RNA and its relation to hepatocellular carcinoma201435350751410.1093/carcin/bgt4052-s2.0-848957887252429658884895788725LeeG. L.DobiA.SrivastavaS.Prostate cancer: diagnostic performance of the PCA3 urine test20118312312410.1038/nrurol.2011.102-s2.0-799526351672139417579952635167ShappellS. B.FulmerJ.ArguelloD.WrightB. S.OppenheimerJ. R.PutziM. J.PCA3 urine mRNA testing for prostate carcinoma: patterns of use by community urologists and assay performance in reference laboratory setting200973236336810.1016/j.urology.2008.08.4592-s2.0-586491134101899589058649113410HesselsD.Klein GunnewiekJ. M.van OortI.KarthausH. F.van LeendersG. J.van BalkenB.KiemeneyL. A.WitjesJ. A.SchalkenJ. A.DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer2003441815discussion 15-1610.1016/S0302-2838(03)00201-X2-s2.0-0037974513128146690037974513XueW. J.YingX. L.JiangJ. H.XuY. H.Prostate cancer antigen 3 as a biomarker in the urine for prostate cancer diagnosis: a meta-analysis201410SupplementC218C2212545028610.4103/0973-1482.1458812-s2.0-84916638772MerolaR.TomaoL.AntenucciA.SperdutiI.SentinelliS.MasiS.MandojC.OrlandiG.PapaliaR.GuaglianoneS.CostantiniM.CusumanoG.CiglianaG.AscenziP.GallucciM.ContiL.PCA3 in prostate cancer and tumor aggressiveness detection on 407 high-risk patients: a National Cancer Institute experience2015341152565191710.1186/s13046-015-0127-82-s2.0-84924214573ChevliK. K.DuffM.WalterP.YuC.CapuderB.ElshafeiA.MalczewskiS.KattanM. W.JonesJ. S.Urinary PCA3 as a predictor of prostate cancer in a cohort of 3,073 men undergoing initial prostate biopsy201419161743174810.1016/j.juro.2013.12.0052-s2.0-849004032082433324184900403208SvobodaM.SlyskovaJ.SchneiderovaM.MakovickyP.BielikL.LevyM.LipskaL.HemmelovaB.KalaZ.ProtivankovaM.VycitalO.LiskaV.SchwarzovaL.VodickovaL.VodickaP.HOTAIR long non-coding RNA is a negative prognostic factor not only in primary tumors, but also in the blood of colorectal cancer patients20143571510151510.1093/carcin/bgu0552-s2.0-849040156742458392684904015674PanzittK.TschernatschM. M.GuellyC.MoustafaT.StradnerM.StrohmaierH. M.BuckC. R.DenkH.SchroederR.TraunerM.ZatloukalK.Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA2007132133034210.1053/j.gastro.2006.08.0262-s2.0-338462232941724188333846223294XieH.MaH.ZhouD.Plasma HULC as a promising novel biomarker for the detection of hepatocellular carcinoma20132013513610610.1155/2013/1361062-s2.0-8487869252123762823ZhaoY.GuoQ.ChenJ.HuJ.WangS.SunY.Role of long non-coding RNA HULC in cell proliferation, apoptosis and tumor metastasis of gastric cancer: a clinical and in vitro investigation201431135836410.3892/or.2013.28502-s2.0-8489193083324247585GuoF.YuF.WangJ.LiY.LiY.LiZ.ZhouQ.Expression of MALAT1 in the peripheral whole blood of patients with lung cancer20153330931210.3892/br.2015.42226137228WeberD. G.JohnenG.CasjensS.BrykO.PeschB.JöckelK. H.KollmeierJ.BrüningT.Evaluation of long noncoding RNA MALAT1 as a candidate blood-based biomarker for the diagnosis of non-small cell lung cancer20136151810.1186/1756-0500-6-5182-s2.0-848890223382431394584889022338WangF.RenS.ChenR.LuJ.ShiX.ZhuY.ZhangW.JingT.ZhangC.ShenJ.XuC.WangH.WangH.WangY.LiuB.LiY.FangZ.GuoF.QiaoM.WuC.WeiQ.XuD.ShenD.LuX.GaoX.HouJ.SunY.Development and prospective multicenter evaluation of the long noncoding RNA MALAT-1 as a diagnostic urinary biomarker for prostate cancer2014522110911110210.18632/oncotarget.26912552602984917730452PangQ.GeJ.ShaoY.SunW.SongH.XiaT.XiaoB.GuoJ.Increased expression of long intergenic non-coding RNA LINC00152 in gastric cancer and its clinical significance2014356544154472452302110.1007/s13277-014-1709-32-s2.0-84904727229TangJ.JiangR.DengL.ZhangX.WangK.SunB.Circulation long non-coding RNAs act as