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Purpose Dysregulation of long non-coding RNAs (lncRNAs) is being found to have relevance to human cancers, including breast cancer (BC). The aim of this study was to further explore the functional role and molecular mechanisms of small nucleolar RNA host gene 14 (SNHG14) on BC progression. Methods The expression levels of SNHG14, miR-543, and kruppel-like factor 7 (KLF7) mRNA were determined by quantitative real-time PCR. Western blot analysis was used to evaluate KLF7 protein level. Cell proliferation, apoptosis, and migration and invasion abilities were detected by Cell Counting kit-8 assay, flow cytometry, and transwell assay, respectively. The direct interactions between miR-543 and SNHG14 or KLF7 were confirmed using dual-luciferase reporter assays. Results Our data indicated that SNHG14 expression was increased in BC tissues and cells, and SNHG14 knockdown mitigated the proliferation, migration, and invasion and facilitated apoptosis of BC cells. SNHG14 directly interacted with miR-543. MiR-543 mediated the regulatory effects of SNHG14 silencing on BC cell behaviors. Moreover, KLF7 was a direct target of miR-543. Overexpressed miR-543-mediated anti-proliferation, anti-migration, anti-invasion, and pro-apoptosis effects were mediated by KLF7. Furthermore, SNHG14 modulated KFL7 expression through acting as a competing endogenous RNA (ceRNA) of miR-543 in BC cells. Conclusion Our study suggested that SNHG14 knockdown hindered BC progression in vitro at least partly through acting as a ceRNA of miR-543 and modulating KLF7 expression, providing evidence for SNHG14 as a potential target for BC therapy.

Long noncoding RNAs (lncRNAs) have emerged as important regulators of osteoarthritis (OA), but the biological roles and clinical significance of most lncRNAs in OA are not fully understood. Microarray analysis was performed to identify differentially expressed lncRNAs, mRNAs, and miRNAs between normal and osteoarthritic cartilage. We found that AC008440.5 (abbreviated AC008), as well as AQP1 and ANKH, were highly expressed in osteoarthritic cartilage, whereas miR-328-3p was expressed at a low level in osteoarthritic cartilage. Functional assays showed that ectopic expression of AC008, AQP1, and ANKH significantly decreased chondrocyte viability and promoted chondrocyte apoptosis and extracellular matrix (ECM) degradation, whereas knockdown of AC008, AQP1, and ANKH resulted in the opposite effects. Moreover, miR-328-3p overexpression increased chondrocyte viability and attenuated chondrocyte apoptosis and ECM degradation, whereas inhibition of miR-328-3p resulted in the opposite effects. Bioinformatics analysis, RNA immunoprecipitation (RIP), and luciferase assays revealed that AC008 functioned as a competing endogenous RNA (ceRNA) to regulate miR-328-3p, which specifically targeted the AQP1 and ANKH genes. In addition, miR-328-3p significantly ameliorated MIA-induced OA, whereas AC008 accelerated OA progression in vivo. Furthermore, fat mass and obesity-associated (FTO)-mediated N6-methyladenosine demethylation downregulated AC008 transcription, while lower FTO expression led to upregulation of AC008 transcription in OA. In conclusion, our data reveal that AC008 plays a critical role in OA pathogenesis via the miR-328-3p‒AQP1/ANKH pathway, suggesting that AC008 may be a potential therapeutic target for OA.

Background: Lung adenocarcinoma (LUAD) is the most common form of non-small-cell lung cancer (NSCLC). Hypoxia has been found in 50 – 60% of locally advanced solid tumors and shown to be associated with poor prognosis in a variety of tumors, including NSCLC. The study focused on the hypoxia associated molecular hallmarks in LUAD.Methods: 15 hypoxia related genes were selected to define the hypoxia status of LUAD by ConsensusClusterPlus based on the data from The Cancer Genome Atlas(TCGA). Then, we investigate the immune status under different hypoxia status. Subsequently, we constructed prognostic models based on hypoxic-related differentially expressed genes (DEGs), identified hypoxia-related microRNAs, lncRNAs and mRNAs, and built a network based on the competing endogenous RNAs (ceRNAs) theory.Results: Two clusters (cluster1 and cluster2) were identified with different hypoxia status, cluster 1 was defined as the hypoxia subgroup, in which all 15 hypoxia-associated genes were upregulated. The infiltration of CD4 + T cells and Tfh cells was lower, while the infiltration of regulatory T (Treg) cells, the expression of PD-1/PD-L1 and TMB were higher in cluster 1, which indicated immunosuppressive status. Based on the DEGs, a risk signature containing 7 genes was established. Furthermore, three differentially expressed microRNAs (hsa-miR-9, hsa-miR-31, hsa-miR-196b) associated prognostic under different hypoxia clusters and its related mRNAs, lncRNAs were identified, then built a ceRNAs network.Conclusion: This study showed that hypoxia was associated with poor prognosis in LUAD and explored the potential mechanism from the perspective of gene signature and ceRNA theory.

Mounting evidence suggests that lncRNAs can exert functions in cancer progression in multiple manners. In recent years, competing endogenous RNA (ceRNA) has been widely reported in human cancers as a lncRNA-dominant molecular pathway. The current study aimed at proving the role of lncRNA downregulated RNA in cancer (DRAIC) in breast cancer (BRCA) progression. To be specific, qRT-PCR assay was conducted to measure the expression of DRAIC and other downstream target genes. It was uncovered that DRAIC was expressed at a high level in BRCA cells. Functional analyses, including CCK-8, colony formation, and EdU assays demonstrated that DRAIC depletion suppressed BRCA cell proliferation. In addition, cell apoptosis was promoted due to DRAIC knockdown. The inhibitory effect of DRAIC reduction on BRCA cell migration and invasion was proven by transwell assays. Mechanistically, DRAIC was confirmed to predominantly distribute in the cytoplasm and could interact with miR-432-5p. In addition, stem-loop binding protein (SLBP) was verified to be a downstream target of miR-432-5p and was positively regulated by DRAIC. Taken together, DRAIC sponged miR-432-5p to enhance SLBP expression, by which malignant behaviors of BRCA cells were promoted. Our findings may help to provide a promising therapeutic target for BRCA patients.

Objective Osteosarcoma is one of the most common types of bone sarcoma with a poor prognosis. However, identifying the predictive factors that contribute to the response to neoadjuvant chemotherapy remains a significant challenge. Methods A public data series (GSE87437) was downloaded to identify differentially expressed genes (DEGs) and differentially expressed lncRNAs (DElncRNAs) between osteosarcoma patients that do and do not respond to preoperative chemotherapy. Subsequently, functional analysis of the transcriptome expression profile, regulatory networks of DEGs and DElncRNAs, competing endogenous RNAs (ceRNA) and protein-protein interaction networks were performed. Furthermore, the function, pathway, and survival analysis of hub genes was performed and drug and disease relationship prediction of DElncRNA was carried out. Results A total of 626 DEGs, 26 DElncRNAs, and 18 hub genes were identified. However, only one gene and two lncRNAs were found to be suitable as candidate gene and lncRNAs respectively. Conclusion The DEGs, hub genes, candidate gene, and candidate lncRNAs screened out in this context were considered as potential biomarkers for the response to neoadjuvant chemotherapy of osteosarcoma.

Diabetic retinopathy (DR) is a serious complication of diabetes mellitus. The purpose of this study was to investigate the potential functional role of long non-coding RNA TUG1 in high glucose (HG)-stimulated human retinal microvascular endothelial cells (hRMECs). The results demonstrated that following 72 h of HG stimulation, enhanced proliferation, migration, and tube formation process were observed in hRMECs. Moreover, HG treatment markedly increased TUG1 expression in hRMECs, and knockdown of TUG1 notably restrained the aberrant phenotypes of hRMECs induced by HG. Mechanistically, TUG1 may serve as a competing endogenous RNA (ceRNA) for miR-145, thereby blocking the repression on VEGF-A in hRMECs. Rescue experiments further indicated that inhibition of miR-145 abolished the beneficial role of TUG1 knockdown in HG-treated hRMECs. Our data suggested that knockdown of TUG1 protects hRMECs against HG stimulation partly by regulating miR-145/VEGF-A axis.

