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Project description:The human 8q24 gene desert contains multiple enhancers that form tissue-specific long-range chromatin loops with the MYC oncogene, but how chromatin looping at the MYC locus is regulated remains poorly understood. Here we demonstrate that a long noncoding RNA (lncRNA), CCAT1-L, is transcribed specifically in human colorectal cancers from a locus 515 kb upstream of MYC. This lncRNA plays a role in MYC transcriptional regulation and promotes long-range chromatin looping. Importantly, the CCAT1-L locus is located within a strong super-enhancer and is spatially close to MYC. Knockdown of CCAT1-L reduced long-range interactions between the MYC promoter and its enhancers. In addition, CCAT1-L interacts with CTCF and modulates chromatin conformation at these loop regions. These results reveal an important role of a previously unannotated lncRNA in gene regulation at the MYC locus.
| S-EPMC4011346 | biostudies-literature
Project description:The objective of the present study was to clarify the expression characteristics of long non‑coding RNA (lncRNA) FGD5 antisense RNA 1 (FGD5‑AS1) in pancreatic cancer, as well as its biological function and underlying mechanism. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was utilized for the detection of FGD5‑AS1 and microRNA (miR)‑577 expression levels in pancreatic cancer tissues. Transfection was performed to upregulate or downregulate FGD5‑AS1 in pancreatic cancer cell lines. MTT and Transwell assays were then utilized to detect the proliferation, migration and invasion of cancer cells, respectively. Subsequently, dual‑luciferase reporter gene assay, RNA immunoprecipitation assay, RNA pull‑down assay, RT‑qPCR, western blotting, and Pearson's correlation analysis were employed to confirm the regulatory relationships among FGD5‑AS1, miR‑577, low‑density lipoprotein receptor‑related protein 6 (LRP6) and β‑catenin. Western blotting was employed to determine the expression levels of Axin2, cyclin D1 and c‑Myc. The expression level of FGD5‑AS1 was upregulated in pancreatic cancer tissues and cell lines. FGD5‑AS1 knockdown inhibited pancreatic cancer cell proliferation, migration and invasion. By contrast, miR‑577 was significantly inhibited in pancreatic cancer cells and tissues; its downregulation promoted pancreatic cancer cell proliferation, migration and invasion, and reversed the effects of FGD5‑AS1 knockdown on pancreatic cancer cells. In addition, it was revealed that miR‑577 was a target of FGD5‑AS1, and FGD5‑AS1 could modulate the expression levels of LRP6, β‑catenin, Axin2, cyclin D1 and c‑Myc via suppressing miR‑577. In conclusion, in pancreatic cancer, highly expressed FGD5‑AS1 activated the Wnt/β‑catenin signaling and promoted cancer cell proliferation, migration and invasion via suppression of miR‑577.
| S-EPMC8630524 | biostudies-literature
Project description:BackgroundNuclear transcription factor Y subunit C antisense RNA 1 (NFYC-AS1) was revealed to be a potential prognostic biomarker in lung adenocarcinoma (LAUD) by analyzing The Cancer Genome Atlas (TCGA) database. However, the function of NFYC-AS1 has not been verified in cancers, including LAUD. We plan to verify the function of NFYC-AS1 in LAUD through this study.MethodsWe determined NFYC-AS1 expression in 4 LAUD cell lines, and 1 normal lung cell line (HBE) by quantitative real-time reverse transcription PCR (qRT-PCR). small interfering RNA (siRNA) was employed to specifically knockdown NFYC-AS1 in H1299 and PC9 cell lines. Cell growth and invasion activity of LAUD cells was assessed by WST-1, colony formation and transwell assay, respectively. The effect of NFYC-AS1 expression on cell apoptosis was then assessed by flow cytometry assay. Furthermore, the expression of downstream proteins of NFYC-AS1 was investigated by Western blot.ResultsThe proliferation, migration, and invasion of cells were inhibited and apoptosis was increased after NFYC-AS1 knockdown in LAUD cells. The cells transfected with NFYC-AS1 siRNA had a higher rate of apoptosis compared with that in control cells. The apoptosis-related proteins p53 and PARP were upregulated. These suggested NFYC-AS1 could inhibit the apoptosis of LAUD cells. In terms of the expression of major autophagy proteins, p62 was downregulated while Beclin 1 was upregulated after NFYC-AS1 knockdown, which suggested that autophagy was activated. The expression of oncogenic proteins MET and c-Myc was downregulated.ConclusionsIn summary, the above results suggest that NFYC-AS1 may promote the proliferation of LAUD through autophagy and apoptosis.