biomarkers for predicting tumorigenesis and metastasis in hepatocellular carcinoma2015664505451510.18632/oncotarget.29342571401684924229324WangX. S.ZhangZ.WangH. C.CaiJ. L.XuQ. W.LiM. Q.ChenY. C.QianX. P.LuT. J.YuL. Z.ZhangY.XinD. Q.NaY. Q.ChenW. F.Rapid identification of UCA1 as a very sensitive and specific unique marker for human bladder carcinoma20061216485148581691457110.1158/1078-0432.CCR-06-01342-s2.0-33748337949DallossoA. R.HancockA. L.MalikS.SalpekarA.King-UnderwoodL.Pritchard-JonesK.PetersJ.MoorwoodK.WardA.MalikK. T.BrownK. W.Alternately spliced WT1 antisense transcripts interact with WT1 sense RNA and show epigenetic and splicing defects in cancer20071312228722991794014010.1261/rna.5629072-s2.0-36249026230YaoY.MaJ.XueY.WangP.LiZ.LiuJ.ChenL.XiZ.TengH.WangZ.LiZ.LiuY.Knockdown of long non-coding RNA XIST exerts tumor-suppressive functions in human glioblastoma stem cells by up-regulating miR-15220153591758610.1016/j.canlet.2014.12.0512-s2.0-849222140972557878084922214097WangY.WangY.LiJ.ZhangY.YinH.HanB.CRNDE, a long-noncoding RNA, promotes glioma cell growth and invasion through mTOR signaling2015367212212810.1016/j.canlet.2015.03.0272-s2.0-849392542082581340584939254208MaJ.WangP.YaoY.LiuY.LiZ.LiuX.LiZ.ZhaoX.XiZ.TengH.LiuJ.XueY.Knockdown of long non-coding RNA MALAT1 increases the blood-tumor barrier permeability by up-regulating miR-14020161859232433810.1016/j.bbagrm.2015.11.0082-s2.0-849498449552661980284949844955YangM. H.HuZ. Y.XuC.XieL. Y.WangX. Y.ChenS. Y.LiZ. G.MALAT1 promotes colorectal cancer cell proliferation/migration/invasion via PRKA kinase anchor protein 920151852116617410.1016/j.bbadis.2014.11.0132-s2.0-849135538552544698784913553855HuangN.ChiY.XueJ.LiuM. Y.HuangS.MoM.ZhouS. L.WuJ.Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) interacts with estrogen receptor and predicted poor survival in breast cancer2016725379573796510.18632/oncotarget.93642-s2.0-8497813162127191888MalakarP.ShiloA.MogilevskyA.SteinI.PikarskyE.NevoY.BenyaminiH.ElgavishS.ZongX.PrasanthK. V.KarniR.Long noncoding RNA MALAT1 promotes hepatocellular carcinoma development by SRSF1 upregulation and mTOR activation20177751155116710.1158/0008-5472.CAN-16-15082799381885015810520YamadaK.KanoJ.TsunodaH.YoshikawaH.OkuboC.IshiyamaT.NoguchiM.Phenotypic characterization of endometrial stromal sarcoma of the uterus200697210611210.1111/j.1349-7006.2006.00147.x2-s2.0-336449261321644142033644926132SilvaJ. M.BoczekN. J.BerresM. W.MaX.SmithD. I.LSINCT5 is over expressed in breast and ovarian cancer and affects cellular proliferation20118349650521532345LiH.ZhuL.XuL.QinK.LiuC.YuY.SuD.WuK.ShengY.Long noncoding RNA linc00617 exhibits oncogenic activity in breast cancer201756131710.1002/mc.223382620751684937790348XuN.ChenF.WangF.LuX.WangX.LvM.LuC.Clinical significance of high expression of circulating serum lncRNA RP11-445H22.4 in breast cancer patients: a Chinese population-based study20153610765976652592980810.1007/s13277-015-3469-02-s2.0-84944277634IacoangeliA.LinY.MorleyE. J.MuslimovI. A.BianchiR.ReillyJ.WeedonJ.DialloR.BöckerW.TiedgeH.BC200 RNA in invasive and preinvasive breast cancer200425112125213310.1093/carcin/bgh2282-s2.0-8844260368152405118844260368YangM.ZhaiX.XiaB.WangY.LouG.Long noncoding RNA CCHE1 promotes cervical cancer cell proliferation via upregulating PCNA20153610761576222592128310.1007/s13277-015-3465-42-s2.0-84944281559TongY. S.WangX. W.ZhouX. L.LiuZ. H.YangT. X.ShiW. H.XieH. W.LvJ.WuQ. Q.CaoX. F.Identification of the long non-coding RNA POU3F3 in plasma as a novel biomarker for diagnosis of esophageal squamous cell carcinoma201514132560846610.1186/1476-4598-14-32-s2.0-84929312910GeX.ChenY.LiaoX.LiuD.LiF.RuanH.JiaW.Overexpression