LncRNA LBX2-AS1 promotes proliferation and migratory capacity of clear cell renal cell carcinoma through mitophagy
Ontology highlight
ABSTRACT:
SUBMITTER: Wang B
PROVIDER: S-EPMC10848470 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:We identify ADIRF-AS1 circadian long non-coding RNA (lncRNA). Deletion of ADIRF-AS1 in U2OS cells alters rhythmicity of clock-controlled genes and expression of extracellular matrix genes. ADIRF-AS1 interacts with all components of the PBAF (PBRM1/BRG1) complex in U2OS cells. Because PBRM1 is a tumor suppressor mutated in over 40% of clear cell renal carcinoma (ccRCC) cases, we evaluate ADIRF-AS1 in ccRCC cells. Reducing ADIRF-AS1 expression in ccRCC cells decreases expression of some PBAF-suppressed genes. Expression of these genes is partially rescued by PBRM1 loss, consistent with ADIRF-AS1 acting in part to modulate PBAF. ADIRF-AS1 expression correlates with survival in human ccRCC, particularly in PBRM1 wild-type, but not mutant, tumors. Loss of ADIRF-AS1 eliminates in vivo tumorigenesis, partially rescued by concurrent loss of PBRM1 only when co-injected with Matrigel, suggesting a PBRM1-independent function of ADIRF-AS1. Our findings suggest that ADIRF-AS1 functions partly through PBAF to regulate specific genes as a BMAL1-CLOCK-regulated, oncogenic lncRNA.
| S-EPMC9652615 | biostudies-literature
Project description:BackgroundRecent reports suggest that the long non-coding RNA LBX2 antisense RNA 1 (LBX2-AS1) acts as an important regulator in cancer progression, but its significance in colorectal cancer (CRC) remains undetermined.MethodsLBX2-AS1 expression levels in CRC were determined from the GEPIA database and CRC tissues to investigate clinical relevance. meRIP-PCR assays investigated the molecular mechanisms underlying the function of m6A in LBX2-AS1. Loss of function experiments was used to define the role of LBX2-AS1 in the progression of CRC. The ceRNA function of LBX2-AS1 was evaluated by RNA immunoprecipitation. In vitro and PDX models were used to determine if LBX2-AS1 promotes 5-fluorouracil resistance.ResultsData from the TCGA and our institutional patient cohorts established that LBX2-AS1 levels were significantly upregulated in most CRC tissues relative to normal adjacent colon tissues. Moreover, LBX2-AS1 levels were positively correlated with aggressive disease characteristics, constituting an independent prognostic indicator of overall patient survival. Mechanistic investigations suggested that the increased LBX2-AS1 in CRC was mediated by METTL3-dependent m6A methylation. In vitro experiments indicated that knockdown of LBX2-AS1 inhibited CRC proliferation, migration and invasion with this phenotype linked to LBX2-AS1-mediated regulation of AKT1, acting as a ceRNA to sponge miR-422a. Ex vivo analysis of patient-derived CRC xenografts showed that low LBX2-AS1 expression cases exhibited 5-FU responsiveness and clinical investigations confirmed that low LBX2-AS1 expression was associated with improved clinical benefits from 5-FU therapy.ConclusionsTogether these results suggest that LBX2-AS1 may serve as a therapeutic target and predictor of 5-FU benefit in CRC patients.