Some lncRNA-associated competing endogenous RNAs (ceRNAs) are considered as potential biomarkers for targeted therapies and prognosis in human cancer. In our present study, we aimed to construct a ceRNA network and establish a genomic-clinicopathologic nomogram to provide insights into the molecular mechanisms and predict survival for HBV-related HCC. The Cancer Genome Atlas (TCGA) database was applied to collect the data of LIHC RNA-seq dataset and miRNA-seq dataset as well as the clinicopathological information. Identification of differentially expressed RNAs (mRNAs, lncRNAs, and miRNAs) between HBV-related HCC samples and normal samples was conducted using Limma package in R. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for performing the functional enrichment analysis of differentially expressed mRNAs. The ceRNA network was carried out using Cytoscape. The LASSO-penalized Cox regression analysis was implemented to identify HCC-related lncRNAs, and the multivariate Cox regression analysis was conducted for the establishment of a genomic-clinicopathology nomogram. A total of 1859 DEmRNAs, 113 DElncRNAs, and 89 DEmiRNAs were screened out etween HBV-related HCC samples and normal samples. A ceRNA network including 44 DEmRNAs, 7 DElncRNAs, and 20 DEmiRNAs was constructed. 7 DElncRNAs (PVT1, LINC01138, LINC02499, AL355488.2, FGF14-AS2, MAFG-AS1 and LINC00261) were finally identified as prognostic indicators. The area under the curve reached 0.8169 for the 7-lncRNA signature. The predictive accuracy and clinical application value were remarkably high for the genomic-clinicopathologic nomogram integrating the histological grade and the 7-gene-based prognostic index. Taken together, we have established a ceRNA network with HBV-related HCC-specific DElncRNAs, DEmiRNAs, and DEmRNAs. Furthermore, the genome-wide data of lncRNA expression were analyzed using the TCGA database, and a 7-lncRNA signature was identified as a potential prognostic predictor for HBV-related HCC patients. Novel functional studies were provided by our current findings for elucidating the molecular mechanism of lncRNA in HBV-related HCC.

Numerous studies have suggested that the abnormal expression of circular RNAs plays an essential role in the pathological progression of numerous tumors. Nonetheless, the functions and underlying mechanisms of the circular RNA circCRIM1 in osteosarcoma (OS) are still not fully understood. In this study, 47 classes of OS tissues and adjoining normal tissues were obtained from patients. Real-time PCR was employed to measure circCRIM1 expression levels in both OS tissues and cell lines. The proliferation, migration, and invasion ability in OS cell lines were measured by MTT assays, EDU assays, transwell migration experiments, and transwell invasion assays. The results demonstrated that the expression of circCRIM1 was notably decreased both in OS tissues and cell lines. Depressed circCRIM1 expression was correlated with lymph node metastasis, advanced FIGO stage, and low overall survival of OS patients. In addition, the results indicated that circCRIM1 could decrease the migration, invasion, and growth of OS cells. Further mechanistic studies indicated that circCRIM1 served as a competing endogenous RNA (ceRNA) of miR-513, leading to decreases in the proliferation, migration, and invasion of OS cells. Taken together, our data uncovered a significant role of the circCRIM1/miR-513 pathway in the proliferation, migration, and invasion of OS cell lines and suggested that circCRIM1 may serve as a possible therapeutic target for OS treatment.

This study was aimed to identify biomarker associated with membranous nephropathy (MN) progression by integration of expression profiles and competitive endogenous RNA (ceRNA) network analysis. The gene (GSE108113) and microRNAs (miRNAs) expression profiles (GSE64306) were downloaded to identify the differentially expressed mRNAs, miRNAs and long non-coding RNAs (lncRNAs) between MN and control groups. The functions and pathways enriched by the differentially expressed mRNAs were analyzed. The mRNA-lncRNA co-expression network was constructed followed by and the ceRNA network construction. Total 264 upregulated and 196 downregulated differentially expressed mRNAs, 79 upregulated and 4 downregulated lncRNAs, as well as 115 upregulated and 93 downregulated miRNAs were obtained between MN and control groups. After analysis, the differential mRNAs were significantly involved in multiple immune-related processes, and cell proliferation, apoptosis and differentiation processes, as well as pathways of taste transduction and lysosome. Finally, a ceRNA network consisting of 4 mRNAs (EPB41L5, FAM43A, PRKG1 and TTC14), 3 lncRNAs (LINC00052, LINC00641 and N4BP2L2-IT2) and 5 miRNAs (hsa-miR-145-5p, hsa-miR-3605-5p, hsa-miR-148a-3p, hsa-miR-497-5p and hsa-miR-148b-3p) was constructed. Our study indicated dysregulation of immune- and apoptosis-associated functions and taste transduction and lysosome pathways may play important roles in MN progression. Deregulated ceRNAs, such as LINC00052-hsa-miR-145-5p-EPB41L5, LINC00052-hsa-miR-148a-3p-FAM43A and LINC00641-hsa-497-5p-PRKG1, may be associated with MN development.

Long non-coding RNAs (lncRNAs) play a key role in a variety of disease processes. Plasmacytoma variant translocation 1 (PVT1), a lncRNA, is known to regulate cell functions and play a key role in the pathogenesis of many malignant tumors. The function and molecular mechanisms of lncRNA-PVT1 in cerebral ischemia remain unknown. Real-time PCR (qRT-PCR) was used to detect lncRNA-PVT1 and microRNA-30c-5p (miR-30c-5p) expression in the brain tissues of mice underwent middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reperfusion (OGD/R)-treated mouse primary brain neurons. Gain- or loss-of-function approaches were used to manipulate PVT1, miR-30c-5p, and Rho-associated protein kinase 2 (Rock2). The mechanism of PVT1 in ischemic stroke was evaluated both in vivo and in vitro via bioinformatics analysis, CCK-8, flow cytometry, TUNEL staining, luciferase activity assay, RNA FISH, and Western blot. PVT1 was upregulated in the brain tissues of mice treated with MCAO/R and primary cerebral cortex neurons of mice treated with OGD/R. Mechanistically, PVT1 knockdown resulted in a lower infarct volume and ameliorated neurobehavior in MCAO mice. Consistent with in vivo results, PVT1 upregulation significantly decreased the viability and induced apoptosis of neurons cultured in OGD/R. Moreover, we demonstrated that PVT1 acts as a competitive endogenous RNA (ceRNA) that competes with miR-30c-5p, thereby negatively regulating its endogenous target Rock2. Overexpression of miR-30c-5p significantly promoted cell proliferation and inhibited apoptosis. Meanwhile, PVT1 was confirmed to target miR-30c-5p, thus activating Rock2 expression, which finally led to the activation of MAPK signaling. We demonstrated that PVT1, as a ceRNA of miR-30c-5p, could target and regulate the level of Rock2, which aggravates cerebral I/R injury via activation of the MAPK pathway. These findings reveal a new function of PVT1, which helps to broadly understand cerebral ischemic stroke and provide a new treatment strategy for this disease.

In recent years, magnesium (Mg) has been extensively studied for manufacturing biodegradable orthopedic devices. Besides other advantages, researches have shown that magnesium-based implants can stimulate osteogenesis thus accelerating orthopedic trauma recovery, but its molecular mechanism is not fully understood. Meanwhile, long non-coding RNA (lncRNA) has been found to play vital role in regulating osteogenic differentiation. To explore the role of lncRNA in Mg2+ (magnesium ions)-induced osteogenesis. The effect of Mg2+ on mBMSCs proliferation was detected by the CCK-8 assay. The optimum concentration of Mg2+ (7.5 mM) in promoting mBMSCs osteogenesis was determined by ALP staining and Alizarin red staining, western blot and RT-qPCR were performed to detect osteogenic markers expressions. The lncRNAs and mRNAs expression profiles of mBMSCs were assessed by RNA-Seq and processed by bioinformatics analysis. The selected lncRNAs expression level was validated by RT-qPCR. The effect of Mg2+ in promoting osteogenesis was confirmed and the optimum concentration was determined as 7.5 mM. The lncRNAs and mRNAs differentially expressed between 7.5 mM Mg2+-treated group and control group was detected and functional analysis revealed that their function were associated with osteogenesis. The ceRNA networks were constructed for H19 and Dubr that aberrantly expressed in two groups. The ceRNA networks of selected lncRNAs (H19 and Dubr) were constructed. This study identified H19 and Dubr as osteogenic associated lncRNAs involved in Mg2+-induced osteogenesis, and they might play their roles through lncRNA-miRNA–mRNA axis.

Long non-coding RNAs (LncRNAs) have recently emerged as vital regulators in the development and progression of hepatocellular carcinoma (HCC), providing new opportunities as novel therapeutic targets. Here we identified the lncRNA NIFK-AS1 as being highly expressed in HCC tissues and cells and showed this up-regulation resulted from METTL3-dependent m6A methylation. Functionally, knockdown of NIFK-AS1 inhibited the proliferation, colony formation, migration, and invasion of HCC cells. Moreover, these effects were elicited though AKT1 and we uncovered a ceRNA network involving an NIFK-AS1/miR-637/AKT1 axis with downstream effects on HCC progression involving regulation of MMP-7 and MMP-9 expression. From the clinical perspective, we showed that knockdown of NIFK-AS1 sensitized HCC cells to sorafenib through the up-regulation of the drug transporters OATP1B1 and OATP1B3. Clinical investigations showed HCC patients with low NIFK-AS1 expression benefited from sorafenib therapy and this phenomenon was reproduced in patient-derived tumor xenograft models (PDX) comparing HCC with low and high expression of NIFK-AS1. Taken together, these results suggest an essential role for NIFK-AS1 in HCC progression and promote NIFK-AS1 as a new therapeutic target and predictor of sorafenib benefit in HCC patients.