of long noncoding RNA PCAT-1 is a novel biomarker of poor prognosis in patients with colorectal cancer20133025882364060710.1007/s12032-013-0588-62-s2.0-84876807416PrensnerJ. R.ChenW.HanS.IyerM. K.CaoQ.KothariV.EvansJ. R.KnudsenK. E.PaulsenM. T.LjungmanM.LawrenceT. S.ChinnaiyanA. M.FengF. Y.The long non-coding RNA PCAT-1 promotes prostate cancer cell proliferation through cMyc201416119009082542596410.1016/j.neo.2014.09.0012-s2.0-84987997395WangW.HeX.ZhengZ.MaX.HuX.WuD.WangM.Serum HOTAIR as a novel diagnostic biomarker for esophageal squamous cell carcinoma2017161752837683210.1186/s12943-017-0643-6LiuX. H.LiuZ. L.SunM.LiuJ.WangZ. X.DeW.The long non-coding RNA HOTAIR indicates a poor prognosis and promotes metastasis in non-small cell lung cancer20131314642410370010.1186/1471-2407-13-4642-s2.0-84885037105LeeM.KimH. J.KimS. W.ParkS. A.ChunK. H.ChoN. H.SongY. S.KimY. T.The long non-coding RNA HOTAIR increases tumour growth and invasion in cervical cancer by targeting the Notch pathway2016728445584457110.18632/oncotarget.100652-s2.0-8497876618027323817KimK.JutooruI.ChadalapakaG.JohnsonG.FrankJ.BurghardtR.KimS.SafeS.HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer20133213161616252261401710.1038/onc.2012.1932-s2.0-84875890253WuY.ZhangL.ZhangL.WangY.LiH.RenX.WeiF.YuW.LiuT.WangX.ZhouX.YuJ.HaoX.Long non-coding RNA HOTAIR promotes tumor cell invasion and metastasis by recruiting EZH2 and repressing E-cadherin in oral squamous cell carcinoma20154662586259410.3892/ijo.2015.29762-s2.0-8492857280925901533GengY. J.XieS. L.LiQ.MaJ.WangG. Y.Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression20113962119212810.1177/1473230011039006082228952784555208731ZhangJ. X.HanL.BaoZ. S.WangY. Y.ChenL. Y.YanW.YuS. Z.PuP. Y.LiuN.YouY. P.JiangT.KangC. S.Chinese Glioma Cooperative GroupHOTAIR, a cell cycle-associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma201315121595160310.1093/neuonc/not1312-s2.0-848918523072420389484891852307KeJ.YaoY. L.ZhengJ.WangP.LiuY. H.MaJ.LiZ.LiuX. B.LiZ. Q.WangZ. H.XueY. X.Knockdown of long non-coding RNA HOTAIR inhibits malignant biological behaviors of human glioma cells via modulation of miR-3262015626219342194910.18632/oncotarget.429026183397QiuM.XuY.YangX.WangJ.HuJ.XuL.YinR.CCAT2 is a lung adenocarcinoma-specific long non-coding RNA and promotes invasion of non-small cell lung cancer2014356537553802450468210.1007/s13277-014-1700-z2-s2.0-84904741838LingH.SpizzoR.AtlasiY.NicolosoM.ShimizuM.RedisR. S.NishidaN.GafàR.SongJ.GuoZ.IvanC.BarbarottoE.De VriesI.ZhangX.FerracinM.ChurchmanM.van GalenJ. F.BeverlooB. H.ShariatiM.HaderkF.EstecioM. R.Garcia-ManeroG.PatijnG. A.GotleyD. C.BhardwajV.ShureiqiI.SenS.MultaniA. S.WelshJ.YamamotoK.TaniguchiI.SongM. A.GallingerS.CaseyG.ThibodeauS. N.Le MarchandL.TiirikainenM.ManiS. A.ZhangW.DavuluriR. V.MimoriK.MoriM.SieuwertsA. M.MartensJ. W.TomlinsonI.NegriniM.Berindan-NeagoeI.FoekensJ. A.HamiltonS. R.LanzaG.KopetzS.FoddeR.CalinG. A.CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer20132391446146110.1101/gr.152942.1122-s2.0-848837365332379695284883736533WuL.JinL.ZhangW.ZhangL.Roles of long non-coding RNA CCAT2 in cervical cancer cell growth and apoptosis2016228758792698397510.12659/MSM.8977542-s2.0-84961239972XuM. D.QiP.WengW. W.ShenX. H.NiS. J.DongL.HuangD.TanC.ShengW. Q.ZhouX. Y.DuX.Long non-coding RNA LSINCT5 predicts negative prognosis and exhibits oncogenic activity in gastric cancer20149328, article e30310.1097/MD.00000000000003032-s2.0-849201714252552647684920171425WangQ.ZhangJ.LiuY.ZhangW.ZhouJ.DuanR.PuP.KangC.HanL.A novel cell cycle-associated lncRNA, HOXA11-AS, is transcribed from the 5-prime end of the HOXA transcript and is a biomarker of progression in