CircRNA-UBE2G1 regulates LPS-induced osteoarthritis through miR-373/HIF-1a axis.
Ontology highlight
ABSTRACT: Abbreviations
OA: Osteoarthritis; Circular RNAs; miRNAs: MicroRNAs; Mut: Mutant; WT: Wild type; UTR: Untranslated region.
SUBMITTER: Chen G
PROVIDER: S-EPMC7469585 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation. Dysregulated autophagy is a major cause of OA. However, the underlying mechanism is unclear. Here, we found that the expression of element-binding protein (CREB) was downregulated in both cartilage tissues of OA patients and mouse OA model. In tert-butyl hydroperoxide solution-treated chondrocytes, increased apoptosis and autophagic blockage were attenuated by CREB overexpression. Mechanically, MiR-373 directly targeted the 3'UTR of methyltransferase-like 3 (METTL3) and led to its downregulation. METTL3 epigenetically suppressed TFEB. The upregulation of miR-373 by CREB overexpression induced the release of TFEB from METTL3 and restored the autophagy activity of chondrocytes. Taken together, our study showed that CREB alleviates OA injury through regulating the expression of miR-373, which directly targeted METTL3, and finally relieved TFEB from METTL3-mediated epigenetic suppression. The CREB/miR-373/METTL3/TFEB axis may be used as a potential target for the treatment of OA.
| S-EPMC9218638 | biostudies-literature
Project description:ObjectiveOsteoarthritis (OA) is a degenerative joint disease characterized by deterioration of articular cartilage functions. Previous studies have confirmed the role of circular RNAs (circRNAs) in OA, but the role of mechanical stress-related circRNA (circRNA-MSR) in OA is unknown.DesignThe human chondrocytes C28/I2 were cultured and treated with lipopolysaccharide (LPS) to establish the OA model. The mRNA and protein levels were measured by qRT-PCR or Western blot. Cell viability was analyzed by MTT assay. Flow cytometry was carried out to detect cell apoptosis. The levels of TNF-α, IL-1β, and IL-6 were determined by enzyme-linked immunosorbent assay (ELISA). Pull-down assay was conducted to measure circRNA-MSR-related miRNA. Dual-luciferase reporter gene detection was performed to detect the target relationships between miR-643 and circRNA-MSR or Mitogen-activated protein kinase kinase 6 (MAP2K6). The RNA-fluorescence in situ hybridization (RNA-FISH) assay was conducted to verify the localization of circRNA-MSR and miR-643.ResultsThe expressions of circRNA-MSR were upregulated in LPS stimulated C28/I2 cells. Knockdown of circRNA-MSR can inhibit LPS-induced apoptosis, inflammatory response, and extracellular matrix (ECM) degradation, and promote cell C28/I2 cells proliferation. Moreover, circRNA-MSR directly targeted miR-643. RNA-FISH exhibited that circRNA-MSR may act as a competing endogenous RNA (ceRNA) of miR-643. Over-expression of miR-643 could alleviate LPS-induced C28/I2 chondrocyte injury and promote cell proliferation. Besides, miR-643 directly bound to MAP2K6 mRNA. MiR-643 inhibition or MAP2K6 overexpression can reverse the role of circRNA-MSR knockdown on LPS-treated chondrocytes.ConclusioncircRNA-MSR can upregulate MAP2K6 by targeting miR-643, thereby inhibiting cell proliferation and promoting apoptosis of C28/I2 cells.
| S-EPMC8804801 | biostudies-literature
Project description:BackgroundOsteosarcoma (OS) is the most prevalent primary fatal bone neoplasm in adolescents and children owing to limited therapeutic methods. Circular RNAs (circRNAs) are identified as vital regulators in a variety of cancers. However, the roles of circRNAs in OS are still unclear.MethodsFirstly, we evaluate the differentially expressed circRNAs in 3 paired OS and corresponding adjacent nontumor tissue samples by circRNA microarray assay, finding a novel circRNA, circ_001722, significantly upregulated in OS tissues and cells. The circular structure of candidate circRNA was confirmed through Sanger sequencing, divergent primer PCR, and RNase R treatments. Proliferation of OS cells was evaluated in vitro and in vivo. The microRNA (miRNA) sponge mechanism of circRNAs was verified by dual-luciferase assay and RNA immunoprecipitation assay.ResultsA novel circRNA, circ_001722, is significantly upregulated in OS tissues and cells. Downregulation of circ_0001722 can suppress proliferation and invasion of human OS cells in vitro and in vivo. Computational algorithms predict miR-204-5p can bind with circ_0001722 and RUNX2 mRNA 3'UTR, which is verified by Dual-luciferase assay and RNA immunoprecipitation assay. Further functional experiments show that circ_0001722 competitively binds to miR-204-5p and prevents it to decrease the level of RUNX2, which upregulates proliferation and invasion of human OS cells.ConclusionCirc_001722 is a novel tumor promotor in OS, and promotes the progression of OS via miR-204-5p/RUNX2 axis.
