lncRNAs In Patients Research Articles

Altered expression of long noncoding RNAs in peripheral blood mononuclear cells in patients with impaired leptomeningeal collaterals after acute anterior large vessel occlusions.

In the event of acute ischemic stroke (AIS) due to anterior large vessel occlusion (aLVO), leptomeningeal collaterals (LMCs) status is a key factor to define the severity and functional prognosis of this disease. However, the extent of LMCs exhibits substantial variability among the patients, which is genetic determined. Long non-coding RNAs (lncRNAs) expression profiles in human peripheral blood have been found to be altered after AIS. But whether there are specific lncRNAs correlated with LMC status in aLVO has not yet been investigated. Differential lncRNA expression panels in peripheral blood mononuclear cells (PBMCs) were assessed by microarray analysis and individual quantitative real-time polymerase chain reaction (RT-PCR) in three independent sets consist of 134 patients with aLVO and 73 healthy controls (HCs). LMCs Status in those patients was assessed based on baseline computed tomographic angiography (CTA). Microarray analysis showed 23 differentially expressed lncRNAs in patients with poor LMCs status. After independent validations by RT-PCR, lncRNA ENST00000422956 was found to be significantly downregulated in patients with poor LMCs status. Receiver-operating characteristic (ROC) analysis revealed the area under the ROC curve (AUC) for ENST00000422956 to predict poor LMCs status was 0.749. Moreover, ENST00000422956 expression level and baseline National Institutes of Health Stroke Scale (NIHSS) score were identified as independent predictors for impaired LMCs, and a significantly positive correlation was observed between ENST00000422956 expression level and LMCs status. Via cis-regulatory analysis, paired box 8 (Pax8) was identified as the target gene for ENST00000422956. The dysregulated lncRNA ENST00000422956 in PBMCs was associated with impairment of LMCs in patients with aLVO, suggesting that measurement of circulatory lncRNAs might be included as possible biomarkers for evaluation of LMCs status in AIS. More importantly, this might be the foundation for understand the potential roles of lncRNAs in LMCs formation after ischemic stroke.

Sex-specific up-regulation of lncRNAs in peripheral blood of patients with schizophrenia

Schizophrenia as a common disabling psychiatric disorder has been associated with dysregulation of several genes and pathways among them are those being regulated by long non-coding RNAs (lncRNAs). Based on the acknowledged roles of lncRNAs in neurodevelopment, in the current study, we assessed expression of six lncRNAs namely HOXA-AS2, Linc-ROR, MALAT1, MEG3, SPRY4-IT1 and UCA1 in peripheral blood of 60 patients with schizophrenia and 60 healthy subjects. HOXA-AS2, Linc-ROR, MEG3, SPRY4-IT1 and UCA1 levels were significantly higher in total patients compared with total controls. However, when evaluating expression of genes in sex-based subgroups, the differences in the expression of these lncRNAs were significant only among females. Assessment of partial correlation between expression of lncRNAs and age of study participants after controlling the effect of sex, revealed significant correlations for HOXA-AS2, MALAT1 and UCA1 in both patients and controls. Besides, expressions of Linc-ROR and SPRY4-IT1 were correlated with age only in patients. Significant pairwise correlations were recognized between expression levels of lncRNAs in both patients with schizophrenia and controls. Based on the area under curve (AUC) values, SPRY4-IT1 had the best performance in differentiation of female patients with schizophrenia from female controls (AUC = 0.85, P < 0.0001). Combination of Linc-ROR, MEG3, SPRY4-IT1 and UCA1 expression levels could differentiate female patients with 95.2% sensitivity, 76.9% specificity and diagnostic power of 0.88 (P < 0.0001). The current study suggests the presence of a sex-based dysregulation of lncRNAs in patients with schizophrenia and their possible application as diagnostic biomarkers.

Dysregulated expression of long noncoding RNAs serves as diagnostic biomarkers of type 2 diabetes mellitus.