The Long non-coding RNA (lncRNA) expression profile data of ten samples including human Mesenchymal Stem Cell (MSC) adipogenic differentiation 0, 3, and 6 days from the GEO database, and then perform gene ID conversion, BLAST comparison, and annotation marking. Finally, group A (treatment group on day 3 of differentiation and control group on day 0 of differentiation) obtained a total of 1180 mRNA and 185 lncRNA; group B (treatment group on day 6 of differentiation and control group on day 0 of differentiation). A total of 1376 mRNA and 206 lncRNA were obtained. Finally, we processed the differential lncRNAs and mRNAs obtained in the two groups, and obtained 113 shared differential lncRNAs to further predict the targeted miRNA, a total of 815 lncRNA-miRNA pairs. The targeted mRNA was further predicted, and the grouped differential mRNAs were combined to obtain 64 differential mRNAs. In the end, we obtained 216 ceRNAs containing 26 lncRNAs, 27 miRNAs and 64 mRNAs. We found that the mRNAs in the ceRNA network were mainly enriched with 45 Gene Ontology (GO) terms, mainly including glucose homeostasis mechanism and insulin stimulation response. 69 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were mainly enriched. It mainly includes many pathways related to lipid metabolism such as Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), Rap1, cAMP, mitogen-activated protein kinase (MAPK), Ras, hypoxia inducible factor-1 (HIF-1), PI3K-Akt, insulin signaling and so on. In the end, we identified 216 ceRNA regulatory relationships related to obesity research. Our research provides a clearer direction for understanding the molecular mechanism of obesity, the screening and determination of drug targets biomarkers in the future.

LncRNAs play essential roles in tumorigenesis and tumor progression. Pseudogene UBE2CP3 is an antisense intronic lncRNA. However, the biological function of UBE2CP3 in gastric cancer (GC) remains unknown. In this study, we revealed that lncRNA UBE2CP3 was aberrantly upregulated in multiple independent gastric cancer cohorts, and its overexpression was clinically associated with poor prognosis in GC. UBE2CP3 was mainly located in cytoplasm and promoted migratory and invasive capacities of GC cells in vitro and in vivo. Mechanismly, a novel dysregulated ceRNA network UB2CP3/miR-138-5p/ITGA2 was identified in GC by transcriptome sequencing. Furthermore, rescue assay further confirmed that UBE2CP3 mainly promoted GC progression through miR-138-5p/ITGA2 axis. More importantly, our data proved that UBE2CP3/IGFBP7 could form an RNA duplex, thereby directly interacting with the ILF3 protein. In turn, this RNA-RNA interaction between IGFBP7 mRNA and UBE2CP3 mediated by ILF3 protein plays an essential role in protecting the mRNA stability of UBE2CP3. In addition, transcription factor ELF3 was identified to be a direct repressor of lncRNA UBE2CP3 in GC. Taken together, overexpression of UBE2CP3 promotes tumor progression via cascade amplification of ITGA2 upregulation in GC. Our finding has revealed that the dysregulation of UBE2CP3 is probably due to the downregulation of ELF3 and/or the overexpression of IGFBP7 mRNA in GC. Our findings reveal, for the first time, that UBE2CP3 plays crucial a role in GC progression by modulating miR-138-5p/ITGA2 axis, suggesting that UBE2CP3 may serve as a potential therapeutic target in GC.

The heart is one of the most common organs involved in sepsis-induced organ dysfunction and about 50% septic patients complicated with myocardial injury. So far, the molecular mechanisms underlying sepsis-induced cardiac damage remain unclear. In this study we aimed to evaluate the effect of miR-642a on sepsis-induced cardiac injury in vitro and explore the possible lncRNA-microRNA mechanism. We first downloaded GSE101639 to identify differentially expressed genes (DEGs) in sepsis. The expression of miR-642a in LPS-induced H9C2 cells was detected by qRT-PCR. MTT assay, cell migration, flow cytometry analysis, ELISA, qRT-PCR and Western blotting analysis were applied to evaluating the effect of miR-642a mimic on LPS-induced H9C2 cells. The bioinformatics analysis and the rescue experiment were devoted to the underlying mechanism. The results showed miR-642a expression was decreased in septic patients and LPS-induced H9C2 cells. Besides, MiR-642a mimic promoted cell viability and migration, inhibited cell apoptosis of LPS-induced H9C2 cells. Bioinformatics analysis showed miR-642a directly targets with 3'-UTR of ROCK1. Moreover, LUCAT1 regulated ROCK1 expression act as a competing endogenous RNA (ceRNA) for miR-642a. Our data demonstrated that lncRNA LUCAT1 could function via sponging miR-642a to regulate ROCK1 expression in LPS-induced H9C2 cells. And knockdown of lncRNA LUCAT1 could suppress LPS-induced cardiac injury in vitro.

Gastric cancer (GC) is a common malignant solid tumor that is characterized by high hypoxia. The transcription of genes associated with hypoxia affects tumor occurrence and development. Long non-coding RNAs (lncRNAs) have been reported to play important roles in cancer development. In this study, we screened for differentially expressed ncRNAs (non-coding RNA) and mRNAs between hypoxia-inducible factor-1 (HIF-1α) knockdown GC cells and scrambled GC cells. Microarray data revealed that HIF-1α regulated the expression of LINC01355 (Hypoxia Yield Proliferation Associated LncRNA, HYPAL). HYPAL was found to be significantly upregulated in GC cells and tissues and was correlated with poor GC prognosis. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays revealed that HIF-1α promoted HYPAL expression by binding the promoter region. A regulatory network for the competing endogenous RNA (ceRNA) was constructed using bioinformatics tools. Mechanistic studies revealed that HYPAL acted as a ceRNA of miR-431-5p to regulate CDK14 expression. Carcinogenic effects of HYPAL were evaluated in vitro and in vivo. The HIF-1α/HYPAL/miR-431-5p/CDK14 (Cyclin-dependent kinase 14) axis activated the Wnt/β-catenin signaling pathway and induced GC cell proliferation while inhibiting apoptosis. In conclusion, HYPAL is a potential molecular target for GC therapy.

Glioma remains the most common malignant tumors in the central nervous system and often has poor prognosis. In recent years, it has been gradually revealed that non-coding RNA effects glioma progression. In this study, we aimed to investigate the significance of circular RNA TLK1 (Circ-TLK1) in predicting the survival of glioma patients as well as its role in glioma development via both in-vitro and in-vivo experiments. We found that Circ-TLK1 was conspicuously up-regulated in glioma tissues compared with adjacent normal tissues, and the up-regulated Circ-TLK1 was significantly correlated with glioma patients' larger tumor volume and higher grades. Functionally, Circ-TLK1 over-expression facilitated glioma growth, migration and invasion, inhibited cell apoptosis, and accelerated PANX1/MAPK/ERK expression, while Circ-TLK1 low expression had the opposite effects. In addition, bioinformatics analysis showed that miR-17-5p was a potential target of Circ-TLK1 and targeted at PANX1. Furthermore, through dual luciferase viability assay, Circ-TLK1 acted as a competing endogenous RNA by sponging miR-17-5p, which targeted and inhibited PANX1/MAPK/ERK expression. MiR-17-5p overexpression mitigated glioma progression, which was significantly inhibited with Circ-TLK1 upregulation. In conclusion, this study confirmed a novel axis of Circ-TLK1-miR-17-5p-PANX1 in modulating glioma development, providing more references for glioma diagnosis and targeted therapy.

