Identification of circRNA CDR1as/miR-214-3p regulatory axis in Legg-Calvé-Perthes disease.

BACKGROUND: Legg-Calvé-Perthes disease (LCPD) commonly occurs among adolescents, threatening their health. However, the potential mechanism underlying LCPD remains unclear. miR-214-3p is shown as a critical role in LCPD development with unspecified upstream regulators. METHODS: Levels of miR-214-3p and circCDR1as in healthy controls and LCPD patients were determined by qRT-PCR. The role of circCDR1as/miR-214-3p axis in LCPD was determined by testing the cell viability and apoptosis in TC28 cells and primary chondrocytes. Regulation between circCDR1as and miR-214-3p was examined by RIP and ChIP assays. The inflammatory response and angiogenesis were evaluated by M2 macrophage polarization and HUVECs tumor formation. RESULTS: circCDR1as was overexpressed in LCPD patients with a negative correlation with miR-214-3p. Inhibition of circCDR1as alleviated the cell viability and apoptosis of DEX-treated chondrocytes, stimulated M2 macrophage polarization and angiogenesis. miR-214-3p was proved as a downstream effector to participate in circCDR1as mediated actions. circCDR1as recruited PRC2 complex to epigenetically suppress miR-214-3p. CONCLUSION: Our study illustrated the role and mechanism of circCDR1as in LCPD development by targeting miR-214-3p, highlighting its potential in the therapy for LCPD.

Value of CDR1-AS as a predictive and prognostic biomarker for patients with breast cancer receiving neoadjuvant chemotherapy in a prospective Chinese cohort.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is an effective treatment for locally advanced breast cancer (BC). However, there are no effective biomarkers for evaluating its efficacy. CDR1-AS, well known for its important role in tumorigenesis, is a famous circular RNA involved in the chemosensitivity of cancers other than BC. However, the predictive role of CDR1-AS in the efficacy and prognosis of NAC for BC has not been fully elucidated. We herein aimed to clarify this role. METHODS: The present study included patients treated with paclitaxel-cisplatin-based NAC. The expression of CDR1-AS was detected by real-time quantitative reverse transcription polymerase chain reaction testing. The predictive value of CDR1-AS expression was examined in pathological complete response (pCR) after NAC using logistic regression analysis. The relationship between CDR1-AS expression and survival was demonstrated using the Kaplan-Meier method, and tested by log-rank test and Cox proportional hazards regression model. RESULTS: The present study enrolled 106 patients with BC. Multivariate logistic regression analysis revealed that CDR1-AS expression was an independent predictive factor for pCR (odds ratio [OR] = 0.244; 95% confidence interval [CI] 0.081-0.732; p = 0.012). Furthermore, pCR benefits with low CDR1-AS expression were observed across all subgroups. The Kaplan-Meier curves and log-rank test suggested that the CDR1-AS high-expression group showed significantly better disease-free survival (DFS; log-rank p = 0.022) and relapse-free survival (RFS; log-rank p = 0.012) than the CDR1-AS low-expression group. Multivariate analysis revealed that CDR1-AS expression was an independent prognostic factor for DFS (adjusted HR = 0.177; 95% CI 0.034-0.928, p = 0.041), RFS (adjusted HR = 0.061; 95% CI 0.006-0.643, p = 0.020), and distant disease-free survival (adjusted HR = 0.061; 95% CI 0.006-0.972, p = 0.047). CONCLUSIONS: CDR1-AS may be a potential novel predictive biomarker of pCR and survival benefit in patients with locally advanced BC receiving NAC. This may help identify specific chemosensitive individuals and build personalized treatment strategies.

ciRS-7 circular RNA overexpression in plasma cells is a promising molecular biomarker of unfavorable prognosis in multiple myeloma.