| S-EPMC8449476 | biostudies-literature
Project description:We identified ADIRF-AS1 as a BMAL1-CLOCK regulated circadian lncRNA. Loss of ADIRF-AS1 in U2OS cells altered rhythmicity of clock-controlled genes and expression of genes associated with cell adhesion and the extracellular matrix (ECM) but did not affect neighboring genes in cis. Affinity based enrichment of U2OS ADIRF-AS1-interacting proteins identified all components of the tumor suppressive PBAF (PBRM1/BRG1) complex. Because PBRM1 is a tumor suppressor mutated in 40% of clear cell renal carcinoma (ccRCC) cases, we studied ccRCC 786O cells and also found PBRM1 bound to ADIRF-AS1. Reducing ADIRF-AS1 expression in 786O and A498 ccRCC cells decreased expression of PBAF-suppressed genes, consistent with ADIRF-AS1 acting to antagonize the function of PBAF. Loss of PBRM1, however, rescued PBAF responsive cell cycle genes in ADIRF-AS1 KO 786O ccRCC cells. Importantly, ADIRF-AS1 expression correlates with survival in human ccRCC, particularly in PBRM1 wild-type, but not mutant PBRM1 tumors. In this regard, loss of ADIRF-AS1 did not affect in vitro 786O cell growth, but strikingly eliminated in vivo tumorigenesis, which was partially rescued by concurrent loss of PBRM1. This rescue, however, requires Matrigel, suggesting a PBRM1-independent function of ADIRF-AS1 in regulating the ECM. Collectively, our findings suggest that ADIRF-AS1 functions partly to antagonize the tumor suppressive effect of the PBAF complex and behaves as an unforeseen BMAL1-regulated, oncogenic lncRNA.
| MSV000090286 | MassIVE
Project description:BackgroundLncRNA GAS8-AS1 has been reported to participate in several types of cancer, while its role in glioblastoma (GBM) is unknown. In the present study, we aimed to investigate the function of GAS8-AS1 in GBM and the underlying mechanisms.MethodsThe expression levels of GAS8-AS1 and NEAT1 in GBM patients and the healthy controls were measured by performing RT-qPCR. Diagnostic values of plasma GAS8-AS1 and NEAT1 for GBM were analyzed by performing ROC curve analysis with GBM patients as true positive cases and the healthy controls as true negative cases. Linear regression analysis was performed to study the correlation between the expression levels of GAS8-AS1 and NEAT1. The expression levels of GAS8-AS1 and NEAT1 in GBM cells were also determined by RT-qPCR. CCK-8 and transwell invasion assays were performed to detect the proliferation and invasion of GBM cells. Western blot assay was performed to detect the expression levels of β-catenin, Axin2, c-myc, cyclin D1, and GAPDH in GBM cells.ResultsGAS8-AS1 was downregulated, while lncRNA NEAT1 was upregulated in the plasma of GBM patients. Altered expression levels of GAS8-AS1 and NEAT1 distinguished GBM patients from the healthy controls. The expression of GAS8-AS1 and NEAT1 was inversely correlated only in GBM patients. Overexpression of GAS8-AS1 reduced the expression levels of NEAT1 in GBM cells, while knock-down of GAS8-AS1 increased the expression levels of NEAT1. However, overexpression of NEAT1 showed no significant effects on the expression of GAS8-AS1. Knock-down of GAS8-AS1 promoted GBM cell proliferation and invasion and enhanced the activation of the Wnt/β-catenin pathway. However, the effects of knock-down of GAS8-AS1 were alleviated by the knock-down of NEAT1.ConclusionOverexpression of GAS8-AS1 inhibits GBM cell proliferation and invasion by downregulating NEAT1.
| S-EPMC8213648 | biostudies-literature
Project description:We identified ADIRF-AS1 as a BMAL1-CLOCK regulated circadian lncRNA. Loss of ADIRF-AS1 in U2OS cells altered rhythmicity of clock-controlled genes and expression of genes associated with cell adhesion and the extracellular matrix (ECM) but did not affect neighboring genes in cis. Affinity based enrichment of U2OS ADIRF-AS1-interacting proteins identified all components of the tumor suppressive PBAF (PBRM1/BRG1) complex. Because PBRM1 is a tumor suppressor mutated in 40% of clear cell renal carcinoma (ccRCC) cases, we studied ccRCC 786O cells and also found PBRM1 bound to ADIRF-AS1. Reducing ADIRF-AS1 expression in 786O and A498 ccRCC cells decreased expression of PBAF-suppressed genes, consistent with ADIRF-AS1 acting to antagonize the function of PBAF. Loss of PBRM1, however, rescued PBAF responsive cell cycle genes in ADIRF-AS1 KO 786O ccRCC cells. Importantly, ADIRF-AS1 expression correlates with survival in human ccRCC, particularly in PBRM1 wild-type, but not mutant PBRM1 tumors. In this regard, loss of ADIRF-AS1 did not affect in vitro 786O cell growth, but strikingly eliminated in vivo tumorigenesis, which was partially rescued by concurrent loss of PBRM1. This rescue, however, requires Matrigel, suggesting a PBRM1-independent function of ADIRF-AS1 in regulating the ECM. Collectively, our findings suggest that ADIRF-AS1 functions partly to antagonize the tumor suppressive effect of the PBAF complex and behaves as an unforeseen BMAL1-regulated, oncogenic lncRNA.