Previous study demonstrated that most long non-coding RNAs (lncRNAs) function as competing endogenous RNAs or molecular sponges to negatively modulate miRNA and regulate tumor development. However, the molecular mechanisms of lncRNAs in cancer are not fully understood. Our study describes the role of the lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) in cancer metastasis by mechanisms related to Staufen1 (STAU1)-mediated mRNA decay (SMD). Briefly, we found that, high SPRY4-IT1 expression was associated with aggressiveness and poor outcome in human colorectal, breast and ovarian cancer tissues. In addition, functional assays revealed that SPRY4-IT1 significantly promoted colorectal, breast and ovarian cancer metastasis in vitro and in vivo. Mechanistically, microarray analyses identified several differentially-expressed genes upon SPRY4-IT1 overexpression in HCT 116 colorectal cancer cells. Among them, the 3′-UTR of transcription elongation factor B subunit 1 (TCEB1) mRNA can base-pair with the Alu element in the 3′-UTR of SPRY4-IT1. Moreover, SPRY4-IT1 was found to bind STAU1, promote STAU1 recruitment to the 3′-UTR of TCEB1 mRNA, and affect TCEB1 mRNA stability and expression, resulting in hypoxia-inducible factor 1α (HIF-1α) upregulation, and thereby affecting cancer cell metastasis. In addition, STAU1 depletion abrogated TCEB1 SMD and alleviated the pro-metastatic effect of SPRY4-IT1 overexpression. Significantly, we revealed that SPRY4-IT1 is also transactivated by NF-κB/p65, which activates SPRY4-IT1 to inhibit TCEB1 expression, and subsequently upregulate HIF-1α. In conclusion, our results highlight a novel mechanism of cytoplasmic lncRNA SPRY4-IT1 in which SPRY4-IT1 affecting TCEB1 mRNA stability via STAU1-mediated degradation during cancer metastasis.

Hepatocellular carcinoma (HCC) is the most common subtype of primary liver cancer and one of the leading causes of cancer-related death worldwide. To gain more insights into the transcriptomic landscape and molecular mechanism of HCC, we performed TMT-labelled tandem mass spectrometry (n = 4) and whole-transcriptome sequencing (n = 3) based on HCC tumour (T) and adjacent normal (N) tissues from seven HCC patients. To comprehensively evaluate the gene-regulatory circuits in HCC, differential expression and enrichment analyses were performed on the differentially expressed proteins (DEPs), genes (DEGs), miRNAs (555), lncRNAs (29) and circRNAs (895). A total of 977 proteins and 243 genes were found to be differentially expressed in HCC tumours compared with adjacent normal tissues. HCC data from The Cancer Genome Atlas were used to validate the results. Combined with the results above, 56 DEP-DEGs with common changes in relative quantity were identified. Functional pathway analysis showed that the DEP-DEGs were mainly enriched in the spliceosome and various metabolic processes. Bioinformatics analysis showed that hsa-miR-1266-5p, hsa-miR-128-1-5p, hsa-miR-139-5p, hsa-miR-34b-3p and hsa-miR-570-3p were involved in the regulation of the hub genes mentioned above. The crucial coexpression (lncRNA-mRNA, circRNA-mRNA) and competing endogenous RNA interaction axes showed the possible functions of the lncRNAs and circRNAs. We explored potential cancer biomarkers by combining proteomic and transcriptomic studies. Our study provides a valuable resource for understanding regulatory mechanisms at the RNA level and may ultimately further assist in the development of diagnostic and/or therapeutic targets for HCC.

Soybean oil is composed of fatty acids and glycerol. The content and composition of fatty acids partly determine the quality of soybean seeds. Circular RNAs (circRNAs) are endogenous non-coding RNAs that competitively bind to microRNAs (miRNAs) through miRNA recognition elements, thereby acting as sponges to regulate the expression of target genes. Although circRNAs have been identified previously in soybean, only their expression has been investigated without exploration of the competitive endogenous RNAs (ceRNAs) network of circRNAs-miRNAs-mRNAs. In this study, circRNAs in immature pods of a low linolenic acid soybean Mutant 72' (MT72) and the wild-type control 'Jinong 18' (JN18) were systematically identified and analyzed at 30 and 40 days after flowering using high-throughput sequencing technology. We identified 6377 circRNAs, of which 114 were differentially expressed. Gene ontology and KEGG pathway analyses of targeted mRNAs in the ceRNAs network indicated that the differentially expressed circRNAs may be involved in fatty acid transport, suggesting that circRNAs may play a post-transcriptional regulatory role in soybean oil synthesis. This study provides a foundation for future exploration of the function of circRNAs in soybean and presents novel insights to guide further studies of plant circRNAs.

Glucocorticoid-induced cataract (GIC)-associated biomarkers were screened by ceRNA network construction. The GIC samples' GSE3040 were obtained from the NCBI-GEO database. R's Limma package was used to identify differentially expressed RNAs (DERs) between the normal and GIC samples group (4- and 16-h). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis for the mRNAs in the constructed GIC lncRNA-miRNA-mRNA ceRNA regulation network was implemented. A total of 1665 and 1443 DERs were obtained in the 4- and 16-h group, respectively. At two time points, 256 overlapping DERs were identified, of which 210 (17 lncRNAs and 203 mRNAs) had significant differential expression (4 down- and 206 up-regulated). A total of 534 co-expressed ligation pairs (all up-regulated) were obtained. A ceRNA regulation network was constructed. RPS6KA5, GAB1, CCR7, CCL2, COL4A4, and PPARG were obtained and significantly enriched in the 4 KEGG signaling pathways and were featured as GIC target molecules.

The discovery of microRNAs (miRNAs) 20 years ago has advocated a new era of "small molecular genetics." About 2000 miRNAs are present that regulate one third of the genome. MiRNA dysregulated expression arising as a response to our environment insult or stress or changes may contribute to several diseases, namely non-communicable diseases, including tumor growth. Their presence in body fluids, reflecting level alteration in various cancers, merit circulating miRNAs as the "next-generation biomarkers" for early-stage tumor diagnosis and/or prognosis. Herein, we performed a comprehensive literature search focusing on the origin, biosynthesis, and role of miRNAs and summarized the foremost studies centering on miR value as non-invasive biomarkers in different environment-related non-communicable diseases, including various cancer types. Moreover, during chemotherapy, many miRNAs were linked to multidrug resistance, via modulating numerous, environment triggered or not, biological processes and/or pathways that will be highlighted as well.

Recent evidences have claimed that circular RNAs are deregulated in docetaxel (DTX) resistance in malignant tumors, including non-small-cell lung cancer (NSCLC). Hsa_circ_0014130 (circ_0014130) is a new biomarker in NSCLC. However, its role in DTX-resistant NSCLC remained to be annotated. In this study, real-time PCR was used to measure expression of circ_0014130, and circ_0014130 was upregulated in NSCLC tumors and DTX-resistant NSCLC cells (NCI-H1299/DTX and A549/DTX). MTT assay analyzed the half inhibitory concentration (IC50) of DTX, and it was lowered by circ_0014130 interference in DTX-resistant NSCLC cells. Moreover, colony formation assay, flow cytometry, transwell assays, and xenograft tumor model revealed that silencing circ_0014130 facilitated apoptosis rate of DTX-resistant NSCLC cells, suppressed the colony formation, migration and invasion, and retarded xenograft tumor growth in nude mice. Dual-luciferase reporter assay and RNA immunoprecipitation confirmed that circ_0014130 was one competing endogenous RNA (ceRNA) for miRNA (miR)-545-3p, and circ_0014130 modulated expression of yes-associated protein 1 (YAP1), a target gene for miR-545-3p. YAP1 upregulation and miR-545-3p downregulation were allied with circ_0014130 upregulation in NSCLC tumors and DTX-resistant NSCLC cells. Functionally, downregulating miR-545-3p could abate the effects of circ_0014130 knockdown in DTX-resistant NSCLC cells in vitro, whereas its overexpression exerted similar effects of circ_0014130 knockdown. Either, restoring YAP1 partially reversed miR-545-3p effects in DTX-resistant NSCLC cells. Collectively, there might be a novel circ_0014130-miR-545-3p-YAP1 ceRNA pathway in regulation of chemoresistance and malignant behaviors of DTX-resistant NSCLC cells, suggesting a potential therapeutic approach for DTX resistance.

The World Health Organization has recognized that testicular function is temperature dependent. Testicular heat exposure caused by occupational factors, lifestyle, and clinical diseases can lead to different degrees of reproductive problems. The aim of this study was to reveal the transcriptional regulatory network and its potential crucial roles in mediating the effects of testicular heat exposure. Testicular tissue was collected from a group of mice subjected to scrotal heat exposure as well as a control group. RNA was isolated from both groups and used for high-throughput sequencing. Using differential transcriptome expression analysis, 172 circRNAs, 279 miRNAs, 465 lncRNAs, and 2721 mRNAs were identified as significantly differentially expressed in mouse testicular tissue after heat exposure compared with the control group. Through Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, differentially expressed lncRNAs and mRNAs were found to have potentially important functions in meiotic cell cycle (GO:0051321), cytoplasm (GO:0005737), membrane raft (GO:0045121), MAPK signaling (mmu04010), purine metabolism (mmu00230), and homologous recombination (mmu03440). Some of the most upregulated and downregulated lncRNAs and circRNAs were predicted to be associated with numerous miRNAs and mRNAs through competing endogenous RNA regulatory network analysis, which were validated with molecular biology experiments. This research provides high-throughput sequencing data of a testicular heat exposure model and lays the foundation for further study on circRNAs, miRNAs, and lncRNAs that are involved in male reproductive diseases related to elevated testicular temperature.

