LncRNA MIR155HG Promotes Temozolomide Resistance by Activating the Wnt/β-Catenin Pathway Via Binding to PTBP1 in Glioma

Temozolomide (TMZ) is widely used for glioma therapy in the clinic. Currently, the development of TMZ resistance has largely led to poor prognosis. However, very little is understood about the role of MIR155HG, as a long noncoding RNA, in TMZ resistance. In our study, MIR155HG level was markedly higher in glioma patients than in normal controls and that poor survival was positively correlated with MIR155HG expression. It was apparent that TMZ sensitivity was promoted by downregulation of MIR155HG, and this could be reversed by MIR155HG overexpression in vivo and in vitro. Furthermore, polypyrimidine tract binding protein 1 (PTBP1) was proven to bind with MIR155HG and to regulate MIR155HG-related TMZ resistance. Mechanistic investigation showed that the expression levels of both MIR155HG and PTBP1 influenced the expression of relevant proteins in the Wnt/β-catenin pathway. Collectively, the study demonstrated that the knockdown of MIR155HG increased glioma sensitivity to TMZ by inhibiting Wnt/β-catenin pathway activation via potently downregulating PTBP1.

     

Identification of key lncRNAs in the carcinogenesis and progression of colon adenocarcinoma by co-expression network analysis

Colon adenocarcinoma (COAD) is one of the most common cancers, and its carcinogenesis and progression is influenced by multiple long non-coding RNAs (lncRNA), especially through the miRNA sponge effect. In this study, more than 4000 lncRNAs were re-annotated from the microarray datasets through probe sequence mapping to obtain reliable lncRNA expression profiles. As a systems biology method for describing the correlation patterns among genes across microarray samples, weighted gene co-expression network analysis was conducted to identify lncRNA modules associated with the five stepwise stages from normal colonic samples to COAD (n = 94). In the most relevant module (R² = −0.78, P = 4E-20), four hub lncRNAs were identified (CTD-2396E7.11, PCGF5, RP11-33O4.1, and RP11-164P12.5). Then, these four hub lncRNAs were validated using two other independent datasets including GSE20916 (n = 145) and GSE39582 (n = 552). The results indicated that all hub lncRNAs were significantly negatively correlated with the three-stage colonic carcinogenesis, as well as TNM stages in COAD (one-way analysis of variance P < 0.05). Kaplan-Meier survival curve showed that patients with higher expression of each hub lncRNA had a significantly higher overall survival rate and lower relapse risk (log-rank P < 0.05). In conclusion, through co-expression analysis, we identified and validated four key lncRNAs in association with the carcinogenesis and progression of COAD, and these lncRNAs might have important clinical implications for improving the risk stratification, therapeutic decision and prognosis prediction in COAD patients.     

Aberrant expression of lncRNAs SNHG6, TRPM2-AS1, MIR4435-2HG,and hypomethylation of TRPM2-AS1 promoter in colorectal cancer

Accumulating evidence has indicated that deregulation of lncRNAs plays essential roles in colorectal cancer (CRC) carcinogenesis. The goal of this study was to analyze the expression of lncRNAs in colorectal cancer and their association with clinicopathological variables. Bioinformatics analysis of published CRC microarray data was performed to identify the important lncRNAs. The expression levels of candidate genes were assessed in the human colon cancer/normal cell lines, CRC, adenomatous colorectal polyps, and their marginal tissues by qRT-PCR. Moreover, the methylation status of the TRPM2-AS1 promoter was studied using qMSP assay. Furthermore, we investigated the molecular mechanisms of these lncRNAs in CRC progression using in silico analysis. Microarray analysis revealed that lncRNAs SNHG6, MIR4435-2HG, and TRPM2-AS1 were upregulated in CRC. These results were validated in colon cell lines. Moreover, qRT-PCR showed that the expression levels of SNHG6 and TRPM2-AS1 were upregulated in the colorectal tumor tissues compared with their paired tissues. Nonetheless, there was no significant increase in MIR4435-2HG expression in CRC samples. Furthermore, we observed a significant hypomethylation of TRPM2-AS1 promoter and its activation in CRC tissues. By in silico analysis, we found that the lncRNAs upregulation could promote proliferation and drug resistance of colorectal cancer cells via miRNAs sponging and modulation of their targets expression. In conclusion, based on our results upregulation of SNHG6 and TRPM2-AS1, and hypomethylation of TRPM2-AS1 promoter might be considered as potential diagnostic biomarkers for CRC initiation and development.     