2022-11-16 | GSE199825 | GEO
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:The expression and function of long non-coding RNAs (lncRNAs) in clear cell renal cell carcinoma (ccRCC) remains unclear. The present study measured the expression profiles of three lncRNAs (uc009yby.1, ENST00000514034, and ENST00000450687) using reverse transcription-quantitative polymerase chain reaction, and assessed their signatures in distinguishing ccRCC from matched normal tissues via analysis of receiver operating characteristic (ROC) curves. The expression of uc009yby.1 was inhibited by transfection of renal cells with small interfering RNA, and then the cell proliferation was evaluated by using a Cell Counting Kit-8. The results showed that the expressions of uc009yby.1 and ENST00000514034 were markedly increased in ccRCC compared with the matched normal tissues (P<0.0001 and P=0.0008, respectively), whereas the ENST00000450687 expression was not significantly altered. ROC curves yielded an area under the curve (AUC) value of 0.7000 for uc009yby.1, with sensitivity of 54.29% and specificity of 82.86%; and an AUC value of 0.6627 for ENST00000514034, with sensitivity of 60.00% and specificity of 67.14%. Furthermore, knockdown of uc009yby.1 suppressed renal cell proliferation (Day 0, P=0.7844; Day 1, P=0.0018; Day 2, P=0.0001; Day 3, P<0.000; Day 4, P<0.0001). Taken together, these findings suggest that the expression profiles of uc009yby.1 and ENST00000514034 may serve as novel biomarkers for ccRCC detection, and that uc009yby.1 is strongly associated with renal cell proliferation.
| S-EPMC4998196 | biostudies-literature
Project description:Because of the lack of sensitivity to radiotherapy and chemotherapy, therapeutic options for renal clear cell carcinoma (KIRC) are scarce. Long noncoding RNAs (lncRNAs) play crucial roles in the progression of cancer. However, their functional roles and upstream mechanisms in KIRC remain largely unknown. Exploring the functions of potential essential lncRNAs may lead to the discovery of novel targets for the diagnosis and treatment of KIRC. Here, according to the integrated analysis of RNA sequencing and survival data in TCGA-KIRC datasets, cyclin-dependent kinase inhibitor 2B antisense lncRNA (CDKN2B-AS1) was discovered to be the most upregulated among the 14 lncRNAs that were significantly overexpressed in KIRC and related to shorter survival. Functionally, CDKN2B-AS1 depletion suppressed cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, CDKN2B-AS1 exerted its oncogenic activity by recruiting the CREB-binding protein and SET and MYND domain-containing 3 epigenetic-modifying complex to the promoter region of Ndc80 kinetochore complex component (NUF2), where it epigenetically activated NUF2 transcription by augmenting local H3K27ac and H3K4me3 modifications. Moreover, we also showed that CDKN2B-AS1 interacted with and was stabilized by insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an oncofetal protein showing increased levels in KIRC. The Kaplan-Meier method and receiver operating curve analysis revealed that patients whose IGF2BP3, CDKN2B-AS1 and NUF2 are all elevated showed the shortest survival time, and the combined panel (containing IGF2BP3, CDKN2B-AS1, and NUF2) possessed the highest accuracy in discriminating high-risk from low-risk KIRC patients. Thus, we conclude that the stabilization of CDKN2B-AS1 by IGF2BP3 drives the malignancy of KIRC through epigenetically activating NUF2 transcription and that the IGF2BP3/CDKN2B-AS1/NUF2 axis may be an ideal prognostic and diagnostic biomarker and therapeutic target for KIRC.