| S-EPMC10587032 | biostudies-literature
Project description:The adrenergic system contributes to the stress-induced onset and progression of cancer. Adrenergic fibers are the primary source of norepinephrine (NE). The underlying mechanisms involved in NE-induced colon cancer remain to be understood. In this study, we describe the function and regulatory network of NE in the progression of colon cancer. We demonstrate that NE-induced phosphorylation of cAMP response element-binding protein 1 (CREB1) promotes proliferation, migration, and invasion of human colon cancer cells. The downstream effector of NE, CREB1, bound to the promoter of miR-373 and transcriptionally activated its expression. miR-373 expression was shown to be necessary for NE-induced cell proliferation, invasion, and tumor growth. We confirmed that proliferation and invasion of colon cancer cells are regulated in vitro and in vivo by miR-373 through targeting of the tumor suppressors TIMP2 and APC. Our data suggest that NE promotes colon cancer cell proliferation and metastasis by activating the CREB1-miR-373 axis. The study of this novel signaling axis may provide mechanistic insights into the neural regulation of colon cancer and help in the design of future clinical studies on stress biology in colorectal cancer.
| S-EPMC7191185 | biostudies-literature
Project description:Changes in the intracellular levels of the essential micronutrient zinc have been implicated in multiple diseases including pancreatic cancer; however, the molecular mechanism is poorly understood. Here, we report a novel mechanism where increased zinc mediated by the zinc importer ZIP4 transcriptionally induces miR-373 in pancreatic cancer to promote tumour growth. Reporter, expression and chromatin immunoprecipitation assays demonstrate that ZIP4 activates the zinc-dependent transcription factor CREB and requires this transcription factor to increase miR-373 expression through the regulation of its promoter. miR-373 induction is necessary for efficient ZIP4-dependent enhancement of cell proliferation, invasion, and tumour growth. Further analysis of miR-373 in vivo oncogenic function reveals that it is mediated through its negative regulation of TP53INP1, LATS2 and CD44. These results define a novel ZIP4-CREB-miR-373 signalling axis promoting pancreatic cancer growth, providing mechanistic insights explaining in part how a zinc transporter functions in cancer cells and may have broader implications as inappropriate regulation of intracellular zinc levels plays an important role in many other diseases.
| S-EPMC3799489 | biostudies-other
Project description:Background:Osteosarcoma (OS) is the most common bone tumor. Many studies have reported that circular RNAs (circRNAs) play an important role in the development of a variety of human cancers. However, the underlying mechanism of circ_0001721 in regulating osteosarcoma progression remains unknown. Materials and Methods:Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the levels of circ_0001721, miR-372-3p, and mitogen-activated protein kinase 7 (MAPK7) in osteosarcoma tissues and cells. Besides, glycolysis was investigated by glucose consumption, lactate production and hexokinase II (HK2) protein level. Cell proliferation and apoptosis were determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and flow cytometry, separately. Cell migration and invasion were determined by transwell assay. Moreover, the protein levels of HK2 and epithelial-to-mesenchymal transition (EMT) markers were determined by Western blot analysis. The relationship between miR-372-3p and circ_0001721 or MAPK7 was predicated by starbase v3.0 and confirmed by dual-luciferase reporter assay or RNA binding protein immunoprecipitation (RIP) assay. Murine xenograft model was established to investigate the role of circ_0001721 in vivo. Results:The levels of circ_0001721 and MAPK7 were upregulated in osteosarcoma tissues and cells, while miR-372-3p was downregulated. Knockdown of circ_0001721 inhibited glycolysis, cell proliferation, cell migration, invasion and epithelial-to-mesenchymal transition (EMT), and promoted apoptosis. Circ_0001721 was validated as a sponge of miR-372-3p and mediated glycolysis, cell proliferation, apoptosis, migration, invasion, and EMT of osteosarcoma cells through miR-372-3p. MAPK7 was a target of miR-372-3p and overexpression of MAPK7 attenuated anti-cancer role of miR-372-3p in OS cells. Further studies revealed that circ_0001721 regulates MAPK7 expression via sponging miR-372-3-p. Finally, knockdown of circ_0001721 inhibited tumor progression in vivo. Conclusion:Circ_0001721 promoted osteosarcoma development through the miR-372-3p/MAPK7 axis.
| S-EPMC7498501 | biostudies-literature
Project description:Our previous proteomics study revealed that thioredoxin-interacting protein (TXNIP) was down-regulated by miR-373. However, little is known of the mechanism by which miR-373 decreases TXNIP to stimulate metastasis. In this study, we show that miR-373 promotes the epithelial-to-mesenchymal transition (EMT) in breast cancer. MiR-373 suppresses TXNIP by binding to the 3'UTR of TXNIP, which in turn, induces cancer cell EMT and metastasis. TXNIP co-expression, but not the TXNIP-3'UTR, reverses the enhancement of EMT, migration, invasion and metastasis induced by miR-373. MiR-373 stimulates EMT, migration and invasion through TXNIP-dependent reactive oxygen species (ROS) reduction. Mechanistically, miR-373 up-regulates and activates the HIF1?-TWIST signaling axis via the TXNIP pathway. Consequently, TWIST induces miR-373 expression by binding to the promoter of the miR-371-373 cluster. Clinically, miR-373 is negatively associated with TXNIP and positively associated with HIF1? and TWIST, and activation of the miR-373-TXNIP-HIF1?-TWIST signaling axis is correlated with a worse outcome in patients with breast cancer. This signaling axis may be an independent prognostic factor for patients with breast cancer.