Long noncoding RNAs (LncRNAs) are widely investigated in various diseases as a novel type of biomarkers. We aimed to elucidate the diagnostic values of lncRNAs in patients with type 2 diabetes mellitus (T2DM). We comprehensively searched PubMed, Web of Science, EMBASE, CBM, Scopus, and the Cochrane Library databases from the inception to 3 January 2019. Studies concerning the association between lncRNAs expression and diagnostic outcomes in type 2 diabetes mellitus patients were included. We employed pooled odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate diagnostic parameters. Seven relevant studies were eligible in our study. The pooled results showed that lncRNAs performed the area under the curve (AUC) of 0.73 (95%Cl: 0.69-0.77), with sensitivity of 0.71 (95%Cl: 0.64-0.77) and specificity of 0.66 (95%Cl: 0.60-0.71) in discriminating type 2 diabetes from healthy controls. As for prediabetes, lncRNAs conducted AUC of 0.75 with 76% sensitivity and 64% specificity. Moreover, subgroup analysis based on expression levels of lncRNAs, sample sizes, and specimen of eligible studies were further performed. This study indicates that lncRNAs may serve as promising indicators for diagnostic evaluation of T2DM patients.

Differential expression of lncRNA in patients with coronary artery disease plus clopidogrel resistance

To explore differential expression of long non-coding RNA (lncRNA) in patients with coronary artery disease plus clopidogrel resistance. Methods: Patients underwent percutaneous coronary intervention (PCI) and treated with clopidogrel were recruited, and their clinical data and blood samples were collected. Patients were divided into a clopidogrel sensitive group and a clopidogrel resistance group according to platelet aggregation rate. lncRNA microarray and real-time RT-PCR were performed in 5 and 34 patients in each group, respectively. Results: lncRNA microarray showed that 11 lncRNAs in peripheral leukocytes were up-regulated and 8 lncRNAs were down-regulated in clopidogrel resistant group. Real-time PCR indicated that two lncRNAs (NONHSAT083775.2 and NONHSAT107804.2) in leukocytes were up-regulated and one lncRNA (NONHSAT133455.2) was down-regulated in the clopidogrel resistant group compared with the clopidogrel sensitive group, consistent with the results of lncRNA microarray. Conclusion: Clopidogrel resistance is associated with the up-regulation of lncRNA NONHSAT083775.2 and NONHSAT107804.2 and the down-regulation of NONHSAT133455.2.

A long noncoding RNAs signature to improve survival prediction in endometrioid endometrial cancer.

The dysregulation of long noncoding RNAs (lncRNAs) has been reported to be correlated to carcinogenesis and cancer progression. Endometrial cancer (EC), arising from the endometrium or the inner lining of the uterus, is one of the most common gynecological malignancies. We aim to explore the prognostic value of the lncRNAs in patients withendometrioid endometrial cancer (EEC) and to identify the potential lncRNA signature for predicting survival of patients with EEC. We performed a genome-wide analysis of the lncRNA expression profiling in The Cancer Genome Atlas (TCGA)-Uterine Corpus Endometrial Carcinoma database (408 EEC) to identify the prognosis related lncRNAs for the EEC. The patients with EEC were randomly divided into a training set (204 for endometrioid) and a testing set (204 for endometrioid). The lncRNA signature was identified in the training set, and then independently validated in the testing set and the complete set (training set plus testing set). We developed a nine-lncRNA signature-based risk score in the patients with EEC. The risk score based on the novel lncRNAs signature was able to separate patients of training set into high-and low-risk groups with significantly different overall survival and progression-free survival. These can also be successfully confirmed in the testing set and complete set. A nine-lncRNA expression signature was identified and validated which can predict EEC patient's survival. These findings may have important implications in the understanding of the potential therapeutic methods for patients with EEC.

The transcriptome profiles and methylation status revealed the potential cancer-related lncRNAs in patients with cervical cancer.