Integrative analysis of OIP5-AS1/HUR1 to discover new potential biomarkers and therapeutic targets in multiple sclerosis

Multiple sclerosis (MS) is a devastating autoimmune disease of the central nervous system associated with demyelination and axonal injury. This study was designed to find potential lncRNAs and their targets that are associated with the molecular basis of MS pathogenesis. In this study, peripheral blood samples were obtained from 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls. lncRNAs and their target were selected for validation using TaqMan Real-Time PCR. Interactions were studied based on approaches that used to investigation biological functions and signaling pathways affected by differentially expressed messenger RNAs (mRNAs). The results of this study indicate an increase in the expression of HUR1 (p = 0.0001), CPSF7 (p = 0.02), and reduction of CSTF2 expression (p = 0.04). Also, an increase in the expression of OIP5-AS1 (p = 0.01) was observed in men less than 30 years old. We performed a comparative analysis of the long noncoding RNAs (lncRNAs), and then we ranked them as candidate biomarkers according to a decreasing area under the receiver operating characteristic (ROC) curve (AUC) and plotted the results. Dysregulation of lncRNA expression has been linked to diseases. Further studies on the HUR1 gene can be used as diagnostic tools for the identification of high-risk individuals in families with a history of disease before, during, and even after treatment. Our data uncovered the expression profiles of lncRNAs and mRNAs in MS patients, which will help delineate the molecular mechanisms in MS pathogenesis. However, further studies need to determine the precise role of these genes in the pathological process in MS.     

Circular RNA HIPK2 regulates astrocyte activation via cooperation of autophagy and ER stress by targeting MIR124–2HG

Circular RNAs are a subclass of noncoding RNAs in mammalian cells; however, whether these RNAs are involved in the regulation of astrocyte activation is largely unknown. Here, we have shown that the circular RNA HIPK2 (circHIPK2) functions as an endogenous microRNA-124 (MIR124–2HG) sponge to sequester MIR124–2HG and inhibit its activity, resulting in increased sigma non-opioid intracellular receptor 1 (SIGMAR1/OPRS1) expression. Knockdown of circHIPK2 expression significantly inhibited astrocyte activation via the regulation of autophagy and endoplasmic reticulum (ER) stress through the targeting of MIR124–2HG and SIGMAR1. These findings were confirmed in vivo in mouse models, as microinjection of a circHIPK2 siRNA lentivirus into mouse hippocampi inhibited astrocyte activation induced by methamphetamine or lipopolysaccharide (LPS). These findings provide novel insights regarding the specific contribution of circHIPK2 to astrocyte activation in the context of drug abuse as well as for the treatment of a broad range of neuroinflammatory disorders.     

Identification of lncRNA‐155 encoded by MIR155HG as a novel regulator of innate immunity against influenza A virus infection

Long noncoding RNAs (lncRNAs) are single‐stranded RNA molecules longer than 200 nt that regulate many cellular processes. MicroRNA 155 host gene (MIR155HG) encodes the microRNA (miR)‐155 that regulates various signalling pathways of innate and adaptive immune responses against viral infections. MIR155HG also encodes a lncRNA that we call lncRNA‐155. Here, we observed that expression of lncRNA‐155 was markedly upregulated during influenza A virus (IAV) infection both in vitro (several cell lines) and in vivo (mouse model). Interestingly, robust expression of lncRNA‐155 was also induced by infections with several other viruses. Disruption of lncRNA‐155 expression in A549 cells diminished the antiviral innate immunity against IAV. Furthermore, knockout of lncRNA‐155 in mice significantly increased IAV replication and virulence in the animals. In contrast, overexpression of lncRNA‐155 in human cells suppressed IAV replication, suggesting that lncRNA‐155 is involved in host antiviral innate immunity induced by IAV infection. Moreover, we found that lncRNA‐155 had a profound effect on expression of protein tyrosine phosphatase 1B (PTP1B) during the infection with IAV. Inhibition of PTP1B by lncRNA‐155 resulted in higher production of interferon‐beta (IFN‐β) and several critical interferon‐stimulated genes (ISGs). Together, these observations reveal that MIR155HG derived lncRNA‐155 can be induced by IAV, which modulates host innate immunity during the virus infection via regulation of PTP1B‐mediated interferon response.     

