ADPGK-AS1 long noncoding RNA switches macrophage metabolic and phenotypic state to promote lung cancer growth
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ABSTRACT:
SUBMITTER: Dr. Annika Karger
PROVIDER: S-SCDT-10_15252-EMBJ_2022111620 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:BackgroundHuman naïve pluripotency state cells can be derived from direct isolation of inner cell mass or primed-to-naïve resetting of human embryonic stem cells (hESCs) through different combinations of transcription factors, small molecular inhibitors, and growth factors. Long noncoding RNAs (lncRNAs) have been identified to be crucial in diverse biological processes, including pluripotency regulatory circuit of mouse pluripotent stem cells (PSCs), but few are involved in human PSCs' regulation of pluripotency and naïve pluripotency derivation. This study initially planned to discover more lncRNAs possibly playing significant roles in the regulation of human PSCs' pluripotency, but accidently identified a lncRNA whose knockdown in human PSCs induced naïve-like pluripotency conversion.MethodsCandidate lncRNAs tightly correlated with human pluripotency were screened from 55 RNA-seq data containing human ESC, human induced pluripotent stem cell (iPSC), and somatic tissue samples. Then loss-of-function experiments in human PSCs were performed to investigate the function of these candidate lncRNAs. The naïve-like pluripotency conversion caused by CCDC144NL-AS1 knockdown (KD) was characterized by quantitative real-time PCR, immunofluorescence staining, western blotting, differentiation of hESCs in vitro and in vivo, RNA-seq, and chromatin immunoprecipitation. Finally, the signaling pathways in CCDC144NL-AS1-KD human PSCs were examined through western blotting and analysis of RNA-seq data.ResultsThe results indicated that knockdown of CCDC144NL-AS1 induces naïve-like state conversion of human PSCs in the absence of additional transcription factors or small molecular inhibitors. CCDC144NL-AS1-KD human PSCs reveal naïve-like pluripotency features, such as elevated expression of naïve pluripotency-associated genes, increased developmental capacity, analogous transcriptional profiles to human naïve PSCs, and global reduction of repressive chromatin modification marks. Furthermore, CCDC144NL-AS1-KD human PSCs display inhibition of MAPK (ERK), accumulation of active ?-catenin, and upregulation of some LIF/STAT3 target genes, and all of these are concordant with previously reported traits of human naïve PSCs.ConclusionsOur study unveils an unexpected role of a lncRNA, CCDC144NL-AS1, in the naïve-like state conversion of human PSCs, providing a new perspective to further understand the regulation process of human early pluripotency states conversion. It is suggested that CCDC144NL-AS1 can be potentially valuable for future research on deriving higher quality naïve state human PSCs and promoting their therapeutic applications.
| S-EPMC6664583 | biostudies-literature
Project description:OBJECTIVES:The long-noncoding RNAs (lncRNAs) are identified as new crucial regulators of diverse cellular processes in glioblastoma (GBM) tissues. However, the expression pattern and biological function of lncRNAs remain largely unknown. Here, for the first time, the effects of lncRNA lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1) on GBM progression both in vitro and in vivo are investigated. MATERIALS AND METHODS:Expression profiles of LEF1-AS1 in GBM specimens were investigated by bioinformatics analyses. LEF1-AS1 expression in GBM tissues was detected using a quantitative polymerase chain reaction. LEF1-AS1 expression was inhibited by transfecting the LEF1-AS1-specific small interfering RNAs (siRNAs) and stable cell lines established were inhibited by transfecting si-LEF1-AS1 viruses. The Cell Counting Kit-8, ethynyl deoxyuridine, and colony formation assay were used to examine proliferation function. The flow cytometry detected cell-cycle change and apoptosis. Migration effects were detected by a Transwell assay. The tumor xenografts and immunohistochemistry were performed to evaluate tumor growth in vivo. RESULTS:In this study, LEF1-AS1 expression was found significantly upregulated in GBM specimens compared with normal tissues. The 5-year overall survival in GBM patients from The Cancer Genome Atlas with high expression of LEF1-AS1 was inferior to that with low expression. It was confirmed that expression of LEF1-AS1 was higher in GBM tissues than normal ones. Knockdown of LEF1-AS1 significantly inhibited the malignancy of GBM cells, including proliferation and invasion, and promoted cell apoptosis. The result of Western blot assays indicated that knockdown of LEF1-AS1-mediated tumor suppression in GBM cells may be via the reduction of ERK and Akt/mTOR signaling activities. Finally, the in vivo experiment also demonstrated that knockdown LEF1-AS1 inhibited the growth-promoting effect of LEF1-AS1 of U87 cells. CONCLUSION:Our result indicated that lncRNA LEF1-AS1 acts as an oncogene in GBM and may be a pivotal target for this disease.