Cervical cancer continues to be a major public health problem. Although long noncoding RNAs (lncRNAs) were involved in the initiation and progression of cancer, few studies focus on the lncRNAs in the cervical cancer. Here, we systematically studied the clinical information, transcriptome profiling, and methylation array data of cervical squamous cell carcinoma and endocervical adenocarcinoma that retrieved from genomic data commons (GDC). Compared with protein-coding genes, the expression levels of pseudogenes and lncRNAs were much lower. A total of 190 differentially expressed lncRNAs and 2,326 protein-coding genes were identified. Meanwhile, 269 differentially methylation regions (DMRs), where 16 lncRNAs were located, were figured out. Only one lncRNA, LINC00592, which was located in the DMRs, was also found differentially expressed. Several transcriptional regulation genes, such as ZNF20, ZNF441, ZNF573, and TMF1, were highly correlated with the expression of LINC00592, which illustrated its possible function on the transcription. Two microRNAs, which were both associated with tumor progression, can bind to LINC00592. Moreover, LINC00592 were also differentially expressed in other tumors. We proposed, with the help of various databases, that LINC00592 is a potential cancer-related lncRNA in cervical cancer and might activate the cancer progression through the regulation of transcription or structural integrity.

Expression Analysis of PVT1, CCDC26, and CCAT1 Long Noncoding RNAs in Acute Myeloid Leukemia Patients.

Recent evidence indicates that the PVT1, CCDC26, and CCAT1 long noncoding RNAs (lncRNAs) are involved in the leukemogenic process. This study quantified the expression levels of the PVT1, CCDC26, and CCAT1 lncRNAs in patients with acute myeloid leukemia (AML) and also correlated their expression levels with the clinicopathological features of the patients. The expression levels of the PVT1, CCDC26, and CCAT1 lncRNAs were analyzed using quantitative reverse transcription-polymerase chain reaction of bone marrow specimens obtained from 86 AML patients, 48 AML-M3 patients, and 40 normal controls. No differences were found between the combined AML patient populations and the healthy controls with respect to the expression levels of PVT1, CCDC26, and CCAT1 (p = 0.35, p = 0.09, and p = 0.77, respectively). However, compared with the controls, the AML-M3 patients had higher PVT1 expression (p = 0.017). Furthermore, high-risk AML-M3 patients manifested higher expression levels of PVT1 than low- and intermediate-risk groups. In addition, distinctive CCDC26 and CCAT1 expression levels were observed among patients with different French-American-British subtypes (p = 0.001 for CCDC26 and p = 0.013 for CCAT1). Compared with the healthy controls, AML-M4 and M5 had higher CCAT1 expression (p = 0.04) and AML-M2 and AML-M4/M5 patients had higher CCDC26 expression (p < 0.001 and p = 0.02, respectively). In addition, different patterns of CCDC26 expression were found among the different cytogenetic risk subtypes (p = 0.005). Finally, patients with intermediate cytogenetic risk showed higher CCDC26 expression levels. The differential expression of the PVT1, CCDC26, and CCAT1 lncRNAs in different AML subtypes suggests that the deregulation of these transcripts may function in the multistep leukemogenic process and that they may serve as new therapeutic targets for this malignancy.

Differential expression of lncRNAs in patients with depression and its relationship with personality traits and social support

Objective To explore the differential expression of lncRNAs in patients with depression and its relationship with personality traits and social support. Methods The differential expression of lncRNAs in 5 patients with depression (MDD) and 5 normal controls (NC) was screened by gene chip.To validate the gene chip dataset, qRT-PCR was used to verify the expression levels of these 10 lncRNAs in a separate set of 138 consecutive patients and 43 normal subjects, and then the relationships of lncRNA expression level with personality traits and social support were analyzed. Results A total of 2 649 lncRNAs were differentially expressed, of which 534 were up-regulated and 2 115 down-regulated.The expression levels of 8 lncRNAs analyzed by qRT-PCR in patients with depression were significantly down-regulated (P<0.05 or P<0.01). The ΔCt value of PY4 was negatively correlated with anxiety/somatization factor (r=-0.210, P<0.05), and the ΔCt values of PY1, PY2 and PY6 were negatively correlated with the social support availability (r=-0.383, -0.391, -0.381 all P<0.05). Apart from PY1, the ΔCt values of the other lncRNAs were negatively correlated with paranoid (P<0.05), the ΔCt values of PY3, PY6 and PY9 were negatively correlated with the borderline and obsessive-compulsive (P<0.05) and except for PY10, the ΔCt values of the other lncRNAs were negatively correlated with the schizoid (P<0.05). Conclusion The expression levels of theses 8 lncRNAs are significantly down-regulated in patients with depression, and there is a certain correlation with anxiety/somatization factor, personality traits and social support. Key words: Depression; LncRNA; Gene chip; qRT-PCR; Personality; Social support