Emerging evidence suggests that long noncoding RNAs (lncRNAs) function as competitive endogenous RNA (ceRNA) targeting proteins and genes; however, the role of lncRNAs in hepatocellular carcinoma (HCC) is not well understood. We investigated the mechanism by which lncRNA SNHG6 promotes the development of HCC. RT-qPCR revealed upregulated lncRNA SNHG6 in the HCC setting. Elevated SNHG6 expression was indicative of poor prognosis in patients with HCC. SNHG6 overexpression resulted in increased cyclin D1, cyclin E1, and E2F1 expression both in vitro and in vivo. SNHG6 also promoted HCC cell proliferation by enhancing G1-S phase transition in vitro. Dual luciferase reporter assays, RIP, and RNA pull-down assays demonstrated SNHG6 competitively bound to miR-204-5p and inhibited its expression preventing miR-204-5p from targeting E2F1. Overexpression of miR-204-5p abolished the effect of SNHG6. Our data suggest that SNHG6 functions as a ceRNA that targets miR-204-5p resulting in an increased E2F1 expression and enhanced G1-S phase transition, thereby promoting the tumorigenesis of HCC.

Pancreatic cancer (PC) is a digestive tract malignancy with poor prognosis. Long noncoding RNA (lncRNA) OPA interacting protein 5 antisense RNA 1 (OIP5-AS1) was regarded to be correlated with human malignancy, working as tumor suppressor or promoter on the basis of tumor types. However, the function of OIP5-AS1 in PC remained unclear. The study focused on the function and regulatory mechanism of OIP5-AS1 in PC. OIP5-AS1 expression was assessed by the quantitative reverse transcription PCR (RT-qPCR) in tumor tissues and PC cell lines. 5-ethynyl-2′-deoxyuridine (EdU) incorporation and cell counting kit-8 (CCK-8) assays were applied to detect cell proliferation ability. Through wound healing and transwell assays, cell migration and invasion capacities were estimated. Flow cytometry analysis was performed to examine apoptosis capability of PC cells. OIP5-AS1 downregulating inhibited cell proliferation, migration, and invasion capacities, while promoting cell apoptosis rates. As a competing endogenous RNA (ceRNA), OIP5-AS1 competed with Forkhead Box M1 (FOXM1) for the binding sites on microRNA-320b (miR-320b). OIP5-AS1 was able to upregulate FOXM1 expression via silencing miR-320b. Furthermore, FOXM1 served as an activator of Wnt/β-catenin pathway and mediated the effect of OIP5-AS1 on Wnt/β-catenin pathway. OIP5-AS1 expedites the proliferative, migrated, and invasive capability of PC cells, while repressing cell apoptosis through regulating miRNA-320b/FOXM1 axis and FOXM1/Wnt/β-catenin pathway in PC. OIP5-AS1 regulation on FOXM1/Wnt/β-catenin pathway may offer novel efficient markers for PC treatments.

Cancer cells undergo metabolic adaption to sustain their survival and growth under metabolic stress conditions, yet the underlying mechanism remains largely unclear. It is also not known if lncRNAs contribute to this metabolic adaption of cancer cells. Here we show that linc01564 is induced in response to glucose deprivation by the transcription factor ATF4. Linc01564 functions to facilitate hepatocellular carcinoma cell survival under glucose deprivation by activating the serine synthesis pathway. Mechanistically, linc01564 acts as a competing endogenous RNA for miR-107/103a-3p and attenuates the inhibitory effect of miR-107/103a-3p on PHGDH, the rate-limiting enzyme of the serine synthesis pathway, thereafter leading to increased PHGDH expression. Furthermore, linc01564 is able to promote hepatocellular carcinogenesis via PHGDH. Together, these findings suggest that linc01564 is an important player in the regulation of metabolic adaption of cancer cells and also implicate linc01564 as a potential therapeutic target for cancer.

Glioma is a common invasive cancer with unfavorable prognosis in patients. Long non-coding RNAs have been reported to participate in modulating diverse cellular processes. Here, we focused on exploring the role of long intergenic non-protein coding RNA 1410 (LINC01410) in glioma and its underlying mechanism. The expression levels and protein levels of genes were analyzed by quantitative real-time PCR (RT-qPCR) analysis and western blot. Loss-of-function assays were performed to assess the function of LINC01410 in glioma cells. The interactions among MYC, LINC01410, microRNA-506-3p (miR-506-3p) and notch receptor 2 (NOTCH2) were validated through Chromatin immunoprecipitation (ChIP), RNA Binding Protein immunoprecipitation (RIP), RNA pull-down and luciferase reporter assays. Our data supported that LINC01410 was up-regulated in glioma cells. Bioinformatics predictions and the integrated experiments identified that MYC activated LINC01410 transcription and LINC01410 promoted the levels of NOTCH2 through sponging miR-506-3p and further motivated Notch signaling pathway. Rescue assays validated that LINC01410 exerted its influential functions on glioma cell proliferation and apoptosis via enhancing NOTCH2 expression. Our studies identified that LINC01410 accelerates the progression of glioma through acting as a ceRNA for miR-506-3p and elevating NOTCH2 expression to further activate the Notch signaling pathway, which indicated that LINC01410 might act as a novel regulator of glioma progression.

Long noncoding RNAs (lncRNAs) have gained much attention in the past few years. Long intergenic non-protein coding RNA 520 (LINC00520) was one of the newly discovered lncRNA which has been demonstrated to be dysregulated in several cancers. So far, the function and mechanism of LINC00520 in non-small cell lung cancer (NSCLC) are unclear. In this paper, our group first showed that LINC00520 level was elevated in non-small cell lung cancer (NSCLC) tissue and cells. In addition, SP1 could bind directly to the promoter region of LINC00520 and thus promote its transcription. Increased LINC00520 was distinctly correlated with advanced tumor stage and shorter survival time in NSCLC patients. Further functional investigations provided evidences that forced down regulation of LINC00520 inhibited NSCLC cell proliferation, invasion, metastasis and EMT, while contributing to cells apoptosis. Mechanistically, we found that LINC00520 serving as a competing endogenous RNA to be involved in the modulation of miR-577 expressions, and thus affected the expression of CCNE2 which was a target gene of miR-577. Moreover, in NSCLC cells with si-LINC00520, up regulation of CCNE2 led to an increase of cell growth and invasion. Taken together, LINC00520 displayed its tumor-promotive roles through modulating the miR-577/CCNE2 axis, highlighting a potential therapeutic strategy for NSCLC patients.

Long non-coding RNAs (lncRNAs) have recently been reported to act as crucial regulators and prognostic biomarkers of human tumorigenesis. Based on microarray data, RP11-301G19.1 was previously identified as an upregulated lncRNA during B cell development. However, the effect of RP11-301G19.1 on multiple myeloma (MM) cells remains unclear. In the present study, the effects of RP11-301G19.1 on tumour progression were ascertained both in vitro and in vivo. Our results demonstrated that RP11-301G19.1 was upregulated in MM cell lines and that its downregulation inhibited the proliferation and cell cycle progression and promoted the apoptosis of MM cells. Bioinformatic analysis and luciferase reporter assay results revealed that RP11-301G19.1 can upregulate the miR-582-5p-targeted gene HMGB2 as a competing endogenous RNA (ceRNA). Furthermore, Western blot results indicated that RP11-301G19.1 knockdown decreased the levels of PI3K and AKT phosphorylation without affecting their total protein levels. Additionally, in a xenograft model of human MM, RP11-301G19.1 knockdown significantly inhibited tumour growth by downregulating HMGB2. Overall, our data demonstrated that RP11-301G19.1 is involved in MM cell proliferation by sponging miR-582-5p and may serve as a therapeutic target for MM.

Subclinical hypothyroidism (SCH) is associated with increased risks of endothelial dysfunction and atherosclerosis, but the mechanisms remain unclear. In our previous study, microRNA-126-3p was downregulated in SCH, but the role and regulatory mechanism of miR-126 in SCH has not been investigated. A SCH mouse model was established by feeding mice methimazole. Both primary endothelial cells (ECs) and HUVECs were cultured. The expression levels of key molecules were detected via quantitative RT-PCR, western blotting, and immunofluorescence. Wire myography was used to analyze the changes in vascular tones. A dual-luciferase assay was used to investigate the relationship between lncRNAs, microRNAs and target genes. In detail, it was shown that the expression levels of miR-126-3p were significantly decreased in both the SCH vasculature and HUVECs. MiR-126 supplementation suppressed HUVEC apoptosis and improved vascular function. Moreover, miR-126 could bind to the 3'-untranslated region of TRAF7, thus, regulating the C-FLIP pathway and endothelial apoptosis. Furthermore, lncRNA NEAT1 was upregulated upon TSH treatment and could function as a ceRNA and bind to miR-126, thus, modulating its expression level and vascular function. Finally, the NEAT1/miR-126/TRAF7 axis functions in response to TSH and regulates endothelial functions in SCH in vitro and in vivo. In conclusion, dysregulation of the NEAT1/miR-126/TRAF7 axis is responsible for impaired endothelial functions in SCH. Targeting this axis might become a promising treatment strategy or improving endothelial functions in SCH.