| S-EPMC5584905 | biostudies-literature
Project description:Long noncoding RNAs (lncRNAs) play roles in the tumorigenesis, proliferation and metastasis of tumor cells. Previous studies indicate that the transcription factor Sp1 is responsible for transcription of the XIAP gene, but it is unknown whether lncRNAs are involved in XIAP transcription. Herein, we identified a novel lncRNA, denoted as XIAP-AS1, transcribed from the first intron of the complementary strand of the XIAP gene. Using RNA FISH, cell fractionation and qRT-PCR, XIAP-AS1 was determined to be located primarily in the nucleus. After various XIAP-AS1 deletion mutants were expressed, RIP assays showed that only the full-length XIAP-AS1 RNA interacted with Sp1 and thereby participated in XIAP transcription. ChIP assays showed that XIAP-AS1 knockdown decreased the binding of Sp1 to the promoter region of XIAP. XIAP-AS1 knockdown promoted tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in gastric tumor cells, as cleaved caspase-3 and caspase-9 was detected. Moreover, in an in vivo mouse xenograft model, tumor cell proliferation was inhibited by XIAP-AS1 knockdown in response to TRAIL administration. In conclusion, our results indicate that XIAP-AS1 is involved in XIAP transcription by interacting with Sp1. Additionally, XIAP-AS1 is a potential target for TRAIL-induced apoptosis in gastric cancer cells.
| S-EPMC5549724 | biostudies-other
Project description:BackgroundSepsis is a systemic inflammatory syndrome caused by infection with a high incidence and mortality. Although long noncoding RNAs have been identified to be closely involved in many inflammatory diseases, little is known about the role of lncRNAs in pediatric septic shock.MethodsWe downloaded the mRNA profiles GSE13904 and GSE4607, of which GSE13904 includes 106 blood samples of pediatric patients with septic shock and 18 health control samples; GSE4607 includes 69 blood samples of pediatric patients with septic shock and 15 health control samples. The differentially expressed lncRNAs were identified through the limma R package; meanwhile, GO terms and KEGG pathway enrichment analysis was performed via the clusterProfiler R package. The protein-protein interaction (PPI) network was constructed based on the STRING database using the targets of differently expressed lncRNAs. The MCODE plug-in of Cytoscape was used to screen significant clustering modules composed of key genes. Finally, stepwise regression analysis was performed to screen the optimal lncRNAs and construct the logistic regression model, and the ROC curve was applied to evaluate the accuracy of the model.ResultsA total of 13 lncRNAs which simultaneously exhibited significant differences in the septic shock group compared with the control group from two sets were identified. According to the 18 targets of differentially expressed lncRNAs, we identified some inflammatory and immune response-related pathways. In addition, several target mRNAs were predicted to be potentially involved in the occurrence of septic shock. The logistic regression model constructed based on two optimal lncRNAs THAP9-AS1 and TSPOAP1-AS1 could efficiently separate samples with septic shock from normal controls.ConclusionIn summary, a predictive model based on the lncRNAs THAP9-AS1 and TSPOAP1-AS1 provided novel lightings on diagnostic research of septic shock.