Several non-coding RNAs are known to be associated with the pathobiology and progression of multiple myeloma (MM). ciRS-7 (also known as CDR1-AS), a key oncogenic circular RNA (circRNA) that sponges miR-7-5p and other cancer-related microRNAs, was recently found to be downregulated in malignant plasma cells resistant to immunomodulatory drugs. Considering that various circRNAs have a strong potential as molecular biomarkers, we aimed to investigate the expression of ciRS-7 in plasma cell disorders, assess its prognostic importance in MM, and compare these findings with those of individuals with smoldering MM (SMM) and monoclonal gammopathy of unknown significance (MGUS). This study included 171 patients (110 newly diagnosed MM, 34 SMM, and 27 MGUS cases), from which bone marrow aspirate samples were collected for CD138+ plasma cell selection. Total RNA was reversely transcribed using random hexamer primers, and the expression levels of ciRS-7 were quantified using an in-house-developed protocol that includes pre-amplification and real-time quantitative polymerase chain reaction. ciRS-7 levels were found to significantly differ among CD138+ plasma cells of MM, SMM, and MGUS patients. ROC analysis indicated that ciRS-7 expression effectively distinguishes between MM and SMM patients. Moreover, high levels of ciRS-7 were associated with unfavorable prognosis in MM, independently of MM patients' age and Revised International Staging System stage. Additionally, in silico analysis predicted the binding of 85 microRNAs to ciRS-7. In conclusion, this study provides novel insights into the role of ciRS-7 as a promising molecular marker able to distinguish MM from SMM and predict prognosis in MM.

Chronic Lead Exposure in Adult Mice: Associations with miR-671/CDR1as Regulation, NF-κB Signaling, and Alzheimer's Disease-like Pathology.

Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases, such as Alzheimer's disease (AD). This study delves into the intricate role of miR-671/CDR1as regulation in the etiology of AD-like lesions triggered by chronic Pb exposure in adult mice. To emulate the chronic effects of Pb, we established a rodent model spanning 10 months of controlled Pb administration, dividing 52 C57BL/6J mice into groups receiving varying concentrations of Pb (1, 2, or 4 g/L) alongside an unexposed control. Blood Pb levels were monitored using serum samples to ensure accurate dosing and to correlate with observed toxicological outcomes. Utilizing the Morris water maze, a robust behavioral assay for assessing cognitive functions, we documented a dose-dependent decline in learning and memory capabilities among the Pb-exposed mice. Histopathological examination of the hippocampal tissue revealed tell-tale signs of AD-like neurodegeneration, characterized by the accumulation of amyloid plaques and neurofibrillary tangles. At the molecular level, a significant upregulation of AD-associated genes, namely amyloid precursor protein (APP), ß-secretase 1 (BACE1), and tau, was observed in the hippocampal tissue of Pb-exposed mice. This was accompanied by a corresponding surge in the protein levels of APP, BACE1, amyloid-ß (Aß), and phosphorylated tau (p-tau), further implicating Pb in the dysregulation of these key AD markers. The expression of CDR1as, a long non-coding RNA implicated in AD pathogenesis, was found to be suppressed in Pb-exposed mice. This observation suggests a potential mechanistic link between Pb-induced neurotoxicity and the dysregulation of the CDR1as/miR-671 axis, which warrants further investigation. Moreover, our study identified a dose-dependent alteration in the intracellular and extracellular levels of the transcription factor nuclear factor-kappa B (NF-κB). This finding implicates Pb in the modulation of NF-κB signaling, a pathway that plays a pivotal role in neuroinflammation and neurodegeneration. In conclusion, our findings underscored the deleterious effects of Pb exposure on the CNS, leading to the development of AD-like pathology. The observed modulation of NF-κB signaling and miR-671/CDR1as regulation provides a plausible mechanistic framework for understanding the neurotoxic effects of Pb and its potential contribution to AD pathogenesis.

miR-7 controls glutamatergic transmission and neuronal connectivity in a Cdr1as-dependent manner.

The circular RNA (circRNA) Cdr1as is conserved across mammals and highly expressed in neurons, where it directly interacts with microRNA miR-7. However, the biological function of this interaction is unknown. Here, using primary cortical murine neurons, we demonstrate that stimulating neurons by sustained depolarization rapidly induces two-fold transcriptional upregulation of Cdr1as and strong post-transcriptional stabilization of miR-7. Cdr1as loss causes doubling of glutamate release from stimulated synapses and increased frequency and duration of local neuronal bursts. Moreover, the periodicity of neuronal networks increases, and synchronicity is impaired. Strikingly, these effects are reverted by sustained expression of miR-7, which also clears Cdr1as molecules from neuronal projections. Consistently, without Cdr1as, transcriptomic changes caused by miR-7 overexpression are stronger (including miR-7-targets downregulation) and enriched in secretion/synaptic plasticity pathways. Altogether, our results suggest that in cortical neurons Cdr1as buffers miR-7 activity to control glutamatergic excitatory transmission and neuronal connectivity important for long-lasting synaptic adaptations.