Glioma is the most common brain tumor of the central nervous system. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified to play a vital role in the initiation and progression of glioma, including tumor cell proliferation, survival, apoptosis, invasion, and therapy resistance. New documents emerged, which indicated that the interaction between long non-coding RNAs and miRNAs contributes to the tumorigenesis and pathogenesis of glioma. LncRNAs can act as competing for endogenous RNA (ceRNA), and molecular sponge/deregulator in regulating miRNAs. These interactions stimulate different molecular signaling pathways in glioma, including the lncRNAs/miRNAs/Wnt/β-catenin molecular signaling pathway, the lncRNAs/miRNAs/PI3K/AKT/mTOR molecular signaling pathway, the lncRNAs-miRNAs/MAPK kinase molecular signaling pathway, and the lncRNAs/miRNAs/NF-κB molecular signaling pathway. In this paper, the basic roles and molecular interactions of the lncRNAs and miRNAs pathway glioma were summarized to better understand the pathogenesis and tumorigenesis of glioma.

Long noncoding RNAs (lncRNAs) have been reported to be implicated in various biological and pathological processes. However, the function and mechanism of XIST in vascular smooth muscle cells (VSMCs) remains unknown. The levels of XIST, miR-599, and TLR4 were tested by RT-qPCR. VSMCs and human mononuclear cells (U937) treated with ox-LDL were used as atherosclerosis (AS) cell models. The CCK-8 assay was adopted to detect cell viability. Cell apoptosis was examined by the TUNEL assay. A dual-luciferase reporter assay was employed to investigate the interaction between miR-599 and XIST or TLR4. In this research, we uncovered that the XIST level was elevated in the serum of AS patients and ox-LDL-treated AS cell models. Functional analysis revealed that XIST depletion restrained cell proliferation, while induced the apoptosis in AS cell models. Besides, miR-599 was verified to be a direct downstream target of XIST and miR-599 inhibitor reversed the effects of XIST knockdown on AS progression. Finally, we demonstrated that XIST increased TLR4 expression by serving as a ceRNA of miR-599. All these findings manifested the role of the XIST/miR-599/TLR4 axis in AS development.

Growth hormone-secreting pituitary adenomas (GH-PAs) are common subtypes of functional PAs. Invasive GH-PAs play a key role in restricting poor outcomes. The transcriptional changes in GH-PAs were evaluated. In this study, the transcriptome analysis of six different GH-PA samples was performed. The functional roles, co-regulatory network, and chromosome location of differentially expressed (DE) genes in invasive GH-PAs were explored. Bioinformatic analysis revealed 101 DE mRNAs and 70 DE long non-coding RNAs (lncRNAs) between invasive and non-invasive GH-PAs. Functional enrichment analysis showed that epithelial cell differentiation and development pathways were suppressed in invasive GH-PAs, whereas the pathways of olfactory transduction, retinol metabolism, drug metabolism-cytochrome P450, and metabolism of xenobiotics by cytochrome P450 had an active trend. In the protein–protein interaction network, 11 main communities were characterized by cell- adhesion, -motility, and -cycle; transport process; phosphorus and hormone metabolic processes. The SGK1 gene was suggested to play a role in the invasiveness of GH-PAs. Furthermore, the up-regulated genes OR51B6, OR52E4, OR52E8, OR52E6, OR52N2, MAGEA6, MAGEC1, ST8SIA6-AS1, and the down-regulated genes GAD1-AS1 and SPINT1-AS1 were identified in the competing endogenous RNA network. The RT-qPCR results further supported the aberrant expression of those genes. Finally, the enrichment of DE genes in chromosome 11p15 and 12p13 regions were detected. Our findings provide a new perspective for studies evaluating the underlying mechanism of invasive GH-PAs.

Long non-coding RNAs (lncRNAs) and their role in competitive endogenous RNA (ceRNA) networks have emerged as fundamental debates in the biological processes of initiation and progression of cancer. This study aimed to identify and measure the expression levels of relevant ceRNA regulatory genes contributing to acute lymphoblastic leukemia (ALL). lncRNA H19 and BCL-2 mRNA were chosen based on in silico studies and their interactions with miR-326. Subsequently, the aforementioned coding/non-coding gene expression profiles were measured using qRT-PCR in 50 bone marrow samples, including 33 cases with pediatric ALL and 17 controls with no evidence of malignancy. lncRNA H19 was identified as an oncogenic factor which was noticeably increased in the newly diagnosed patients (P = 0.0019, AUC = 0.84) and negatively associated with miR-326 (r = -0.6, P = 0.02). Furthermore, a negative correlation was introduced between the transcriptional levels of miR-326 and the anti-apoptotic BCL-2 gene (r = -0.6, P = 0.028). The novel experimental and bioinformatic results achieved in this study may provide new insights into the molecular leukemogenesis of pediatric ALL.

Skeletal muscle differentiation is a highly coordinated process that involves many cellular signaling pathways and microRNAs (miRNAs). A group of muscle-specific miRNAs has been reported to promote myogenesis by suppressing key signaling pathways for cell growth. However, the functional role and regulatory mechanism of most non-muscle-specific miRNAs with stage-specific changes during differentiation are largely unclear. Here, we describe the functional characterization of miR-101a/b, a pair of non-muscle-specific miRNAs that show the largest change among a group of transiently upregulated miRNAs during myogenesis in C2C12 cells. The overexpression of miR-101a/b inhibits myoblast differentiation by suppressing the p38/MAPK, Interferon Gamma, and Wnt pathways and enhancing the C/EBP pathway. Mef2a, a key protein in the p38/MAPK pathway, was identified as a direct target of miR-101a/b. Interestingly, we found that the long non-coding RNA (lncRNA) Malat1, which promotes muscle differentiation, interacts with miR-101a/b, and this interaction competes with Mef2a mRNA to relieve the inhibition of the p38/MAPK pathway during myogenesis. These results uncovered a “braking” role in differentiation of transiently upregulated miRNAs and provided new insights into the competing endogenous RNA (ceRNA) regulatory mechanism in myoblast differentiation and myogenesis.

Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) play vital roles in the tumorigenesis of esophageal squamous cell carcinoma (ESCC). Nevertheless, the mechanism and regulatory network associated with this process remain largely unknown. In this study, we performed a comprehensive analysis of the expression of mRNAs, lncRNAs, and circRNAs by RNA-seq. A total of 3265 mRNAs, 1084 lncRNAs, and 38 circRNAs were found to be differentially expressed. Among these, 269 mRNAs were found to encode transcription factors (TFs). Functional enrichment analysis indicated that the dysregulated TFs are associated with the Hedgehog, Jak-STAT, TGF-beta, and MAPK signaling pathways. Furthermore, we constructed co-expression networks to screen the core lncRNAs and circRNAs involved in the regulation of transcription factors in these four pathways. Finally, we constructed a competing endogenous RNA (ceRNA) network of ESCC based on the abovementioned pathways. Our findings provide important insight into the role of lncRNAs and circRNAs in ESCC; the differentially expressed lncRNAs and circRNAs may represent potential targets for ESCC diagnosis and therapy.

Trastuzumab resistance has been becoming a major obstacle for treatment of HER-2-positive breast cancer patients. Increasing evidence suggests that mesenchymal stem cells (MSCs) play critical roles during the formation of drug resistance, however, the underlying mechanism is not well known. In this study, mass spectrometry, RNA pulldown and RNA immunoprecipitation assays were performed to verify the direct interactions among AGAP2-AS1 and other associated targets, such as human antigen R (HuR), miR-15a-5p, and carnitine palmitoyl transferase 1 (CPT1). In vitro and in vivo experimental assays were done to clarify the functional role of AGAP2-AS1 in trastuzumab resistance, stemness, and fatty acid oxidation (FAO). The results showed that MSC co-culture induced trastuzumab resistance. AGAP2-AS1 was upregulated in MSC-cultured cells, and knockdown of AGAP2-AS1 reversed the MSC-mediated trastuzumab resistance. Furthermore, MSC culture-induced AGAP2-AS1 regulates stemness and trastuzumab resistance via activating FAO. Mechanistically, AGAP2-AS1 is associated with HuR, and the AGAP2-AS1-HuR complex could directly bind to the CPT1, increasing its expression via improving RNA stability. In addition, AGAP2-AS1 could serve as ceRNA via sponging miR-15a-5p and releasing CPT1 mRNA. Clinically, increased expression of serum AGAP2-AS1 predicts poor response to trastuzumab treatment in breast cancer patients. In conclusion, MSC culture-induced AGAP2-AS1 caused stemness and trastuzumab resistance via promoting CPT1 expression and inducing FAO. Our results provide new insight of the role of MSCs in trastuzumab resistance and AGAP2-AS1 could be promising predictive biomarker and therapeutic target for HER-2+ breast cancer patients.