| S-EPMC7725549 | biostudies-literature
Project description:Long noncoding RNAs (lncRNAs) regulate gene expression via their RNA product or through transcriptional interference, yet a strategy to differentiate these two processes is lacking. To address this, we used multiple small interfering RNAs (siRNAs) to silence GNG12-AS1, a nuclear lncRNA transcribed in an antisense orientation to the tumour-suppressor DIRAS3. Here we show that while most siRNAs silence GNG12-AS1 post-transcriptionally, siRNA complementary to exon 1 of GNG12-AS1 suppresses its transcription by recruiting Argonaute 2 and inhibiting RNA polymerase II binding. Transcriptional, but not post-transcriptional, silencing of GNG12-AS1 causes concomitant upregulation of DIRAS3, indicating a function in transcriptional interference. This change in DIRAS3 expression is sufficient to impair cell cycle progression. In addition, the reduction in GNG12-AS1 transcripts alters MET signalling and cell migration, but these are independent of DIRAS3. Thus, differential siRNA targeting of a lncRNA allows dissection of the functions related to the process and products of its transcription.
| S-EPMC4740813 | biostudies-other
Project description:The discovery of probabilistic promoter switches in genes that code for class I major histocompatibility complex receptors in mouse and human provides a useful paradigm to explain programmed cell fate decisions. These switches have preset probabilities of transcribing in either the sense or antisense direction, and the characteristics of individual switches are programmed by the relative affinity of competing transcription factor-binding sites. The noncoding RNAs produced from these switches can either activate or suppress gene transcription, based on their location relative to the promoter responsible for gene expression in mature cells. The switches are active in a developmental phase that precedes gene expression by mature cells, thus temporally separating the stochastic events that determine gene activation from the protein expression phase. This allows the probabilistic generation of variegated gene expression in the absence of selection and ensures that mature cells have stable expression of the genes. Programmed probabilistic switches may control cell fate decisions in many developmental systems, and therefore, it is important to investigate noncoding RNAs expressed by progenitor cells to determine if they are expressed in a stochastic manner at the single cell level. This review provides a summary of current knowledge regarding murine and human switches, followed by speculation on the possible involvement of probabilistic switches in other systems of programmed differentiation.
| S-EPMC4222648 | biostudies-other
Project description:Acquired endocrine therapy resistance is a significant clinical problem for breast cancer patients. In recent years, increasing attention has been paid to long noncoding RNA (lncRNA) as a critical modulator for cancer progression. Based on RNA-sequencing data of breast invasive carcinomas in The Cancer Genome Atlas database, we identified thymopoietin antisense transcript 1 (TMPO-AS1) as a functional lncRNA that significantly correlates with proliferative biomarkers. TMPO-AS1 positivity analyzed by in situ hybridization significantly correlates with poor prognosis of breast cancer patients. TMPO-AS1 expression was upregulated in endocrine therapy-resistant MCF-7 cells compared with levels in parental cells and was estrogen inducible. Gain and loss of TMPO-AS1 experiments showed that TMPO-AS1 promotes the proliferation and viability of estrogen receptor (ER)-positive breast cancer cells in vitro and in vivo Global expression analysis using a microarray demonstrated that TMPO-AS1 is closely associated with the estrogen signaling pathway. TMPO-AS1 could positively regulate estrogen receptor 1 (ESR1) mRNA expression by stabilizing ESR1 mRNA through interaction with ESR1 mRNA. Enhanced expression of ESR1 mRNA by TMPO-AS1 could play a critical role in the proliferation of ER-positive breast cancer. Our findings provide a new insight into the understanding of molecular mechanisms underlying hormone-dependent breast cancer progression and endocrine resistance.