The Plasma LncRNA Acting as Fingerprint in Hilar Cholangiocarcinoma

Background & Aims: Current studies have indicated that long non-coding RNAs (lncRNAs) could act as tumor biomarkers for disease diagnosis and prognosis prediction. In this study, we mainly focused on determining the expression of circulating lncRNAs in patients suffering for hilar cholangiocarcinoma (HC), aiming to reveal the potential lncRNA as a fingerprint. Methods: A total 12 lncRNAs were previously proven to be aberrantly expressed in HC tumor tissues. All of the 12 lncRNAs were selected as candidate targets for subsequent circulating lncRNA assay. The candidate lncRNAs were validated by qRT-PCR arranged in training and validation sets. The risk score analysis was employed. Data was presented with receiver operating characteristic curve (ROC). Results: Circulating PCAT1, MALAT1, and CPS1-IT1 were significantly increased in plasma samples of HC patients in both the training set and validation set. Through ROC analysis, we found that the three plasmatic lncRNAs presented the area under ROC curve value (AUC) as 0.784, 0.860, and 0.677. Further combination with the three factors indicated a higher power (AUC, 0.893; sensitivity, 85.5%; specificity, 93.2%). Conclusion: This was the first time to reveal the potential circulating fingerprints for predicting HC. PCAT1, MALAT1, and CPS1-IT1 may act as novel early diagnosis biomarkers for predicting HC.

Role of the Long Non-Coding RNA Growth Arrest-Specific 5 in Glucocorticoid Response in Children with Inflammatory Bowel Disease.

Glucocorticoids (GCs) are widely employed in inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in inflammatory bowel disease (IBD). Given the high incidence of suboptimal response, associated with a significant number of side-effects, that are particularly severe in paediatric patients, the identification of subjects that are most likely to respond poorly to GCs is extremely important. Recent evidence suggests that the long non-coding RNA (lncRNA) GAS5 could be a potential marker of GC resistance. To address this issue, we evaluated the association between the lncRNA GAS5 and the efficacy of steroids, in terms of inhibition of proliferation, in two cell lines derived from colon and ovarian cancers, to confirm the sensitivity and specificity of these lncRNAs. These cells showed a different sensitivity to GCs and revealed differential expression of GAS5 after treatment. GAS5 was up-regulated in GC-resistant cells and accumulated more in the cytoplasm compared to the nucleus in response to the drug. The functions of GAS5 were assessed by silencing, and we found that GAS5 knock-down reduced the proliferation during GC treatment. Furthermore, for the first time, we measured GAS5 levels in 19 paediatric IBD patients at diagnosis and after the first cycle of GCs, and we demonstrated an up-regulation of the lncRNA in patients with unfavourable steroid response. Our preliminary results indicate that GAS5 could be considered a novel pharmacogenomic marker useful for the personalization of GC therapy.

LncRNA AK054921 and AK128652 are potential serum biomarkers and predictors of patient survival with alcoholic cirrhosis.

Alcoholic liver disease (ALD) is one of the leading causes of chronic liver disease. Recent studies have demonstrated the roles of long noncoding RNAs (lncRNAs) in the pathogenesis of several disease processes. However, the roles of lncRNAs in patients with ALD remain unexplored. Global profiling for human lncRNAs from peripheral blood RNA was performed in a well‐characterized cohort of healthy controls (HC; n = 4), excessive drinkers (ED) without liver disease (n = 4), and those with alcoholic cirrhosis (AC) with different severities (n = 12). The expression of unique lncRNA signatures were validated in a separate cohort of HC (n = 17), ED (n = 19), AC (n = 48), and human liver tissues with ALD (n = 19). A detailed analysis of plasma lncRNAs in AC subjects with different severities compared with HC identified 244 commonly up‐regulated lncRNAs and 181 commonly down‐regulated lncRNAs. We further validated top 20 most differentially up‐ and down‐regulated lncRNAs in ED and AC compared with HC and also determined the expression of selected lncRNAs in human liver tissues with or without AC. Among those lncRNAs, AK128652 and AK054921 were two of the most abundantly expressed lncRNAs in normal human plasma and liver, and their levels were significantly elevated in AC. The prognostic significance of AK128652 and AK054921 was determined in 48 subjects with AC who were followed prospectively for 520 days. The expression of AK128652 and AK054921 was inversely associated with survival in patients with AC. Conclusion: lncRNAs AK054921 and AK128652 are potential biomarkers to predict the progression to ALD in individuals with excessive alcohol consumption and are predictors of survival in patients with AC. (Hepatology Communications 2017;1:513–523)