glioma2016373225125910.1016/j.canlet.2016.01.0392-s2.0-849586730402682813684958673040GuoH.WuL.YangQ.YeM.ZhuX.Functional linc-POU3F3 is overexpressed and contributes to tumorigenesis in glioma2015554111411910.1016/j.gene.2014.10.0382-s2.0-849125256462544528284912525646MaC. C.XiongZ.ZhuG. N.WangC.ZongG.WangH. L.BianE. B.ZhaoB.Long non-coding RNA ATB promotes glioma malignancy by negatively regulating miR-200a2016351902726790210.1186/s13046-016-0367-2HuL.LvQ. L.ChenS. H.SunB.QuQ.ChengL.GuoY.ZhouH. H.FanL.Up-regulation of long non-coding RNA AB073614 predicts a poor prognosis in patients with glioma201613443310.3390/ijerph130404332-s2.0-849642848162710454984964284816ZhouT.GaoY.Increased expression of LncRNA BANCR and its prognostic significance in human hepatocellular carcinoma201514182675876210.1186/s12957-015-0757-52-s2.0-84953884822ZhangT.CaoC.WuD.LiuL.SNHG3 correlates with malignant status and poor prognosis in hepatocellular carcinoma2016372237923852637373510.1007/s13277-015-4052-42-s2.0-84941655447ShiY.SongQ.YuS.HuD.ZhuangX.Microvascular invasion in hepatocellular carcinoma overexpression promotes cell proliferation and inhibits cell apoptosis of hepatocellular carcinoma via inhibiting miR-199a expression201582303231010.2147/OTT.S868072-s2.0-8494070736526347410NieF. Q.ZhuQ.XuT. P.ZouY. F.XieM.SunM.XiaR.LuK. H.Long non-coding RNA MVIH indicates a poor prognosis for non-small cell lung cancer and promotes cell proliferation and invasion2014358758775942479301710.1007/s13277-014-2009-72-s2.0-84922393142WhiteN. M.CabanskiC. R.Silva-FisherJ. M.DangH. X.GovindanR.MaherC. A.Transcriptome sequencing reveals altered long intergenic non-coding RNAs in lung cancer20141584292511694310.1186/s13059-014-0429-82-s2.0-84907915122QiuM.XuY.WangJ.ZhangE.SunM.ZhengY.LiM.XiaW.FengD.YinR.XuL.A novel lncRNA, LUADT1, promotes lung adenocarcinoma proliferation via the epigenetic suppression of p27201568, article e18582629131210.1038/cddis.2015.2032-s2.0-84989282618ZengZ.BoH.GongZ.LianY.LiX.LiX.ZhangW.DengH.ZhouM.PengS.LiG.XiongW.AFAP1-AS1, a long noncoding RNA upregulated in lung cancer and promotes invasion and metastasis20163717297372624599110.1007/s13277-015-3860-x2-s2.0-84938702364HanX.WangL.NingY.LiS.WangZ.Long non-coding RNA AFAP1-AS1 facilitates tumor growth and promotes metastasis in colorectal cancer2016491362757819110.1186/s40659-016-0094-3LuX.ZhouC.LiR.LiangZ.ZhaiW.ZhaoL.ZhangS.Critical role for the long non-coding RNA AFAP1-AS1 in the proliferation and metastasis of hepatocellular carcinoma2016377969997072680351310.1007/s13277-016-4858-82-s2.0-84955317436LuoH. L.HuangM. D.GuoJ. N.FanR. H.XiaX. T.HeJ. D.ChenX. F.AFAP1-AS1 is upregulated and promotes esophageal squamous cell carcinoma cell proliferation and inhibits cell apoptosis20165102879288510.1002/cam4.8482-s2.0-849924578662757775484992457866NieF. Q.SunM.YangJ. S.XieM.XuT. P.XiaR.LiuY. W.LiuX. H.ZhangE. B.LuK. H.ShuY. Q.Long noncoding RNA ANRIL promotes non-small cell lung cancer cell proliferation and inhibits apoptosis by silencing KLF2 and P21 expression201514126827710.1158/1535-7163.MCT-14-04922-s2.0-849214441032550475584921444103HuangM.ChenW.QiF.XiaR.SunM.XuT. P.YinL.ZhangE. B.DeW.ShuY. Q.Long non-coding RNA ANRIL is upregulated in hepatocellular carcinoma and regulates cell apoptosis by epigenetic silencing of KLF220158502596684510.1186/s13045-015-0146-02-s2.0-84938971230ZhuH.LiX.SongY.ZhangP.XiaoY.XingY.Long non-coding RNA ANRIL is up-regulated in bladder cancer and regulates bladder cancer cell proliferation and apoptosis through the intrinsic pathway2015467222322810.1016/j.bbrc.2015.10.0022-s2.0-849443938442644946384944393844NieW.GeH. J.YangX. Q.SunX.HuangH.TaoX.ChenW. S.LiB.LncRNA-UCA1 