CircRNA CDR1as affects functional repair after spinal cord injury and regulates fibrosis through the SMAD pathway.

Spinal cord injury (SCI) is a complex problem in modern medicine. Fibroblast activation and fibroscarring after SCI impede nerve recovery. Non-coding RNA plays an important role in the progression of many diseases, but the study of its role in the progression of spinal fibrosis is still emerging. Here, we investigated the function of circular RNAs, specifically antisense to the cerebellar degeneration-related protein 1 (CDR1as), in spinal fibrosis and characterized its molecular mechanism and pathophysiology. The presence of CDR1as in the spinal cord was verified by sequencing and RNA expression assays. The effects of inhibition of CDR1as on scar formation, inflammation and nerve regeneration after spinal cord injury were investigated in vivo and in vitro. Further, gene expression of miR-7a-5p and protein expression of transforming Growth Factor Beta Receptor II (TGF-ßR2) were measured to evaluate their predicted interactions with CDR1as. The regulatory effects and activation pathways were subsequently verified by miR-7a-5p inhibitor and siCDR1as. These results indicate that CDR1as/miR-7a-5p/TGF-ßR2 interactions may exert scars and nerves functions and suggest potential therapeutic targets for treating spinal fibrotic diseases.

Circular RNA CDR1as Mediated by Human Antigen R (HuR) Promotes Gastric Cancer Growth via miR-299-3p/TGIF1 Axis.

Background: Gastric cancer (GC) remains a common malignancy worldwide with a limited understanding of the disease mechanisms. A novel circular RNA CDR1as has been recently reported to be a crucial regulator of human cancer. However, its biological role and mechanism in the GC growth are still far from clear. Methods: Small interfering RNAs (siRNAs), lentivirus or plasmid vectors were applied for gene manipulation. The CDR1as effects on the GC growth were evaluated in CCK8 and colony formation assays, a flow cytometry analysis and mouse xenograft tumor models. A bioinformatics analysis combined with RNA immunoprecipitation (RIP), RNA pull-down assays, dual-luciferase reporter gene assays, Western blot, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and functional rescue experiments were used to identify the CDR1as target miRNA, the downstream target gene and its interaction with human antigen R (HuR). Results: The CDR1as overexpression promoted the GC growth in vitro and in vivo and reduced the apoptotic rate of GC cells. Its knockdown inhibited the GC cell proliferation and viability and increased the cell apoptotic rate. Proliferation-related proteins PCNA and Cyclin D1 and apoptosis-related proteins Bax, Bcl-2, Caspase-3 and Caspase-9 were regulated. Mechanically, the cytoplasmic CDR1as acted as a miR-299-3p sponge to relieve its suppressive effects on the GC cell growth. Oncogenic TGIF1 was a miR-299-3p downstream target gene that mediated the promotive effects of CDR1as and regulated the PCNA and Bax levels. HuR interacted with CDR1as via the RRM2 domain and positively regulated the CDR1as level and its oncogenic role as well as downstream target TGIF1. Conclusions: CDR1as promotes the GC growth through the HuR/CDR1as/miR-299-3p/TGIF1 axis and could be used as a new therapeutic target for GC.

The role of CDR1as/ciRS-7 in cardio-cerebrovascular diseases.

Cerebellar degeneration-related protein 1 antisense RNA (CDR1as), also known as ciRS-7, is a circular natural antisense transcript of CDR1. It is a widely studied and powerful representative of circular RNAs. Based on its widely reported role in cancer, CDR1as is considered one of the most promising biomarkers for diagnosing and treating tumours. However, some recent studies have extensively focused on its regulatory role in cardio-cerebrovascular diseases instead of in tumours. Studies have shown that CDR1as plays a unique role in the occurrence of cardio-cerebrovascular diseases; thus, it may be a potential target for preventing and treating cardio-cerebrovascular diseases. Furthermore, CDR1as has also been found to be related to signal transduction pathways related to inflammatory response, oxidative stress, etc., which may reveal its potential mechanism in cardio-cerebrovascular diseases. However, there is no literature to summarize the role and possible mechanism of CDR1as in cardio-cerebrovascular diseases. Therefore, in the present review, we have comprehensively summarised the latest progress in the biological characteristics, development processes, regulatory mechanisms, and roles of CDR1as in cardio-cerebrovascular diseases, aiming to provide a reference and guidance for future studies.