Circulating LncRNAs as predictive biomarkers by molecular subtypes in advanced breast tumors.

e23041 Background: Breast cancer is the most common malignant tumor in women worldwide. The leading breast cancer deaths are due to advanced disease stage. For this reason, identification of novel breast cancer progression-associated biomarkers would enhance the clinical management of each patient. Long non-coding RNAs (LncRNAs) are defined as noncoding RNAs longer than 200 nucleotides and are involved in several regulatory processes, such as regulation of gene expression. Moreover, it has been described that LncRNA expression is deregulated in different human diseases such as breast cancer. However, it is unclear if circulating LncRNAs could be used as progression biomarkers of breast cancers. The purpose of this study was to evaluate the role of circulating LncRNAs in patients with advanced breast cancer. Methods: Expression of 84 LncRNAs was quantified by “RT2 IncRNA PCR Array Human Cancer PathwayFinder” (Qiagen) in plasma from 24 subjects (12 patients with advanced breast cancer and 12 healthy subjects). cDNAs were pooled into four groups, two groups containing a mixture of six patients with advanced breast cancer and another two groups containing a mixture of six cDNAs from healthy subjects. Three differentially expressed LncRNAs were selected for validation by specific real-time PCR assay. Results: Three deregulated LncRNAs were identified and validated in patients with advanced breast cancer versus healthy subjects. We found that LncRNAs GAS5 and ZFAS1 expression was decreased in the Luminal, Her2-positive and Triple Negative advance cancer groups compared to healthy subjects. In contrast, LncRNA RMRP expression was increased in Luminal and Her2-positive advance cancer groups. To our knowledge, there are no publications relating the LncRNA RMRP expression with advance breast cancer research. Conclusions: These results contribute to unreveal the role of circulating LncRNAs as biomarkers in the advanced breast cancer and provide novel non-invasive tools in this disease.

Study of long non-coding RNA HOTAIR expression in middle ear cholesteatoma

Objective:To discuss the different expression of some long-chain noncoding RNA between middle ear cholesteatoma epithelial tissue and normal external ear canal skin.Method:Real-time quantitative PCR was used to detect the expression of 6 kinds of lncRNA: HOTAIR, ANCR, TINCR, PRINS, BANCR, PICSAR in 25 cases of cholesteatoma epithelial tissues and 15 cases of normal external auditory canal skin tissue samples, respectively. And compared the expression level of lncRNA in patients with different degree of bone destruction.Result:Expression level of HOTAIR was significantly increased in cholesteatoma epithelial tissues compared with the normal external auditory canal skin tissues,and the difference is statistically significant (P< 0.01). While there was no statistically significant difference expression of the rest of the five kinds of lncRNA between middle ear cholesteatoma epithelial tissues and normal external ear canal skin (P> 0.05). And there was no statistically significant difference expression of HOTAIR in patients with different degree of bone destruction (P> 0.05).Conclusion:Expression level of HOTAIR was up-regulated in middle ear cholesteatoma epithelial tissue compared with the normal external auditory canal skin tissues, and the expression level of HOTAIR has no obvious correlation with degree of bone destruction in patients with cholesteatoma.

Prognostic value of abnormally expressed lncRNAs in ovarian carcinoma: a systematic review and meta-analysis.