| S-EPMC8640918 | biostudies-literature
Project description:Molecular processes involving lncRNAs regulate cell function. By applying transcriptomics, we identify lncRNAs whose expression is regulated by transforming growth factor β (TGF-β). Upon silencing individual lncRNAs, we identify several that regulate TGF-β signaling. Among these lncRNAs, TGFB2-antisense RNA1 (TGFB2-AS1) is induced by TGF-β through Smad and protein kinase pathways and resides in the nucleus. Depleting TGFB2-AS1 enhances TGF-β/Smad-mediated transcription and expression of hallmark TGF-β-target genes. Increased dose of TGFB2-AS1 reduces expression of these genes, attenuates TGF-β-induced cell growth arrest, and alters BMP and Wnt pathway gene profiles. Mechanistically, TGFB2-AS1, mainly via its 3' terminal region, binds to the EED adaptor of the Polycomb repressor complex 2 (PRC2), promoting repressive histone H3K27me3 modifications at TGF-β-target gene promoters. Silencing EED or inhibiting PRC2 methylation activity partially rescues TGFB2-AS1-mediated gene repression. Thus, the TGF-β-induced TGFB2-AS1 lncRNA exerts inhibitory functions on TGF-β/BMP signaling output, supporting auto-regulatory negative feedback that balances TGF-β/BMP-mediated responses.
| S-EPMC6859500 | biostudies-literature
Project description:The long noncoding RNA CDKN2B-AS1 harbors a major coronary artery disease risk haplotype, which is also associated with progressive forms of the oral inflammatory disease periodontitis as well as myocardial infarction (MI). Despite extensive research, there is currently no broad consensus on the function of CDKN2B-AS1 that would explain a common molecular role of this lncRNA in these diseases. Our aim was to investigate the role of CDKN2B-AS1 in gingival cells to better understand the molecular mechanisms underlying the increased risk of progressive periodontitis. We downregulated CDKN2B-AS1 transcript levels in primary gingival fibroblasts with LNA GapmeRs. Following RNA-sequencing, we performed differential expression, gene set enrichment analyses and Western Blotting. Putative causal alleles were searched by analyzing associated DNA sequence variants for changes of predicted transcription factor binding sites. We functionally characterized putative functional alleles using luciferase-reporter and antibody electrophoretic mobility shift assays in gingival fibroblasts and HeLa cells. Of all gene sets analysed, collagen biosynthesis was most significantly upregulated (Padj=9.7 × 10- 5 (AUC > 0.65) with the CAD and MI risk gene COL4A1 showing strongest upregulation of the enriched gene sets (Fold change = 12.13, Padj = 4.9 × 10- 25). The inflammatory "TNFA signaling via NFKB" gene set was downregulated the most (Padj=1 × 10- 5 (AUC = 0.60). On the single gene level, CAPNS2, involved in extracellular matrix organization, was the top upregulated protein coding gene (Fold change = 48.5, P < 9 × 10- 24). The risk variant rs10757278 altered a binding site of the pathogen responsive transcription factor STAT1 (P = 5.8 × 10- 6). rs10757278-G allele reduced STAT1 binding 14.4% and rs10757278-A decreased luciferase activity in gingival fibroblasts 41.2% (P = 0.0056), corresponding with GTEx data. CDKN2B-AS1 represses collagen gene expression in gingival fibroblasts. Dysregulated collagen biosynthesis through allele-specific CDKN2B-AS1 expression in response to inflammatory factors may affect collagen synthesis, and in consequence tissue barrier and atherosclerotic plaque stability.
| S-EPMC11294485 | biostudies-literature
Project description:[This corrects the article DOI: 10.21037/atm-21-4995.].