| S-EPMC4741723 | biostudies-literature
Project description:CircRNAs are implicated in the development of several cancers. Nevertheless, the involvement of circ_0000118 in the development of cervical cancer (CC) remains unclear. Circ_0000118 levels in tumor tissues and cells were examined by qRT-PCR. The function of circ_0000118 in regulating the malignancy of CC cells was investigated using functional assays, including CCK-8, colony formation, transwell, and tube formation experiments. The functional interaction between circ_0000118 and microRNAs were validated by dual-luciferase activity assay and RNA precipitation experiments. In vivo mouse model was employed to assess the effect of circ_0000118 in the tumorigenesis of CC cells. Circ_0000118 was overexpressed in CC cells and tissues. Loss-of-function experiments demonstrated that circ_0000118 knockdown impaired the proliferation and tumor sphere formation, as well as the angiogenic potential of CC cells. RNA interaction experiments confirmed that circ_0000118 sponged miR-211-5p and miR-377-3p. AKT2 was found to be a target gene negatively modulated by miR-211-5p and miR-377-3p. AKT2 overexpression rescued the inhibition of circ_0000118 downregulation on CC cells. Our study suggested that circ_0000118 functions as an oncogenic factor in progression of CC by maintaining AKT2 level through targeting miR-211-5p and miR-377-3p as a ceRNA (competitive endogenous RNA), which provides novel therapeutic target in the management of CC.
| S-EPMC10371915 | biostudies-literature
Project description:Background Hepatocellular carcinoma (HCC) is a common lethal malignant tumor worldwide. Circular RNAs (circRNAs) have been reported to affect the development of human cancers, including HCC. In this project, we aim to clarify the functional effect of circular CDR1as (circ_CDR1as) on HCC progression. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot is implemented to detect the expression of circ_CDR1as, microRNA (miR)-1287 and Raf-1 proto-oncogene, serine/threonine kinase (Raf1). Cell proliferation is assessed via colony formation and 3-(4, 5)-dimethylthiazole-2-y1)-2, 5-biphenyl tetrazolium bromide (MTT) assays. Cell migration and invasion are measured by Transwell assay. The target relationship between miR-1287 and circ_CDR1as or Raf1 is validated through dual-luciferase reporter assay. The levels of epithelia–mesenchymal transition (EMT) markers and the MEK/ERK signal pathway-related proteins are examined by Western blot. Model in nude mice is constructed to determine the role of circ_CDR1as in vivo. Results Expression of circ_CDR1as and Raf1 is elevated, while miR-1287 expression is decreased in HCC. Depletion of circ_CDR1as or Raf1 could inhibit proliferation and metastasis of HCC cells. Besides, circ_CDR1as regulates Raf1 expression by targeting miR-1287. MiR-1287 upregulation or Raf1 depletion could partially counterbalance circ_CDR1as depletion-mediated inhibitory effects on HCC cell behaviors. Moreover, circ_CDR1as depletion represses HCC progression through inactivating MEK/ERK pathway. In addition, circ_CDR1as depletion suppresses tumor growth in vivo via regulating miR-1287/Raf1 pathway. Conclusion Circ_CDR1as depletion inhibits HCC cell proliferation and metastasis by miR-1287/Raf1 and MEK/ERK pathways, highlighting a promising molecular target for HCC treatment.
| S-EPMC7522432 | biostudies-literature
Project description:Unexplained recurrent spontaneous abortion (URSA) is one of the most intractable clinical challenges in reproduction. As a specific type of endogenous non-coding RNA, circular RNAs (circRNAs) have great pre-clinical diagnostic and therapeutic values in diseases. Recently, thousands of circRNAs were detected in human pre-implantation embryos, indicating that circRNAs potentially have important regulatory functions. However, the roles of circRNAs in URSA remain largely unknown. In this study, we elucidated deregulated circRNA expression and distinct competing endogenous RNA (ceRNA) networks by comparing URSA placental villus with that of patients with normal pregnancy using microarrays. We characterized a distinct circRNA, circRNA-0050703, which is downregulated in URSA placental villus (thus we named it circRNA-DURSA). Silencing of circRNA-DURSA results in trophoblast cell apoptosis in vitro. Furthermore, mechanistic dissection revealed that circRNA-DURSA exerts its effects by competitively binding to miR-760, which post-transcriptionally targets HIST1H2BE. Additionally, after circRNA-DURSA silencing in vivo, the numbers of implanted embryos decreased significantly. These results reveal the regulatory roles of circRNA-DURSA in trophoblasts and identified a distinct circRNA-DURSA/miR-760/HIST1H2BE axis as potentially important diagnostic and therapeutic targets for URSA treatment.
| S-EPMC8655312 | biostudies-literature