CDR1as promotes arrhythmias in myocardial infarction via targeting the NAMPT-NAD+ pathway.

Cardiac ventricular arrhythmia triggered by acute myocardial infarction (AMI) is a major cause of sudden cardiac death. We have reported previously that an increased serum level of circular RNA CDR1as is a potential biomarker of AMI. However, the possible role of CDR1as in post-infarct arrhythmia remains unclear. This study in MI mice investigated the effects and underlying mechanism of CDR1as in ventricular arrhythmias associated with MI. We showed that knockdown of CDR1as abbreviated the duration of the abnormally prolonged QRS complex and QTc intervals and decreased susceptibility to ventricular arrhythmias. Optical mapping demonstrated knockdown of CDR1as also reduced post-infarct arrhythmia by increasing the conduction velocity and decreasing dispersion of repolarization. Mechanistically, CDR1as led to the depletion of NAD+ and caused mitochondrial dysfunction by directly targeting the NAMPT protein and repressing its expression. Moreover, CDR1as aggravated dysregulation of the NaV1.5 and Kir6.2 channels in cardiomyocytes, a change which was alleviated by the replenishment of NAD+. These findings suggest that anti-CDR1as is a potential therapeutic approach for ischemic arrhythmias.

CircRNA CDR1as: a novel diagnostic and prognostic biomarker for gastric cancer.

BACKGROUND: Circular RNA (circRNA) CDR1as is emerging as a vital tumour regulator. This study aimed to investigate its diagnostic and prognostic value and molecular mechanisms for gastric cancer (GC). METHODS: CDR1as expression in GC and adjacent normal tissues (n = 82), paired plasma (n = 65) and plasma exosome samples (n = 68) from GC patients and healthy controls were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Correlations between CDR1as level and clinicopathological factors of GC patients were analysed. Its diagnostic and prognostic value was evaluated by receiver operating characteristic (ROC) curves and Cox regression analysis combined with Kaplan-Meier plots. CDR1as-regulated proteins and signalling pathways were identified by quantitative proteomics and bioinformatic analysis. RESULTS: CDR1as was downregulated in GC tissues and associated with tumour size and neural invasion. Plasma- and exosome-derived CDR1as was upregulated in GC patients while plasma-derived CDR1as level was related to lymphatic metastasis. Area under ROC curve (AUC) of tissue-, plasma- and exosome-derived CDR1as was 0.782, 0.641, 0.536 while combination of plasma CDR1as, serum CEA and CA19-9 increased AUC to 0.786. Distal metastasis, TNM stage and tissue-derived CDR1as level were independent predictors for overall survival (OS) of patients. MiRNA signalling networks and glycine, serine and threonine metabolism were regulated by CDR1as and HSPE1 might be a key protein. CONCLUSIONS: CDR1as is a crucial regulator and promising biomarker for GC diagnosis and prognosis.

CDR1as level in tumour tissues and plasma of GC patients was associated with tumour progression. The findings indicate that CDR1as is involved in GC progression and is a potential diagnostic and prognostic biomarker.

miR-145-3p Inhibits MuSCs Proliferation and Mitochondria Mass via Targeting MYBL1 in Jianzhou Big-Eared Goats.

Muscle growth and injury-induced regeneration are controlled by skeletal muscle satellite cells (MuSCs) through myogenesis in postnatal animals. Meanwhile, myogenesis is accompanied by mitochondrial function and enzyme activity. Nevertheless, the underlying molecular mechanisms involving non-coding RNAs including circular RNAs (circRNAs) and microRNAs (miRNAs) remain largely unsolved. Here, we explored the myogenic roles of miR-145-3p and MYBL1 on muscle development and mitochondrial mass. We noticed that overexpression of miR-145-3p inhibited MuSCs proliferation and reduced the number of viable cells. Meanwhile, deficiency of miR-145-3p caused by LNAantimiR-145-3p or an inhibitor retarded the differentiation of MuSCs. miR-145-3p altered the mitochondrial mass in MuSCs. Moreover, miR-145-3p targeted and negatively regulated the expression of CDR1as and MYBL1. The knockdown of the MYBL1 using ASO-2'MOE modification simulated the inhibitory function of miR-145-3p on cell proliferation. Additionally, MYBL1 mediated the regulation of miR-145-3p on Vexin, VCPIP1, COX1, COX2, and Pax7. These imply that CDR1as/miR-145-3p/MYBL1/COX1, COX2, VCPIP1/Vexin expression at least partly results in a reduction in mitochondrial mass and MuSCs proliferation. These novel findings confirm the importance of mitochondrial mass during myogenesis and the boosting of muscle/meat development in mammals.