Ovarian cancer (OC) is the most deadly gynecological cancer and it is urgently needed to find a new marker for the progress of OC. Many long noncoding RNAs (lncRNAs) have been reported to be aberrantly expressed in ovarian carcinoma, and may serve as prognostic markers. Therefore, we conducted this meta-analysis to gain a better understanding of the prognostic value of lncRNAs in patients with varian carcinoma. We systematically searched PubMed, EMBASE, and Web of Science. A total of 13 eligible studies, including 10 on clinicopathological features, 13 on prognosis were identified. Pooled hazard ratios (HRs) or odds ratios (OR) and 95% confidence intervals (95% CIs) were calculated using random- or fixed-effects models. Our results revealed that the increased expressions of 8 lncRNAs were associated with poor prognosis and the decreased expressions of 5 lncRNAs were related to poor prognosis in ovarian carcinoma. High HOTAIR expression was associated with shorter overall survival in ovarian cancer (pooled HR: 2.05, 95% CI: 1.51-2.77, P < 0.001). In conclusion, our meta-analysis suggested that LncRNAs could function as potential prognostic markers for ovarian cancer patients and high expression HOTAIR was associated with shorter overall survival in ovarian cancer.

The plasma lncRNA acting as fingerprint in non-small-cell lung cancer.

Recent studies have indicated that long non-coding RNAs (lncRNAs) could act as non-invasive tumor markers in both diagnosis and predicting the prognosis. In this study, we focused to determine the expression of circulating lncRNAs in patients suffering from non-small-cell lung cancer (NSCLC), aiming to found the potential lncRNA as predictor. Twenty-one lncRNAs which previously identified were selected as candidate targets for subsequent circulating lncRNA assay. The candidate lncRNAs were validated by qRT-PCR arranged in the training and validation sets. Circulating SPRY4-IT1, ANRIL, and NEAT1 were significantly increased in plasma samples of NSCLC patients during training set and validation set. Receiver operating characteristic curve (ROC) analysis revealed that plasma ANRIL provided the highest diagnostic performance with an area under ROC curve value (AUC) of 0.798. Further combination with the three factors indicated a higher power (AUC, 0.876; sensitivity, 82.8%; specificity, 92.3%). The stableness detection of the three factors indicated that circulating SPRY4-IT1, ANRIL, and NEAT might serve as a predictor for the early warning of non-small-cell lung cancer.

Circulating Long Noncoding RNA TapSAKI Is a Predictor of Mortality in Critically Ill Patients with Acute Kidney Injury

Abstract BACKGROUND Long noncoding RNAs (lncRNAs) are novel intracellular noncoding ribonucleotides regulating gene expression. Intriguingly, these RNA transcripts are detectable and stable in the blood of patients with cancer and cardiovascular disease. We tested whether circulating lncRNAs in plasma of critically ill patients with acute kidney injury (AKI) at inception of renal replacement therapy were deregulated and might predict survival. METHODS We performed a global lncRNA expression analysis using RNA isolated from plasma of patients with AKI, healthy controls, and ischemic disease controls. This global screen revealed several deregulated lncRNAs in plasma samples of patients with AKI. lncRNA-array–based alterations were confirmed in kidney biopsies of patients as well as in plasma of 109 patients with AKI, 30 age-matched healthy controls, and 30 disease controls by quantitative real-time PCR. RESULTS Circulating concentrations of the novel intronic antisense lncRNA TrAnscript Predicting Survival in AKI (TapSAKI) (P &amp;lt; 0.0001) were detectable in kidney biopsies and upregulated in plasma of patients with AKI. Cox regression and Kaplan–Meier curve analysis revealed TapSAKI as an independent predictor of 28-day survival (P &amp;lt; 0.01). TapSAKI was enriched in tubular epithelial cells subjected to ATP depletion (P = 0.03). CONCLUSIONS The alteration of circulating concentrations of lncRNAs in patients with AKI supports TapSAKI as a predictor of mortality in this patient cohort.

Long noncoding RNAs in patients with acute myocardial infarction.