| S-EPMC6851347 | biostudies-literature
Project description:BackgroundThe long noncoding RNA actin filament associated protein 1 antisense RNA1 (AFAP1-AS1) is a critical player in various cancers. However, the clinical value and functional mechanisms of AFAP1-AS1 during the tumorigenicity of nasopharyngeal carcinoma (NPC) remain unclear. Here, we investigated the clinical application and potential molecular mechanisms of AFAP1-AS1 in NPC tumorigenesis and progression.MethodsThe expression level of AFAP1-AS1 was determined by qRT-PCR in 10 paired fresh human NPC tissues and adjacent normal tissues. RNAscope was performed on 100 paired paraffin-embedded NPC and adjacent nontumor specimens. The biological functions of AFAP1-AS1 were assessed by in vitro and in vivo functional experiments. RNA-protein pull-down assays were performed to detect and identify the AFAP1-AS1-interacting protein KAT2B. Protein-RNA immunoprecipitation (RIP) assays were conducted to examine the interaction of AFAP1-AS1 and KAT2B. Chromatin immunoprecipitation (ChIP) and luciferase analyses were utilized to identify the binding site of transcription intermediary factor 1 alpha (TIF1?) and H3K14ac on the RBM3 promoter.ResultsAFAP1-AS1 is upregulated in NPC and is a poor prognostic indicator for survival in NPC patients. AFAP1-AS1 was required for NPC proliferation in vitro and tumorigenicity in vivo. Mechanistic investigations suggested that AFAP1-AS1 binds to KAT2B and promotes acetyltransferase activation at two residues (E570/D610). KAT2B further promotes H3K14 acetylation and protein binding to the bromo domain of TIF1?. Consequently, TIF1? acts as a nuclear transcriptional coactivator of RBM3 transcription, leading to YAP mRNA stabilization and enhanced NPC tumorigenicity.ConclusionsOur findings suggest that AFAP1-AS1 functions as an oncogenic biomarker and promotes NPC tumorigenicity through enhanced KAT2B acetyltransferase activation and YAP mRNA stabilization.
| S-EPMC7719841 | biostudies-literature
Project description:BackgroundLBX2 antisense RNA 1 (LBX2-AS1), a long noncoding RNA, has been identified to be closely associated with the progression of various cancers. However, the role of LBX2-AS1 in colorectal cancer (CRC) is still poorly understood. In this study, we aimed to investigate the expression and function of LBX2-AS1 in CRC.Material and methodsExpression data from the Gene Expression Omnibus (GEO) and Gene Expression Profiling Interactive Analysis (GEPIA) databases and results obtained from clinical samples/patients were used to determine the correlation between LBX2-AS1 expression and pathological stages, overall survival (OS). Furthermore, knockdown of LBX2-AS1 in CRC cells using the short interfering RNA (siRNA) technique, and observed its biological functions using western blotting, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), cell counting kit-8 (CCK-8) and flow cytometry assay in the CRC cell line.ResultsOur study demonstrated that the expression levels of LBX2-AS1 were higher in CRC cell lines than in normal colon mucosal cell lines. Bioinformatics analysis revealed that CRC patients with high LBX2-AS1 expression levels had poor OS. Furthermore, knockdown of LBX2-AS1 in CRC cells could attenuate the proliferative ability of CRC cells in vitro, which is associated with decreased expression of cyclin-dependent kinase (CDK) 3, CDK6, and CCND1 and enhanced expression of cyclin-dependent kinase inhibitor 1A.ConclusionsLBX2-AS1 plays a crucial role in the tumorigenesis of CRC, providing a potential therapeutic target for CRC patients.
| S-EPMC7983235 | biostudies-literature
Project description:Aromatase inhibition is an efficient endocrine therapy to block ectopic estrogen production for postmenopausal estrogen receptor (ER)-positive breast cancer patients, but many develop resistance. Here, we show that aromatase inhibitor (AI)-resistant breast tumors display features of enhanced aerobic glycolysis with upregulation of long noncoding RNA (lncRNA) DIO3OS, which correlates with poor prognosis of breast cancer patients on AI therapies. Long-term estrogen deprivation induces DIO3OS expression in ER-positive breast tumor cells, which further enhances aerobic glycolysis and promotes estrogen-independent cell proliferation in vitro and in vivo. Mechanistically, DIO3OS interacts with polypyrimidine tract binding protein 1 (PTBP1) and stabilizes the mRNA of lactate dehydrogenase A (LDHA) by protecting the integrity of its 3'UTR, and subsequently upregulates LDHA expression and activates glycolytic metabolism in AI-resistant breast cancer cells. Our findings highlight the role of lncRNA in regulating the key enzyme of glycolytic metabolism in response to endocrine therapies and the potential of targeting DIO3OS to reverse AI resistance in ER-positive breast cancer.
| S-EPMC9684133 | biostudies-literature