Localised Cdr1as activity is required for fear extinction memory.

Circular RNAs (circRNAs) comprise a novel class of regulatory RNAs that are abundant in the brain, particularly within synapses. They are highly stable, dynamically regulated, and display a range of functions, including serving as decoys for microRNAs and proteins and, in some cases, circRNAs also undergo translation. Early work in animal models revealed an association between circRNAs and neurodegenerative and neuropsychiatric disorders; however, little is known about the link between circRNA function and memory. To address this, we examined circRNA in synaptosomes derived from the medial prefrontal cortex of fear extinction-trained male C57BL/6J mice and found 12,837 circRNAs that were enriched at the synapse, including cerebellar degeneration-related protein 1 antisense RNA (Cdr1as). Targeted knockdown of Cdr1as in the neural processes of the infralimbic cortex led to impaired fear extinction memory. These findings highlight the involvement of localised circRNA activity at the synapse in memory formation.

TGF-ß signaling promotes cervical cancer metastasis via CDR1as.

BACKGROUND: Due to the lack of effective treatment, metastasis is the main cause of cancer related deaths. TGF-ß pathway has been reported related to cervical cancer metastasis. However, mechanism is still unclear. METHODS: After agonist of TGF-ß treatment, RNA sequencing revealed the expression profiles of circRNA in cervical cancer. In situ hybridization was used to analysis relationship between CDR1as and prognosis. Real-time PCR, Western blot, RNA interference, Transwell assay, Wound healing assay, RNA pulldown assay and RIP assays were performed in vitro. And in vivo cervical cancer model (including foot pad model and subcutaneous tumor formation) was also performed. RESULTS: CDR1as was found upregulated obviously following TGF-ß activation. In situ hybridization showed CDR1as was positively correlated with lymph node metastasis and shortened survival length. Simultaneously, overexpression of CDR1as promoted cervical cancer metastasis in vitro and in vivo. It was also found that CDR1as could facilitate the orchestration of IGF2BP1 on the mRNA of SLUG and stabilize it from degradation. Silencing IGF2BP1 hampers CDR1as related metastasis in cervical cancer. Additionally, effective CDR1as has been proven to activate TGF-ß signaling factors known to promote EMT, including P-Smad2 and P-Smad3. CONCLUSIONS: Our study proved TGF-ß signaling may promote cervical cancer metastasis via CDR1as.

Analyses of circRNA Expression throughout the Light-Dark Cycle Reveal a Strong Regulation of Cdr1as, Associated with Light Entrainment in the SCN.

Circular RNAs (circRNAs) are a large class of relatively stable RNA molecules that are highly expressed in animal brains. Many circRNAs have been associated with CNS disorders accompanied by an aberrant wake-sleep cycle. However, the regulation of circRNAs in brain homeostasis over daily light-dark (LD) cycles has not been characterized. Here, we aim to quantify the daily expression changes of circRNAs in physiological conditions in healthy adult animals. Using newly generated and public RNA-Seq data, we monitored circRNA expression throughout the 12:12 h LD cycle in various mouse brain regions. We identified that Cdr1as, a conserved circRNA that regulates synaptic transmission, is highly expressed in the suprachiasmatic nucleus (SCN), the master circadian pacemaker. Despite its high stability, Cdr1as has a very dynamic expression in the SCN throughout the LD cycle, as well as a significant regulation in the hippocampus following the entry into the dark phase. Computational integration of different public datasets predicted that Cdr1as is important for regulating light entrainment in the SCN. We hypothesize that the expression changes of Cdr1as in the SCN, particularly during the dark phase, are associated with light-induced phase shifts. Importantly, our work revises the current beliefs about natural circRNA stability and suggests that the time component must be considered when studying circRNA regulation.