Long noncoding RNA MIR155HG facilitates pancreatic cancer progression through negative regulation of miR-802

Long noncoding RNAs (lncRNAs) present the key regulatory functions in tumorigenesis. More and more studies have suggested that lncRNA MIR155HG is involved in different human cancers. However, the underlying regulatory role of lncRNA MIR155HG and potential mechanisms in pancreatic cancer (PC) remain illusive. In this research, our group found that lncRNA MIR155HG expression was remarkably increased in PC tumor tissue and cells compared to that in the adjacent normal tissue and cells. In addition, higher MIR155HG expression was positively associated with the poor prognosis of patients. In addition, we exhibited that silence of MIR155HG by short hairpin RNA knockdown significantly inhibited cell growth and promoted cell apoptosis in PC cells. We performed bioinformatics analysis to search for the target of MIR155HG. As demonstrated by Luciferase reporter assay, we found that miR-802, a tumor suppressor in various cancer, is a direct target of MIR155HG. We demonstrated that the tumor-promoting effects of MIR155HG were contributed by negative regulation of miR-802 in PC cells. In summary, our results suggest that lncRNA MIR155HG might be applied as a novel diagnostic and therapeutic target for PC.     

Taurine-upregulated gene 1: A functional long noncoding RNA in tumorigenesis

Taurine-upregulated gene 1 (TUG1) is a 7.1 kb long noncoding RNA (lncRNA) first recognized in 2005 as an important element for retinal development in rodents. Subsequently, this lncRNA has been shown to participate in oncogenic processes through alteration in chromatin structure, sponging microRNAs, and affecting the expression of some cancer-related pathways. While most of the studies have revealed an oncogenic role for this lncRNA, some reports have shown downregulation of TUG1 in lung cancer samples compared with noncancerous samples. In triple negative breast cancer samples, the expression of this lncRNA has been decreased. Besides, its expression has been higher in HER2-enriched and basal-like subtypes compared with luminal A. In the current review, we discuss the latest literature about the expression pattern and functional roles of TUG1 in diverse cancer types. In addition, its role in epithelial−mesenchymal transition and activation of Wnt/β-catenin pathway in human malignancies will be explored.     

A prognostic 11 long noncoding RNA expression signature for breast invasive carcinoma

Breast cancer, the most common cancer in women worldwide, is associated with high mortality. The long non-coding RNAs (lncRNAs) with a little capacity of coding proteins is playing an increasingly important role in the cancer paradigm. Accumulating evidences demonstrate that lncRNAs have crucial connections with breast cancer prognosis while the studies of lncRNAs in breast cancer are still in its primary stage. In this study, we collected 1052 clinical patient samples, a comparatively large sample size, including 13 159 lncRNA expression profiles of breast invasive carcinoma (BRCA) from The Cancer Genome Atlas database to identify prognosis-related lncRNAs. We randomly separated all of these clinical patient samples into training and testing sets. In the training set, we performed univariable Cox regression analysis for primary screening and played the model for Robust likelihood-based survival for 1000 times. Then 11 lncRNAs with a frequency more than 600 were selected for prediction of the prognosis of BRCA. Using the analysis of multivariate Cox regression, we established a signature risk-score formula for 11 lncRNA to identify the relationship between lncRNA signatures and overall survival. The 11 lncRNA signature was validated both in the testing and the complete set and could effectively classify the high-/low-risk group with different OS. We also verified our results in different stages. Moreover, we analyzed the connection between the 11 lncRNAs and the genes of ESR1, PGR, and Her2, of which protein products (ESR, PGR, and HER2) were used to classify the breast cancer subtypes widely. The results indicated correlations between 11 lncRNAs and the gene of PGR and ESR1. Thus, a prognostic model for 11 lncRNA expression was developed to classify the BRAC clinical patient samples, providing new avenues in understanding the potential therapeutic methods of breast cancer.     