Nutrient stress is the most important environmental stress that limits plant growth and development. Although recent evidence highlights the vital functions of long non-coding RNAs (lncRNA) in response to single nutrient stress in some model plants, a comprehensive investigation of the effect of lncRNAs in response to nutrient stress has not been performed in Arabidopsis thaliana. Here, we presented the identification and characterization of lncRNAs under seven nutrient stress conditions. The expression pattern analysis revealed that aberrant expression of lncRNAs is a stress-specific manner under nutrient stress conditions and that lncRNAs are more sensitive to nutrient stress than protein-coding genes (PCGs). Moreover, competing endogenous RNA (ceRNA) network and lncRNA-mRNA co-expression network (CEN) were constructed to explore the potential function of these lncRNAs under nutrient stress conditions. We further combined different expressed lncRNAs with ceRNA network and CEN to select key lncRNAs in response to nutrient stress. Together, our study provides important information for further insights into the role of lncRNAs in response to stress in plants.

Renal cell carcinoma (RCC) accounts for over 90% of primary renal tumors in adults. Although treatment approaches have steadily improved over the years, the prognosis outcome remains poor. With the aim of developing novel targets for RCC treatment, we explored the role of the circular RNA (circRNA) circ_001504 in the progression of RCC. We initially detected the expression of circ_001504 and microRNA (miRNA)-149 in RCC tissues and cells. RT-qPCR results showed that circ_001504 was highly expressed in RCC tissues, whereas miR-149 was poorly expressed. Interestingly, downregulation of circ_001504 suppressed malignant phenotypes in RCC cells, and upregulation of miR-149 exerted a similar effect. Bioinformatics analysis suggested potential binding sites between circ_001504 and miR-149, verified by a dual-luciferase reporter gene assay. Next, we identified nucleobindin 2 (NUCB2), a calcium-binding protein, as a target gene of miR-149. Furthermore, our data suggested that circ_001504 might serve as a competing endogenous RNA of miR-149, serving to elevate the expression of NUCB2. The silencing of circ_001504 resulted in decreased NUCB2 expression, which could be reversed by miR-149 inhibition. In addition, in vivo experiments demonstrated that circ_001504 depletion could suppress tumor growth in an established mouse RCC model. Collectively, reduced expression of circ_001504 lowered NUCB2 expression by sponging miR-149, thereby attenuating RCC progression, providing insight into circ_001504/miR-149/NUCB2 feedback loop into RCC treatment.

Growing evidence indicates that the non-coding 3'-untranslated region (3'UTR) of genes acts as competing endogenous RNAs (ceRNAs) to exert their roles in a number of diseases, including cancer. In the present study, MMP1 messenger RNA was identified to be significantly up-regulated in oral squamous cell carcinoma (OSCC) tissues, and both MMP1 and its 3'UTR promoted tumor growth and cell motility. Further mechanism investigations indicated that MMP1 3'UTR was able to antagonize miR-188-5p; in addition, overexpression of MMP1 3'UTR up-regulated the expression level of SOX4 and CDK4, target genes of miR-188-5p, which have also been identified as oncogenic driver genes in OSCC. Therefore, a ceRNA regulatory network among MMP1, SOX4, and CDK4 mediated via competing for binding to miR-188-5p was proved. Taken together, the present study demonstrates for the first time that MMP1 mRNA participates in the development of OSCC via ceRNA regulatory mechanism and genes involved in the ceRNA network may provide a novel avenue for target therapy.

Our study was aimed to identify potential lncRNAs related to laryngeal cancer (LC) and explore their potential regulatory mechanisms. RNA sequencing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to identify differentially expressed genes (DEGs). Receiver operating characteristic (ROC) curve analysis was performed to analyze the sensitivity and specificity of differentially expressed lncRNAs (DElncRNAs) as biomarkers. Weighted gene co-expression network analysis (WGCNA) was applied to identify co-expressed DElncRNAs and differentially expressed mRNAs (DEmRNAs) associated with clinical indicators. We performed functional enrichment analysis on target genes and constructed a lncRNA–miRNA–mRNA ceRNA network. The expression of lncRNA and mRNAs in ceRNA network were validated via RT-qPCR. By differential expression analyzing TCGA and GEO data, 6 up-regulated DElncRNAs were consistently identified, and their predictive performance were suggested to be considerable via ROC curve. 1998 DEmRNAs and 6 lncRNAs were involved in the construction of WGCNA network, in which the MEblue module was positively correlated with clinical stage. Functional enrichment analysis of this module suggested that the functions of DEmRNAs were closely involved in PI3K/Akt pathway. A ceRNA network composed of MSC-AS1, miR-429, COL4A1 and ITGAV was constructed. It was verified by RT-qPCR that the lncRNA and mRNAs in the ceRNA network were highly expressed in multiple LC tissues. This study identified lncRNA MSC-AS1 as a potential biomarker of LC. Besides, we constructed a ceRNA network, which provides a basis for the research of ceRNA in LC.

Acute pancreatitis (AP) is a common acute abdominal disease with high mortality and mortality rates. Increasing evidences clarified that Traditional Chinese Medicine (TCM) adjuvant therapy for AP can be used and it gives a positive effect. Quercetin (3,3',4',5,7-pentahydroxyflavone, QE) is a type of flavone compound with positive effect on cancer and inflammation prevention. The current study aims to identify the effect of QE on AP and potential molecular effect. In this case, caerulein (CAE) induced AP cell and mice model were used. QE alleviated inflammatory mediators TNF-α, IL-6, and IL-10 in experiments. In addition, miR-216b was increased based on QE treatment. In further study, MAP2K6 of p38/MAPK signaling pathway was identified as a direct target of miR-216b, and QE inhibited p38/MAPK signaling pathway through up-regulating miR-216b. Our study also first confirmed that long non-coding RNA NEAT1 is a direct target of miR-216b and can be suppressed by QE. Because of the target, NEAT1, miR-216b, and MAP2K6 formed a competitive endogenous RNA (ceRNA) network. Besides direct target mediated by QE, it also decreased TNF-α which down-regulated TRAF2 and MAP3K5 located on upstream of p38/MAPK signaling and formed a feedback loop. In conclusion, QE has a protective effect on AP through inhibiting p38/MAPK signaling pathway by up-regulating miR-216b and suppressing TNF-α.

Glioblastoma is one of the most frequent and aggressive primary tumor of glial brain tumors. Long non-coding RNA Prostate cancer-associated ncRNA transcript 6 (PCAT6) has been identified to influence the progression of many cancers, but its expression and functions in glioblastoma remain unclear. In this study, we intended to investigate the expression, functions and the corresponding mechanisms of PCAT6 in glioblastoma. We observed that PCAT6 expression was upregulated in glioblastoma tissues and cell lines and its high expression was due to the transcriptional activation by Yin Yang 1. miR-513 was a target of PCAT6 and Insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) was a target of miR-513. Hence, PCAT6 upregulated IGF2BP1 expression via miR-513 in a competing endogenous RNAs manner. PCAT6 and IGF2BP1 functioned as oncogenes while miR-513 acted as a tumor suppressor gene in glioblastoma. PCAT6 and miR-513 modulated the proliferation and survival of glioblastoma cells via AKT signaling by mediating IGF2BP1. IGF2BP1 raised the expression of PCAT6 by increasing its stability. In conclusion, our results indicate that PCAT6/miR-513/IGF2BP1 positive feedback loop plays a crucial role in facilitating glioblastoma progression.

As a momentous post-transcriptional regulator, microRNAs (miRNAs) are attracting more and more attention. The classical miRNAs regulated mechanism shows it binds to the targets' 3'UTR thus play the role in post-transcription. Meanwhile, single miRNA can target multiple genes, so those should compete to bind that miRNA. Vice versa, single gene can sponge mass of miRNAs as well. Thus the competitive endogenous RNAs (ceRNAs) hypothesis was put forward in 2011. The ceRNA hypothesis has made huge achievements, in particular in non-coding genes, which including long non-coding RNAs (lncRNAs), circle RNAs (circRNAs) and pseudogenes, even viral transcripts. It also contributed greatly to epigenetics development. However, an increasing number of controversies have occurred with applause. Based on this situation, this review introduces something in detail about the ceRNAs hypothesis achieved in lncRNAs, circRNAs, pseudogenes and viral transcripts, respectively. Meanwhile, it also covers controversy of the ceRNAs hypothesis.