Role of circular RNA cdr1as in modulation of macrophage phenotype.

AIMS: Macrophages are crucial for the initiation and resolution of an inflammatory response. Non-coding circular RNAs are ubiquitously expressed in mammalian tissue, highly conserved among species, and recently implicated in the regulation of macrophage activation. We sought to determine whether circRNAs modulate monocyte/macrophage biology and function. MATERIALS AND METHODS: We performed circRNA microarray analyses to assess transcriptome changes using RNA isolated from bone marrow derived macrophages polarized to a pro-inflammatory phenotype (INFγ + TNFα) or an anti-inflammatory phenotype (IL-10, IL-4, and TGF-ß). Among differentially expressed circRNAs, circ-Cdr1as was chosen for further investigation. Additionally, we performed loss or gain of function studies to investigate if circ-Cdr1as is involved in phenotypic switching. For gain of function, we overexpressed circ-Cdr1as using pc3.1 plasmid with laccase2 flanking regions to promote circularization. For loss of function, we used a lentiviral short hairpin RNA targeting the circ-Cdr1as splicing junction. KEY FINDINGS: Among circRNAs that are highly conserved and differentially expressed in pro- and anti-inflammatory lineages, circ-Cdr1as was one of the most downregulated in pro-inflammatory macrophages and significantly upregulated in anti-inflammatory macrophages in vitro. Overexpression of circ-Cdr1as increased transcription of anti-inflammatory markers and percentage of CD206+ cells in naïve and pro-inflammatory macrophages in vitro. Meanwhile, knockdown decreased transcription of anti-inflammatory markers and increased the percentage of CD86+ cells in naïve and anti-inflammatory macrophages in vitro. SIGNIFICANCE: This study suggests that circ-Cdr1as plays a key role in regulating anti-inflammatory phenotype of macrophages and may potentially be developed as an anti-inflammatory regulator in tissue inflammation.

The circular RNA circ_0099630/miR-940/receptor-associated factor 6 regulation cascade modulates the pathogenesis of periodontitis.

Background/purpose: Periodontitis is one of the highly prevalent chronic inflammatory conditions in adults. The importance of circular RNAs (circRNAs) in the regulation of inflammation has been gradually reported in recent years, but the role of circRNA circ_0099630 in periodontitis has not been reported. Materials and methods: The contents of circ_0099630, microRNA-940 (miR-940) and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) were measured using quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Inflammatory factor secretion, cell proliferation, and apoptosis were analyzed under the application of Enzyme-linked immunosorbent assay (ELISA), Cell Counting Kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) and flow cytometry, respectively. The Western blot also analyzed the phosphorylation levels of RELA proto-oncogene (P65) and IkappaBalpha (IκBα), key molecules of the nuclear factor kappa-B (NF-κB) pathway. The relationship between miR-940 and circ_0099630 or TRAF6 was verified by luciferase reporter system and RNA immunoprecipitation (RIP) assay. Results: Higher abundance of circ_0099630 and TRAF6 and lower miR-940 expression were observed in periodontitis, and circ_0099630 knockdown attenuated the damage of human PDL cells (PDLCs) induced by lipopolysaccharides (LPS). The relationship between miR-940 and circ_0099630 or TRAF6 was evidenced, while miR-940 downregulation diminished the repair effect of si-circ_0099630 on overexpression LPS-induced damage in PDLCs. Similarly, TRAF6 upregulation impaired the mitigating effect of miR-940 overexpression on LPS-induced injury in PDLCs. Circ_0099630 silencing evidently curbed the phosphorylation levels of P65 and IκBα and thus attenuating the inflammatory response by acting on the miR-940/TRAF6 axis. Conclusion: Silencing circ_0099630 alleviates LPS-induced periodontal ligament cell injury via targeting miR-940/TRAF6/NF-κB in periodontitis.

Circ_CDR1as: A circular RNA with roles in the carcinogenesis.