exerts oncogenic functions in non-small cell lung cancer by targeting miR-193a-3p201637119910610.1016/j.canlet.2015.11.0242-s2.0-849518298542665527284951829854YangY. T.WangY. F.LaiJ. Y.ShenS. Y.WangF.KongJ.ZhangW.YangH. Y.Long non-coding RNA UCA1 contributes to the progression of oral squamous cell carcinoma by regulating the WNT/β-catenin signaling pathway201610711158115892756054610.1111/cas.130582-s2.0-84997050494SrivastavaA. K.SinghP. K.RathS. K.DalelaD.GoelM. M.BhattM. L.Appraisal of diagnostic ability of UCA1 as a biomarker of carcinoma of the urinary bladder2014351111435114422512326710.1007/s13277-014-2474-z2-s2.0-84927786047HanY.YangY. N.YuanH. H.ZhangT. T.SuiH.WeiX. L.LiuL.HuangP.ZhangW. J.BaiY. X.UCA1, a long non-coding RNA up-regulated in colorectal cancer influences cell proliferation, apoptosis and cell cycle distribution20144653964012497773410.1097/PAT.00000000000001252-s2.0-84906809916XiaoJ. N.YanT. H.YuR. M.GaoY.ZengW. L.LuS. W.QueH. X.LiuZ. P.JiangJ. H.Long non-coding RNA UCA1 regulates the expression of Snail2 by miR-203 to promote hepatocellular carcinoma progression2017143698199010.1007/s00432-017-2370-12827121485014562425TuoY. L.LiX. M.LuoJ.Long noncoding RNA UCA1 modulates breast cancer cell growth and apoptosis through decreasing tumor suppressive miR-143201519183403341126439035LiJ. Y.MaX.ZhangC. B.Overexpression of long non-coding RNA UCA1 predicts a poor prognosis in patients with esophageal squamous cell carcinoma20147117938794425550835LessardL.LiuM.MarzeseD. M.WangH.ChongK.KawasN.DonovanN. C.KiyoharaE.HsuS.NelsonN.IzraelyS.Sagi-AssifO.WitzI. P.MaX. J.LuoY.HoonD. S.The CASC15 long intergenic noncoding RNA locus is involved in melanoma progression and phenotype switching2015135102464247410.1038/jid.2015.2002-s2.0-849414214102601689584941421410KhaitanD.DingerM. E.MazarJ.CrawfordJ.SmithM. A.MattickJ. S.PereraR. J.The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion201171113852386210.1158/0008-5472.CAN-10-44602-s2.0-799579077412155839179957907741MazarJ.ZhaoW.KhalilA. M.LeeB.ShelleyJ.GovindarajanS. S.YamamotoF.RatnamM.AftabM. N.CollinsS.FinckB. N.HanX.MattickJ. S.DingerM. E.PereraR. J.The functional characterization of long noncoding RNA SPRY4-IT1 in human melanoma cells20145198959896910.18632/oncotarget.18632534485984910068881LiuH.LvZ.GuoE.Knockdown of long noncoding RNA SPRY4-IT1 suppresses glioma cell proliferation, metastasis and epithelial-mesenchymal transition2015889140914626464658LuoM.LiZ.WangW.ZengY.LiuZ.QiuJ.Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression2013333221322110.1016/j.canlet.2013.01.0332-s2.0-848767143852335459184876714385TanD.WuY.HuL.HeP.XiongG.BaiY.YangK.Long noncoding RNA H19 is up-regulated in esophageal squamous cell carcinoma and promotes cell proliferation and metastasis2017301192724702210.1111/dote.124812-s2.0-84973138153YangW.NingN.JinX.The lncRNA H19 promotes cell proliferation by competitively binding to miR-200a and derepressing beta-catenin expression in colorectal cancer201720178276748410.1155/2017/276748428164117ShiY.WangY.LuanW.WangP.TaoT.ZhangJ.QianJ.LiuN.YouY.Long non-coding RNA H19 promotes glioma cell invasion by deriving miR-675201491, article e8629510.1371/journal.pone.00862952-s2.0-848998085142446601184899808514PengW.GaoW.FengJ.Long noncoding RNA HULC is a novel biomarker of poor prognosis in patients with pancreatic cancer201431123462541293910.1007/s12032-014-0346-42-s2.0-84946238770ZhuY.ZhangX.QiL.CaiY.YangP.XuanG.JiangY.HULC long noncoding RNA silencing suppresses angiogenesis by regulating ESM-1 via the PI3K/Akt/mTOR signaling pathway in human