Genome‐wide characterization and developmental expression profiling of long non‐coding RNAs in Sogatella furcifera

The genome‐wide characterization of long non‐coding RNA (lncRNA) in insects demonstrates their importance in fundamental biological processes. Essentially, an in‐depth understanding of the functional repertoire of lncRNA in insects is pivotal to insect resources utilization and sustainable pest control. Using a custom bioinformatics pipeline, we identified 1861 lncRNAs encoded by 1852 loci in the Sogatella furcifera genome. We profiled lncRNA expression in different developmental stages and observed that the expression of lncRNAs is more highly temporally restricted compared to protein‐coding genes. More up‐regulated Sogatella furcifera lncRNA expressed in the embryo, 4th and 5th instars, suggesting that increased lncRNA levels may play a role in these developmental stages. We compared the relationship between the expression of Sogatella furcifera lncRNA and its nearest protein gene and found that lncRNAs were more correlated to their downstream coding neighbors on the opposite strand. Our genome‐wide profiling of lncRNAs in Sogatella furcifera identifies exciting candidates for characterization of lncRNAs, and also provides information on lncRNA regulation during insect development.     

Microarray analysis of long-noncoding RNAs and mRNA expression profiles in human steroid-induced avascular necrosis of the femoral head

This study performed the first microarray analysis of long-noncoding RNA (lncRNA) and mRNA expression profiles in human steroid-induced avascular necrosis of the femoral head (SAVNFH). Expression levels of lncRNAs and mRNAs in three human SAVNFH samples and three human femoral head fracture samples (controls) were detected using third-generation lncRNA microarrays (KangChen Biotech, Shanghai, China). The fold change, false discovery rate, and P value were utilized to filter genes with significant differential expression in the SAVNFH samples compared with the control samples. In total, there were 1179 upregulated and 3214 downregulated lncRNAs (P2. zerofold, P < 0.05). Meanwhile, 1092 upregulated and 565 downregulated mRNAs were found in the SAVNFH samples compared with the control samples. Then, quantitative real-time polymerase chain reaction was used to confirm the previous microarray results using 8 and 20 selected dysregulated lncRNAs and mRNAs, respectively, and the results generally confirmed the microarray findings. Finally, we used Gene Ontology (GO) and pathway analysis to investigate the functions of the altered mRNAs and their associated GO terms and biological pathways. The Immune system process term (GO:0002376) was the most significantly upregulated GO term, and the Regulation of blood coagulation term (GO:0030193) was the most significantly downregulated GO term in the biological process category for the SAVNFH samples. “Hematopoietic cell lineage - Homo sapiens (human) (Pathway ID: hsa04640)” and “Complement and coagulation cascades - Homo sapiens (human) (Pathway ID: hsa04610)” were the most significantly up- and downregulated pathways in the SAVNFH samples compared with the controls. In conclusion, the differential expression of lncRNAs and mRNAs may be correlated with the pathogenesis of SAVNFH, and these significantly dysregulated lncRNAs and mRNAs may function through networks or participate in several specific biological processes. Further research is needed to understand their exact functions and mechanisms in SAVNFH.     

Expression analysis of circulating plasma long noncoding RNAs in colorectal cancer: The relevance of lncRNAs ATB and CCAT1 as potential clinical hallmarks