| S-EPMC7895987 | biostudies-literature
Project description:BackgroundClear cell renal cell carcinoma (ccRCC) is closely associated with steroid hormones and their receptors affected by lipid metabolism. Recently, there has been growing interest in the carcinogenic role of NR3C1, the sole gene responsible for encoding glucocorticoid receptor. However, the specific role of NR3C1 in ccRCC remains unclear. The present study was thus developed to explore the underlying mechanism of NR3C1's carcinogenic effects in ccRCC.MethodsExpression of NR3C1 was verified by various tumor databases and assessed using RT-qPCR and western blot. Stable transfected cell lines of ccRCC with NR3C1 knockdown were constructed, and a range of in vitro and in vivo experiments were performed to examine the effects of NR3C1 on ccRCC proliferation and migration. Transcriptomics and lipidomics sequencing were then conducted on ACHN cells, which were divided into control and sh-NR3C1 group. Finally, the sequencing results were validated using transmission electron microscopy, mitochondrial membrane potential assay, immunofluorescence co-localization, cell immunofluorescent staining, and Western blot. The rescue experiments were designed to investigate the relationship between endoplasmic reticulum stress (ER stress) and mitophagy in ccRCC cells after NR3C1 knockdown, as well as the regulation of their intrinsic signaling pathways.ResultsThe expression of NR3C1 in ccRCC cells and tissues was significantly elevated. The sh-NR3C1 group, which had lower levels of NR3C1, exhibited a lower proliferation and migration capacity of ccRCC than that of the control group (P < 0.05). Then, lipidomic and transcriptomic sequencing showed that lipid metabolism disorders, ER stress, and mitophagy genes were enriched in the sh-NR3C1 group. Finally, compared to the control group, ER stress and mitophagy were observed in the sh-NR3C1 group, while the expression of ATF6, CHOP, PINK1, and BNIP3 was also up-regulated (P < 0.05). Furthermore, Ceapin-A7, an inhibitor of ATF6, significantly down-regulated the expression of PINK1 and BNIP3 (P < 0.05), and significantly increased the proliferation and migration of ccRCC cells (P < 0.05).ConclusionsThis study confirms that knockdown of NR3C1 activates ER stress and induces mitophagy through the ATF6-PINK1/BNIP3 pathway, resulting in reduced proliferation and migration of ccRCC. These findings indicate potential novel targets for clinical treatment of ccRCC.
| S-EPMC10560440 | biostudies-literature
Project description:BackgroundThe crucial role of long non-coding RNAs (lncRNAs) has been certified in human cancers. The lncRNAs with abnormal expressions could act as tumor inhibitors or oncogenes in the advancement of tumors. LBX2-AS1 was once reported to accelerate esophageal squamous cell carcinoma. Nonetheless, its function in gastric cancer (GC) remained a riddle.MethodsRT-qPCR was used to examine the expression of NFIC/LBX2-AS1/miR-491-5p/ZNF703 in GC cell lines. The functions of LBX2-AS1 in GC were appraised by colony formation, EdU, flow cytometry analysis, transwell and wound healing assays. Luciferase reporter, ChIP and RNA pull down assays were utilized to evaluate the interactions among genes.ResultsLBX2-AS1 was up-regulated in GC cell lines. Knockdown of LBX2-AS1 repressed the proliferative, migratory, and invasive abilities of GC cells. Moreover, LBX2-AS1 was transcriptionally activated by NFIC. And LBX2-AS1 could bind with miR-491-5p. Besides, miR-491-5p depletion or ZNF703 upregulation could counteract the repressing effects of LBX2-AS1 silence on GC progression.ConclusionIn a word, LBX2-AS1 up-regulated by NFIC promoted GC progression via targeting miR-491-5p/ZNF703, implying LBX2-AS1 was an underlying treatment target for GC patients.
| S-EPMC7183605 | biostudies-literature