gliomas2016712144291444010.18632/oncotarget.74182-s2.0-8497164398326894862YlipaaA.KivinummiK.KohvakkaA.AnnalaM.LatonenL.ScaravilliM.KartasaloK.LeppänenS. P.KarakurtS.SeppäläJ.Yli-HarjaO.TammelaT. L.ZhangW.VisakorpiT.NykterM.Transcriptome sequencing reveals PCAT5 as a novel ERG-regulated long noncoding RNA in prostate cancer201575194026403110.1158/0008-5472.CAN-15-02172-s2.0-849453958612628217284945395861CreaF.WatahikiA.QuagliataL.XueH.PikorL.ParoliaA.WangY.LinD.LamW. L.FarrarW. L.IsogaiT.MorantR.Castori-EppenbergerS.ChiK. N.WangY.HelgasonC. D.Identification of a long non-coding RNA as a novel biomarker and potential therapeutic target for metastatic prostate cancer20145376477410.18632/oncotarget.17692451992684896847392ChungS.NakagawaH.UemuraM.PiaoL.AshikawaK.HosonoN.TakataR.AkamatsuS.KawaguchiT.MorizonoT.TsunodaT.DaigoY.MatsudaK.KamataniN.NakamuraY.KuboM.Association of a novel long non-coding RNA in 8q24 with prostate cancer susceptibility2011102124525210.1111/j.1349-7006.2010.01737.x2-s2.0-786502006182087484378650200618HeC.JiangB.MaJ.LiQ.Aberrant NEAT1 expression is associated with clinical outcome in high grade glioma patients2016124316917410.1111/apm.124802-s2.0-849574427592658208484957442759ZhenL.Yun-HuiL.Hong-YuD.JunM.Yi-LongY.Long noncoding RNA NEAT1 promotes glioma pathogenesis by regulating miR-449b-5p/c-Met axis20163716736832624226610.1007/s13277-015-3843-y2-s2.0-84938723417GuoS.ChenW.LuoY.RenF.ZhongT.RongM.DangY.FengZ.ChenG.Clinical implication of long non-coding RNA NEAT1 expression in hepatocellular carcinoma patients2015855395540226191242LuY.LiT.WeiG.LiuL.ChenQ.XuL.ZhangK.ZengD.LiaoR.The long non-coding RNA NEAT1 regulates epithelial to mesenchymal transition and radioresistance in through miR-204/ZEB1 axis in nasopharyngeal carcinoma201637911733117412702059210.1007/s13277-015-4773-42-s2.0-84961615175ZhouQ.ChenJ.FengJ.WangJ.Long noncoding RNA PVT1 modulates thyroid cancer cell proliferation by recruiting EZH2 and regulating thyroid-stimulating hormone receptor (TSHR)2016373310531132642766010.1007/s13277-015-4149-92-s2.0-84944675703KongR.ZhangE. B.YinD. D.YouL. H.XuT. P.ChenW. M.XiaR.WanL.SunM.WangZ. X.DeW.ZhangZ. H.Long noncoding RNA PVT1 indicates a poor prognosis of gastric cancer and promotes cell proliferation through epigenetically regulating p15 and p162015141822589017110.1186/s12943-015-0355-82-s2.0-84927933540TakahashiY.SawadaG.KurashigeJ.UchiR.MatsumuraT.UeoH.TakanoY.EguchiH.SudoT.SugimachiK.YamamotoH.DokiY.MoriM.MimoriK.Amplification of PVT-1 is involved in poor prognosis via apoptosis inhibition in colorectal cancers201411011641712419678510.1038/bjc.2013.6982-s2.0-84891883037YanR.WangK.PengR.WangS.CaoJ.WangP.SongC.Genetic variants in lncRNA SRA and risk of breast cancer2016716224862249610.18632/oncotarget.79952-s2.0-8496502877326967566WangP.RenZ.SunP.Overexpression of the long non-coding RNA MEG3 impairs in vitro glioma cell proliferation201211361868187410.1002/jcb.240552-s2.0-848595616162223479884859561616LiJ.BianE. B.HeX. J.MaC. C.ZongG.WangH. L.ZhaoB.Epigenetic repression of long non-coding RNA MEG3 mediated by DNMT1 represses the p53 pathway in gliomas201648272373310.3892/ijo.2015.32852-s2.0-8495692010826676363Askarian-AmiriM. E.CrawfordJ.FrenchJ. D.SmartC. E.SmithM. A.ClarkM. B.RuK.MercerT. R.ThompsonE. R.LakhaniS. R.VargasA. C.CampbellI. G.BrownM. A.DingerM. E.MattickJ. S.SNORD-host RNA Zfas1 is a regulator of mammary development and a potential marker for breast cancer201117587889110.1261/rna.25288112-s2.0-7995500545821460236Mourtada-MaarabouniM.PickardM. R.HedgeV. L.FarzanehF.WilliamsG. T.GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer20092821952081883648410.1038/onc.2008.3732-s2.0-58249098615ZhaoX.WangP.LiuJ.ZhengJ.LiuY.ChenJ.XueY.Gas5 exerts tumor-suppressive functions in