Long noncoding RNAs (lncRNAs) have been demonstrated to regulate a variety of cell processes and involve in the development and progression of colorectal cancer (CRC). Recently, the circulating lncRNAs have emerged as minimally invasive biomarkers for cancer diagnosis and prognosis. We aimed to examine the plasma expression level of long noncoding RNAs lnc-ATB, lnc-CCAT1, and lnc-OCC-1 in CRC patients and evaluate the clinical values. A total of 74 pretreatment CRC and 74 healthy blood biopsies were subjected to differentially evaluate the expression levels of three lncRNAs (OCC-1, CCAT1, and ATB). Briefly, after plasma separation and total RNA extraction, RNAs were reversely transcribed to complementary DNA followed by amplification using a quantitative real-time polymerase chain reaction technique for lncRNA expression analysis. The results showed that the expression levels of lnc-ATB (p < 0.001) and CCAT1 (p = 0.024), but not OCC-1 (p = 0.24), were significantly upregulated in the CRC compared with the healthy group. The calculated AUC of ROC was 0.78 (95% confidence interval [CI]: 0.811–0.94) for lnc-ATB and 0.64 (95% CI: 0.811–0.94) for CCAT1, which were indicative of a high discriminatory power (p < 0.001). The highest accuracy for lncRNA-ATB was obtained at a cutoff point of 2.5, which corresponded to sensitivity and specificity of 82% and 75%, respectively. Our results suggested a significant accuracy of lncRNA-ATB and lncRNA-CCAT1 in distinguishing CRC patients from healthy individuals.     

Identification of messenger and long noncoding RNAs associated with gallbladder cancer via gene expression profile analysis

The present study aimed to investigate the long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) involved in the progression of gallbladder cancer and explore the potential physiopathologic mechanisms of gallbladder cancer in terms of competing endogenous RNAs (ceRNAs). The original lncRNA and mRNA expression profile data (nine gallbladder cancer tissues samples and nine normal gallbladder samples) in GSE76633 was downloaded from the Gene Expression Omnibus database. Differentially expressed mRNAs and lncRNAs between gallbladder cancer tissue and normal control were selected and the pathways in which they are involved were analyzed using bioinformatics analyses. MicroRNAs (miRNAs) were also predicted based on the differentially expressed mRNAs. Finally, the co-expression relation between lncRNA and mRNA was analyzed and the ceRNA network was constructed by combining the lncRNA-miRNA, miRNA-mRNA, and lncRNA-mRNA pairs. Overall, 373 significantly differentially expressed mRNAs and 47 lncRNAs were identified between cancer and normal tissue samples. The upregulated genes were significantly enriched in the extracellular matrix (ECM)-receptor interaction pathway, while the downregulated genes were involved in the complement and coagulation cascades. Altogether, 128 co-expression relations between lncRNA and mRNA were obtained. In addition, 196 miRNA-mRNA regulatory relations and 145 miRNA-lncRNA relation pairs were predicted. Finally, the lncRNA-miRNA-gene ceRNA network was constructed by combining the three types of relation pairs, such as XLOC_011309-miR-548c-3p-SPOCK1 and XLOC_012588-miR-765-CEACAM6. mRNAs and lncRNAs may be involved in gallbladder cancer progression via ECM-receptor interaction pathways and the complement and coagulation cascades. Moreover, ceRNAs such as XLOC_011309-miR-548c-3p-SPOCK1 and XLOC_012588-miR-765-CEACAM6 can also be implicated in the pathogenesis of gallbladder cancer.     

Identification of LINC01234 and MIR210HG as novel prognostic signature for colorectal adenocarcinoma

This study aimed to identify potential biomarkers and the therapeutic targets for colorectal adenocarcinoma by systematically evaluate a large scale of long noncoding RNAs (lncRNAs) expression data from TCGA. The algorithm t-distributed stochastic neighbor embedding and hierarchical clustering were utilized to group the samples into three clusters that showed a different prognosis. To identify the relationship between the clustered groups and different histoclinical features, different statistical methods were used. The functions of LINC01234 and MIR210HG were investigated with the help of the public database. The results showed that the expression levels of lncRNAs were able to distinguish the tumor samples from the normal tissues and in further they were able to predict the prognosis of the patients. We proposed two potential lncRNAs, which might serve as a biomarker or therapeutic targets. LINC01234 can be a good biomarker. In contrast, MIR210HG participated in the progression of colorectal adenocarcinoma by regulating hypoxia. It might function through an lncRNA–microRNA–messenger RNA regulatory network with MIR210 and RASSF7.