Long noncoding RNAs (lncRNAs) constitute a novel class of noncoding RNAs that regulate gene expression. Although recent data suggest that lncRNAs may be associated with cardiac disease, little is known about lncRNAs in the setting of myocardial ischemia. To measure lncRNAs in patients with myocardial infarction (MI). We enrolled 414 patients with acute MI treated by primary percutaneous coronary intervention. Blood samples were harvested at the time of reperfusion. Expression levels of 5 lncRNAs were measured in peripheral blood cells by quantitative polymerase chain reaction: hypoxia inducible factor 1A antisense RNA 2, cyclin-dependent kinase inhibitor 2B antisense RNA 1 (ANRIL), potassium voltage-gated channel, KQT-like subfamily, member 1 opposite strand/antisense transcript 1 (KCNQ1OT1), myocardial infarction-associated transcript, and metastasis-associated lung adenocarcinoma transcript 1. Levels of hypoxia inducible factor 1A antisense RNA 2, KCNQ1OT1, and metastasis-associated lung adenocarcinoma transcript 1 were higher in patients with MI than in healthy volunteers (P<0.01), and levels of ANRIL were lower in patients with MI (P=0.003). Patients with ST-segment-elevation MI had lower levels of ANRIL (P<0.001), KCNQ1OT1 (P<0.001), myocardial infarction-associated transcript (P<0.001), and metastasis-associated lung adenocarcinoma transcript 1 (P=0.005) when compared with patients with non-ST-segment-elevation MI. Levels of ANRIL were associated with age, diabetes mellitus, and hypertension. Patients presenting within 3 hours of chest pain onset had elevated levels of hypoxia inducible factor 1A antisense RNA 2 when compared with patients presenting later on. ANRIL, KCNQ1OT1, myocardial infarction-associated transcript, and metastasis-associated lung adenocarcinoma transcript 1 were significant univariable predictors of left ventricular dysfunction as assessed by an ejection fraction ≤40% at 4-month follow-up. In multivariable and reclassification analyses, ANRIL and KCNQ1OT1 improved the prediction of left ventricular dysfunction by a model, including demographic features, clinical parameters, and cardiac biomarkers. Levels of lncRNAs in blood cells are regulated after MI and may help in prediction of outcome. This motivates further investigation of the role of lncRNAs after MI.

Long noncoding intronic RNAs are differentially expressed in primary and metastatic pancreatic cancer

BackgroundPancreatic ductal adenocarcinoma (PDAC) is known by its aggressiveness and lack of effective therapeutic options. Thus, improvement in current knowledge of molecular changes associated with pancreatic cancer is urgently needed to explore novel venues of diagnostics and treatment of this dismal disease. While there is mounting evidence that long noncoding RNAs (lncRNAs) transcribed from intronic and intergenic regions of the human genome may play different roles in the regulation of gene expression in normal and cancer cells, their expression pattern and biological relevance in pancreatic cancer is currently unknown. In the present work we investigated the relative abundance of a collection of lncRNAs in patients' pancreatic tissue samples aiming at identifying gene expression profiles correlated to pancreatic cancer and metastasis.MethodsCustom 3,355-element spotted cDNA microarray interrogating protein-coding genes and putative lncRNA were used to obtain expression profiles from 38 clinical samples of tumor and non-tumor pancreatic tissues. Bioinformatics analyses were performed to characterize structure and conservation of lncRNAs expressed in pancreatic tissues, as well as to identify expression signatures correlated to tissue histology. Strand-specific reverse transcription followed by PCR and qRT-PCR were employed to determine strandedness of lncRNAs and to validate microarray results, respectively.ResultsWe show that subsets of intronic/intergenic lncRNAs are expressed across tumor and non-tumor pancreatic tissue samples. Enrichment of promoter-associated chromatin marks and over-representation of conserved DNA elements and stable secondary structure predictions suggest that these transcripts are generated from independent transcriptional units and that at least a fraction is under evolutionary selection, and thus potentially functional.Statistically significant expression signatures comprising protein-coding mRNAs and lncRNAs that correlate to PDAC or to pancreatic cancer metastasis were identified. Interestingly, loci harboring intronic lncRNAs differentially expressed in PDAC metastases were enriched in genes associated to the MAPK pathway. Orientation-specific RT-PCR documented that intronic transcripts are expressed in sense, antisense or both orientations relative to protein-coding mRNAs. Differential expression of a subset of intronic lncRNAs (PPP3CB, MAP3K14 and DAPK1 loci) in metastatic samples was confirmed by Real-Time PCR.ConclusionOur findings reveal sets of intronic lncRNAs expressed in pancreatic tissues whose abundance is correlated to PDAC or metastasis, thus pointing to the potential relevance of this class of transcripts in biological processes related to malignant transformation and metastasis in pancreatic cancer.