human glioma cells by targeting miR-222201523121899191110.1038/mt.2015.1702-s2.0-8495263652026370254DingJ.LuB.WangJ.ShiY.LianY.ZhuY.WangJ.FanY.WangZ.DeW.WangK.Long non-coding RNA Loc554202 induces apoptosis in colorectal cancer cells via the caspase cleavage cascades2015341, article 10010.1186/s13046-015-0217-72-s2.0-8494164359326362196DongL.QiP.XuM. D.NiS. J.HuangD.XuQ. H.WengW. W.TanC.ShengW. Q.ZhouX. Y.DuX.Circulating CUDR, LSINCT-5 and PTENP1 long noncoding RNAs in sera distinguish patients with gastric cancer from healthy controls201513751128113510.1002/ijc.294842-s2.0-849315705952569435184931570595PolisenoL.SalmenaL.ZhangJ.CarverB.HavemanW. J.PandolfiP. P.A coding-independent function of gene and pseudogene mRNAs regulates tumour biology201046573011033103810.1038/nature091442-s2.0-779539576332057720677953957633FeiZ. H.YuX. J.ZhouM.SuH. F.ZhengZ.XieC. Y.Upregulated expression of long non-coding RNA LINC00982 regulates cell proliferation and its clinical relevance in patients with gastric cancer2016372198319932633461810.1007/s13277-015-3979-92-s2.0-84940703306QinX.YaoJ.GengP.FuX.XueJ.ZhangZ.LncRNA TSLC1-AS1 is a novel tumor suppressor in glioma2014763065307225031725YaoJ.ZhouB.ZhangJ.GengP.LiuK.ZhuY.ZhuW.A new tumor suppressor LncRNA ADAMTS9-AS2 is regulated by DNMT1 and inhibits migration of glioma cells2014358793579442483308610.1007/s13277-014-1949-22-s2.0-84920928879YueH.ZhuJ.XieS.LiF.XuQ.MDC1-AS, an antisense long noncoding RNA, regulates cell proliferation of glioma20168120320910.1016/j.biopha.2016.03.0022-s2.0-8496361150827261595LiJ.ZhangM.AnG.MaQ.LncRNA TUG1 acts as a tumor suppressor in human glioma by promoting cell apoptosis2016241664464910.1177/15353702156227082-s2.0-8496040327626748401FengS.YaoJ.ChenY.GengP.ZhangH.MaX.ZhaoJ.YuX.Expression and functional role of reprogramming-related long noncoding RNA (lincRNA-ROR) in glioma201556362363010.1007/s12031-014-0488-z2-s2.0-849315755542565189384931575554WangP.LiuY. H.YaoY. L.LiZ.LiZ. Q.MaJ.XueY. X.Long non-coding RNA CASC2 suppresses malignancy in human gliomas by miR-21201527227528210.1016/j.cellsig.2014.11.0112-s2.0-849188092022544626184918809202ZhouC. C.YangF.YuanS. X.MaJ. Z.LiuF.YuanJ. H.BiF. R.LinK. Y.YinJ. H.CaoG. W.ZhouW. P.WangF.SunS. H.Systemic genome screening identifies the outcome associated focal loss of long noncoding RNA PRAL in hepatocellular carcinoma201663385086310.1002/hep.283932-s2.0-8495905076926663434HeH.NagyR.LiyanarachchiS.JiaoH.LiW.SusterS.KereJ.de la ChapelleA.A susceptibility locus for papillary thyroid carcinoma on chromosome 8q24200969262563110.1158/0008-5472.CAN-08-10712-s2.0-583490883141914757758349088314YangJ. H.LiJ. H.JiangS.ZhouH.QuL. H.ChIPBase: a database for decoding the transcriptional regulation of long non-coding RNA and microRNA genes from ChIP-Seq data201341Database issueD177D18710.1093/nar/gks10602-s2.0-8487656691423161675WeirickT.JohnD.DimmelerS.UchidaS.C-It-Loci: a knowledge database for tissue-enriched loci201531213537354310.1093/bioinformatics/btv4102-s2.0-8494755324426163692ZhaoZ.BaiJ.WuA.WangY.ZhangJ.WangZ.LiY.XuJ.LiX.Co-LncRNA: investigating the lncRNA combinatorial effects in GO annotations and KEGG pathways based on human RNA-Seq data20152015, article bav0822636302010.1093/database/bav0822-s2.0-84943156256ParaskevopoulouM. D.GeorgakilasG.KostoulasN.ReczkoM.MaragkakisM.DalamagasT. M.HatzigeorgiouA. G.DIANA-LncBase: experimentally verified and computationally predicted microRNA targets on long non-coding RNAs201341Database issueD239D24510.1093/nar/gks12462-s2.0-8487652309623193281ParaskevopoulouM. D.VlachosI. S.KaragkouniD.GeorgakilasG.KanellosI.VergoulisT.ZagganasK.TsanakasP.FlorosE.DalamagasT.HatzigeorgiouA. G.DIANA-LncBase