| S-EPMC11534751 | biostudies-literature
Project description:AimsAltered activities of long noncoding RNAs (lncRNAs) have been associated with cancer development, and lncRNA FOXD1-AS1 (FOXD1-AS1) is the antisense transcript of the gene encoding for FOXD1, known for its role as an oncogene in several tumor types including glioma. However, the role of FOXD1-AS1 in the differentiation and progression of glioma is not well known.MethodsExpression profile chip and qPCR were used to screen and identify FOXD1-AS1. Glioma cells were transfected with siRNA or eukaryotic expression vector to observe FOXD1-AS1 function in vitro and in vivo. Dual luciferase reporter gene analysis, Western blot, and ChIRP-MS were used to detect microRNAs and protein that combine with FOXD1-AS1.ResultsFOXD1-AS1 was upregulated and directly correlated with the glioma grade, and it was localized in both the nucleus and the cytoplasm of the glioma cell. FOXD1-AS1 silencing caused tumor suppressive effects via inhibiting cell proliferation, migration, and apoptosis, while FOXD1-AS1 overexpression resulted in opposite effects. Additionally, in vivo experiments showed that FOXD1-AS1 knockdown reduced tumor volume and weight. More importantly, mechanical studies revealed that FOXD1-AS1 targeted both miR339-5p and miR342-3p (miR339/342). Furthermore, protein eukaryotic translation initiation factor 5 subunit A (eIF5a) resulted a direct target of FOXD1-AS1.ConclusionsThese data indicated that FOXD1-AS1, a miR339/342 target, affected biological processes via protein eIF5a; thus, it might be considered as a new therapeutic target for glioblastoma.
| S-EPMC6930828 | biostudies-literature
Project description:Cancer remains the second leading life-threatening disease worldwide. Increasing evidence indicates that long non-coding RNAs (lncRNAs) play an important role in multiple physiological and pathological processes, including gene amplification, mutation, rearrangement, and overexpression regulations. In this review, we comprehensively summarize the current knowledge of lncRNA AGAP2-AS1 from a cancer perspective. As a member of the lncRNA family, lncRNA AGAP2-AS1 is upregulated in solid tumor malignancies, functions as an oncogene, and plays a key role in tumorigenesis and tumor progression. AGAP2-AS1 expression is significantly increased in clinical cancer tissue samples, cell lines, and in vivo, and is closely related to an unfavorable prognosis in several cancers. Upregulated lncRNA AGAP2-AS1 binds with microRNAs (miRNAs) and promotes activation of downstream genes. This aberrant regulation induces carcinogenesis and tumorigenesis. Here we provide a comprehensive overview of AGAP2-AS1 in cancer progression that leads to an improved understanding of the effects of AGAP2-AS1 on early detection and therapeutic approaches. This information is essential for the future development of lncRNA AGAP2-AS1 as a potential therapy against these devastating cancers.
| S-EPMC7868831 | biostudies-literature
Project description:BackgroundInjury to kidney podocytes often results in chronic glomerular disease and consecutive nephron malfunction. For most glomerular diseases, targeted therapies are lacking. Thus, it is important to identify novel signaling pathways contributing to glomerular disease. Neurotrophic tyrosine kinase receptor 3 (TrkC) is expressed in podocytes and the protein transmits signals to the podocyte actin cytoskeleton.MethodsNephron-specific TrkC knockout (TrkC-KO) and nephron-specific TrkC-overexpressing (TrkC-OE) mice were generated to dissect the role of TrkC in nephron development and maintenance.ResultsBoth TrkC-KO and TrkC-OE mice exhibited enlarged glomeruli, mesangial proliferation, basement membrane thickening, albuminuria, podocyte loss, and aspects of FSGS during aging. Igf1 receptor (Igf1R)-associated gene expression was dysregulated in TrkC-KO mouse glomeruli. Phosphoproteins associated with insulin, erb-b2 receptor tyrosine kinase (Erbb), and Toll-like receptor signaling were enriched in lysates of podocytes treated with the TrkC ligand neurotrophin-3 (Nt-3). Activation of TrkC by Nt-3 resulted in phosphorylation of the Igf1R on activating tyrosine residues in podocytes. Igf1R phosphorylation was increased in TrkC-OE mouse kidneys while it was decreased in TrkC-KO kidneys. Furthermore, TrkC expression was elevated in glomerular tissue of patients with diabetic kidney disease compared with control glomerular tissue.ConclusionsOur results show that TrkC is essential for maintaining glomerular integrity. Furthermore, TrkC modulates Igf-related signaling in podocytes.
| S-EPMC8054883 | biostudies-literature
Project description:Here we show that the non-conserved lncRNA HHIP-AS1 promotes tumorigenesis in human SHH-driven brain tumors, including medulloblastoma, atypical teratoid / rhabdoid tumors (AT/RT). We reveal that GLI2 regulates a bidirectional promoter shared between the well-characterized SHH regulator HHIP and HHIP-AS1. We found a novel regulatory lncRNA mechanism, termed blocking endogenous RNA (beRNA), extending the concept of competing endogenous RNA (ceRNA), where HHIP-AS1 binds its target DYCN1I2 to avoid miRNA-425-based degradation.
2022-05-23 | GSE140741 | GEO