Glioma is the most common malignant tumor in the central nervous system. Altered long noncoding RNAs (lncRNAs) are playing regulatory roles in physiological and pathogenic processes in cancer. Here, we uncovered a differentially expressed lncRNA called brain cytoplasmic RNA 1 (BCYRN1), and elucidated its function and molecular mechanism in the progression and development of glioma. Three fresh tumor tissues from glioma patients and three normal brain tissues from craniocerebral trauma patients were prepared for high-throughput RNA sequencing. Differential RNA transcripts and BCYRN1 were identified by RT-qPCR in glioma samples and controls. CCK-8, colony formation assays, flow cytometry, TUNEL assays, cell migration assays, wound-healing assays, and xenograft model were established to investigate the biological function of BCYRN1 both in vitro and in vivo. Various bioinformatics analysis, dual-luciferase reporter assays, biotinylated RNA pulldown assays, and rescue experiments were conducted to reveal the underlying mechanisms of competitive endogenous RNAs (ceRNAs). 183 lncRNAs were identified with significant dysregulation in glioma and randomly selected differential RNAs were further confirmed by RT-qPCR. Among them, BCYRN1 was the most downregulated lncRNA, and its low expression positively correlated with glioma progression. Functionally, BCYRN1 overexpression inhibited cell proliferation, migration in glioma cell lines, whereas BCYRN1 depletion resulted in the opposite way. MiR-619-5p was further confirmed as the direct target of BCYRN1. Mechanistically, miR-619-5p specifically targeted the CUE domain containing protein 2 (CUEDC2), and BCYRN1/miR-619-5p suppressed glioma tumorigenesis by inactivating PTEN/AKT/p21 pathway in a CUEDC2-dependent manner. Overall, our data presented that the reduced expression of BCYRN1 was associated with poor patient outcome in glioma. BCYRN1 functioned as a ceRNA to inhibit glioma progression by sponging miR-619-5p to regulate CUEDC2 expression and PTEN/AKT/p21 pathway. Our results indicated that BCYRN1 exerted tumor suppressor potential and might be a candidate in the diagnosis and treatment of glioma.

Viral infection induces the initiation of antiviral effectors and cytokines which are critical mediators of innate antiviral responses. The critical molecular determinants are responsible for triggering an appropriate immune response. Long noncoding RNAs (lncRNAs) have emerged as new gene modulators involved in various biological processes, while how lncRNAs operate in lower vertebrates are still unknown. Here, we discover a long noncoding RNA, termed antiviral-associated long noncoding RNA (AANCR), as a novel regulator for innate antiviral responses in teleost fish. The results indicate that fish MITA plays an essential role in host antiviral responses and inhibition of Siniperca chuatsi rhabdovirus (SCRV) production. miR-210 reduces MITA expression and suppress MITA-mediated antiviral responses, which may help viruses evade host antiviral responses. Further, AANCR functions as a competing endogenous RNA (ceRNA) for miR-210 to control protein abundance of MITA, thereby inhibiting SCRV replication and promoting antiviral responses. Our data not only shed new light on understanding the function role of lncRNA in biological processes in teleost fish, but confirmed the hypothesis that ceRNA networks exist widely in vertebrates.

Duchenne muscular dystrophy (DMD) is one of the most severe neuromuscular disorders. Long non-coding RNAs (lncRNAs) are a group of non-coding transcripts, which could regulate messenger RNA (mRNA) by binding the mutual miRNAs, thus acting as competing endogenous RNAs (ceRNAs). So far, the role of lncRNA in DMD pathogenesis remains unclear. In the current study, expression profile from a total of 33 DMD patients and 12 healthy people were downloaded from Gene Expression Omnibus (GEO) database (GSE38417 and GSE109178). Differentially expressed (DE) lncRNAs were discovered and targeted mRNAs were predicted. The ceRNA network of lncRNAs-miRNAs-mRNAs was then constructed. Genome Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the putative mRNAs in the ceRNA network were performed through Database for Annotation, Visualization and Integration Discovery (DAVID) website. Topological property of the network was analyzed using Cytoscape to disclose the hub lncRNAs. According to our assessments, 19 common DElncRNAs and 846 common DEmRNAs were identified in DMD compared to controls. The created ceRNA network contained 6 lncRNA nodes, 69 mRNA nodes, 27 miRNA nodes and 102 edges, while four hub lncRNAs (XIST, AL132709, LINC00310, ALDH1L1-AS2) were uncovered. In conclusion, our latest bioinformatic analysis demonstrated that lncRNA is likely involved in DMD. This work highlights the importance of lncRNA and provides new insights for exploring the molecular mechanism of DMD. The created ceRNA network contained 6 lncRNA nodes, 69 mRNA nodes, 27 miRNA nodes and 102 edges, while four hub lncRNAs (XIST, AL132709, LINC00310, ALDH1L1-AS2) were uncovered. Remarkably, KEGG analysis indicated that targeted mRNAs in the network were mainly enriched in "microRNAs in cancer" and "proteoglycans in cancer". Our study may offer novel perspectives on the pathogenesis of DMD from the point of lncRNAs. This work might be also conducive for exploring the molecular mechanism of increased incidence of tumorigenesis reported in DMD patients and experimental models.

Long non-coding RNAs (lncRNAs) are bound up with various human diseases. However, their roles in brain ischemia-reperfusion (I/R) injury remain largely unknown. This study aimed to reveal the potential mechanism of LncRNA SNHG3 on autophagy-induced neuronal cell apoptosis in the brain I/R injury. LncRNA SNHG3 and miR-485 or autophagy markers LC3II/I and Beclin-1 expressions were detected by qRT-PCR or Western blot and the apoptosis of N2a cells was analyzed by flow cytometry. Besides, the interactions between LncRNA SNHG3 and miR-485, miR-485 and ATG7 were validated by RNA pull-down and dual-luciferase reporter system assays. After the Oxygen and Glucose Deprivation (OGD) treatment of N2a cells transfected with pcDNA-SNHG3, pcDNA-SNHG3 + miR-485 mimic for 6 h, 1 mM autophagy inhibitor 3-MA was added and reoxygenated for 24 h, the effect of LncRNA SNHG3 on the autophagy-induced neuronal cell apoptosis was measured by Western blot and flow cytometry. LncRNA SNHG3 was highly expressed in the mouse model of transient middle cerebral artery occlusion and cell model of Oxygen and Glucose Deprivation/Reperfusion, while miR-485 was lowly expressed. Furthermore, miR-485 negatively regulated the luciferase activities of LncRNA SNHG3 and ATG7. After the OGD treatment of N2a cells transfected with pcDNA-SNHG3, pcDNA-SNHG3 + miR-485 mimic for 6 h, 1 mM 3-MA was added and reoxygenated for 24 h, the overexpression of LncRNA SNHG3 raised the ratio of LC3-II/LC3-I and Beclin-1 expression and boosted the apoptosis of N2a cells, while these effects were reversed after the transfection of miR-485 mimic. In general, our data expounded that the interference with LncRNA SNHG3 improved brain I/R injury by up-regulating miR-485 and down-regulating ATG7 to restrain autophagy and neuronal cell apoptosis.

Endometriosis is one of the most common gynecological diseases that adversely effects the lives of women. Our previous studies showed that LINC01541 plays a key role in 17β-estradiol (17β-E2)-stimulated endometrial stromal cells (ESCs); however, the mechanism by which LINC01541 exerts if effects requires further elaboration. Here, we report that LINC01541 serves to reduce the bioavailability of miR-506-5p by acting as a molecular sponge. Samples of control endometrial tissue and ectopic endometrial tissue were obtained from 10 healthy volunteers and 18 patients with endometriosis, respectively, and the levels of LINC01541 and miR-506-5p expressions in those tissues were measured. The relationship between LINC01541 and miR-506-5p was verified in 17β-E2-stimulated ESCs. Overexpression or silencing of miR-506-5p in ESCs was performed explore its role in endometriosis, and we also investigated whether WNT inhibitory factor 1 (WIF1) might be a target gene of miR-506-5p. Our results showed that LINC01541 was expressed at low levels and miR-506-5p was expressed at high levels in ectopic tissues. LINC01541 expression was negatively correlated with miR-506-5p expression. We also found that miR-506-5p activated the Wnt/β-catenin pathway by inhibiting WIF1 expression, and thereby induced the proliferation, migration, and invasion of ESCs. Furthermore, silencing of miR-506-5p promoted apoptosis and suppressed the proliferation of 17β-E2-treated ESCs. Overexpression of miR-506-5p could reverse the inhibitory effect of LINC01541 in endometriosis. In summary, this study found that in endometriosis, LINC01541 functions as a ceRNA that modulates the Wnt/β-catenin pathway by decoying miR-506-5p.