v2: indexing microRNA targets on non-coding transcripts201644D1D231D23810.1093/nar/gkv12702-s2.0-849768751642661286484976875164LiuK.YanZ.LiY.SunZ.Linc2GO: a human LincRNA function annotation resource based on ceRNA hypothesis201329172221222210.1093/bioinformatics/btt3612-s2.0-8488264338523793747NingS.ZhangJ.WangP.ZhiH.WangJ.LiuY.GaoY.GuoM.YueM.WangL.LiX.Lnc2Cancer: a manually curated database of experimentally supported lncRNAs associated with various human cancers201644D1D980D98510.1093/nar/gkv10942-s2.0-849768830412648135684976883041WangP.NingS.ZhangY.LiR.YeJ.ZhaoZ.ZhiH.WangT.GuoZ.LiX.Identification of lncRNA-associated competing triplets reveals global patterns and prognostic markers for cancer20154373478348910.1093/nar/gkv2332-s2.0-849305053762580074684930505376VoldersP. J.HelsensK.WangX.MentenB.MartensL.GevaertK.VandesompeleJ.MestdaghP.LNCipedia: a database for annotated human lncRNA transcript sequences and structures201341Database issueD246D25110.1093/nar/gks9152-s2.0-8487553054023042674VoldersP. J.VerheggenK.MenschaertG.VandepoeleK.MartensL.VandesompeleJ.MestdaghP.An update on LNCipedia: a database for annotated human lncRNA sequences20154384363436410.1093/nar/gkv2952-s2.0-849302257732582917884930225773ChakrabortyS.DebA.MajiR. K.SahaS.GhoshZ.LncRBase: an enriched resource for lncRNA information201499, article e10801010.1371/journal.pone.01080102-s2.0-849072127062523309284907212706JiangQ.MaR.WangJ.WuX.JinS.PengJ.TanR.ZhangT.LiY.WangY.LncRNA2Function: a comprehensive resource for functional investigation of human lncRNAs based on RNA-seq data201516Supplement 3S210.1186/1471-2164-16-S3-S22-s2.0-849651864212570751184965186421AmaralP. P.ClarkM. B.GascoigneD. K.DingerM. E.MattickJ. S.lncRNAdb: a reference database for long noncoding RNAs201139Database issueD146D1512111287310.1093/nar/gkq11382-s2.0-78651325932QuekX. C.ThomsonD. W.MaagJ. L.BartonicekN.SignalB.ClarkM. B.GlossB. S.DingerM. E.lncRNAdb v2.0: expanding the reference database for functional long noncoding RNAs201543Database issueD168D17310.1093/nar/gku9882-s2.0-8494601317525332394ChenG.WangZ.WangD.QiuC.LiuM.ChenX.ZhangQ.YanG.CuiQ.LncRNADisease: a database for long-non-coding RNA-associated diseases201341Database issueD983D9862317561410.1093/nar/gks10992-s2.0-84876125829GongJ.LiuW.ZhangJ.MiaoX.GuoA. Y.lncRNASNP: a database of SNPs in lncRNAs and their potential functions in human and mouse201543Database issueD181D18610.1093/nar/gku10002-s2.0-8494606595825332392BhartiyaD.PalK.GhoshS.KapoorS.JalaliS.PanwarB.JainS.SatiS.SenguptaS.SachidanandanC.RaghavaG. P.SivasubbuS.ScariaV.lncRNome: a comprehensive knowledgebase of human long noncoding RNAs20132013bat03410.1093/database/bat0342-s2.0-8488591247223846593JeggariA.MarksD. S.LarssonE.miRcode: a map of putative microRNA target sites in the long non-coding transcriptome201228152062206310.1093/bioinformatics/bts3442-s2.0-8486513869022718787LiuC.BaiB.SkogerboG.CaiL.DengW.ZhangY.BuD.ZhaoY.ChenR.NONCODE: an integrated knowledge database of non-coding RNAs200533Database issueD112D11510.1093/nar/gki0412-s2.0-1344426784115608158ZhaoY.LiH.FangS.KangY.WuW.HaoY.LiZ.BuD.SunN.ZhangM. Q.ChenR.NONCODE 2016: an informative and valuable data source of long non-coding RNAs201644D1D203D20810.1093/nar/gkv12522-s2.0-849768928062658679984976892806YangJ. H.LiJ. H.ShaoP.ZhouH.ChenY. Q.QuL. H.starBase: a database for exploring microRNA-mRNA interaction maps from Argonaute CLIP-Seq and Degradome-Seq data201139Database issueD202D20910.1093/nar/gkq10562-s2.0-7865130769421037263LiJ. H.LiuS.ZhouH.QuL. H.YangJ. H.starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data201442Database issueD92D9710.1093/nar/gkt12482-s2.0-8489181892424297251