Circular RNAs are a group of ancient but recently appreciated transcripts that affect carcinogenesis. An example of cancer-related circular RNAs is circ_CDR1as. It is mostly regarded as an oncogenic circular RNA, yet in bladder cancer and glioma it has the opposite effect. In gastric and ovarian cancer, both roles have been reported for this circular RNA. Circ_CDR1as has regulatory effects on miR-1270/AFP, miR-1287/Raf1, miR-7-5p/KLF4, miR-641/HOXA9, miR-219a-5p/SOX5, miR-7/HOXB13 and miR-876-5p/MAGE-A molecular axes. miR-7 is the most appreciated interacting miRNA with circ_CDR1as, since its interaction with circ_CDR1as has been validated in liver cancer, lung cancer, colorectal cancer, esophageal carcinoma, gastric cancer, pancreatic cancer, thyroid cancer, oral squamous cell carcinoma, nasopharyngeal carcinoma and osteosarcoma. The present article aims at summarization of the role of circ_CDR1as in neoplasms and its application as a biomarker in human cancers.

Hotspots and development frontiers of circRNA based on bibliometric analysis.

Background and purpose: Circular RNAs (circRNAs) are a big group of members of the noncoding RNA family following long non-coding RNA and microRNA. They play a regulatory role in many biological processes. Analyzing their current research status and future development trends is conducive to a more comprehensive understanding of circRNAs and contributes to the dedication to the biological field. Methods: The literature on circRNA from 2000 to 2021 in the Web of Science Core Collection of the Web of Science database with "circular RNA" as the subject was searched. R Studio's Bibliometrix package and biblioshiny software were used for publication trend analysis, citation analysis, keyword analysis, author analysis, research institution analysis, source analysis, country analysis, and collaboration analysis for all documents and highly cited documents. Results: From 2000 to 2021, 3,186 circRNA-related articles were published worldwide, of which 193 were highly cited. The number of published articles had shown an explosive increase after 2013. These articles were mainly from Chinese research institutions and authors, but the country with the highest average number of citations per year in highly cited documents was Germany. Scientific research institutions came from countries represented by Germany, USA, China, Australia and Canada all had different degrees of cooperation. The theme and key points of the research had evolved over time from expression to the role and mechanism of circRNA in diseases, especially in cancer. CDR1as, circFOXO3, circHIPK3, circITCH, circMTO1, circSMARCA5 and circZNF609 are circRNAs that are mainly studied currently, their studies mainly involve cell biology, biological functions and cancer. The future research direction and trend would still be the application of circRNA in diseases. Conclusion: The basic situation and development trend of circRNA related research we described provide a direction for future research.

CircRNA CDR1as promotes cardiomyocyte apoptosis through activating hippo signaling pathway in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM), as a major complication of diabetic patients, can cause myocardial metabolic remodeling and lead to severe and irreversible cardiac dysfunction. Previously, we found that the circular RNA cerebellar degeneration-related protein 1 antisense (Circ-CDR1as) independently predicted acute myocardial infarction (AMI) and might be a new indicator marker for this. However, CDR1as was not clearly described in diabetic cardiomyopathy. Therefore, our purpose was to deeply explore the function of CDR1as in DCM. In this study, we found that CDR1as was upregulated in DCM, and knockdown of CDR1as could improve the apoptosis caused by DCM. Mechanistically, CDR1as activates the Hippo signaling pathway by significantly inhibiting Mammalian sterile 20-like kinase 1 (MST1) ubiquitination level. Furthermore, as a transcriptional factor of CDR1as, Forkhead box group O3a (FOXO3) was identified to activate the Hippo signaling pathway. Notably, the total m6A level was downregulated in the cardiac tissue of DCM. Alk B homolog 5 (ALKBH5), a m6A demethylation enzyme, was upregulated in the cardiomyocytes of DCM mice and posttranscriptionally activated FOXO3 by m6A demethylation in an m6A-YTHDF2-dependent manner. Hence, our work reveals the key function of the ALKBH5-FOXO3-CDR1as/Hippo signaling pathway in DCM and provides insight into the critical roles of m6A methylation in DCM.

Circulating expression levels of CircHIPK3 and CDR1as circular-RNAs in type 2 diabetes patients.

BACKGROUND: Recent investigations suggested that deregulated levels of Circular RNAs (circRNAs) could be associated with type 2 diabetes mellitus (T2DM) pathogenesis. Accordingly, this study aimed to determine the expression levels of circulating CircHIPK3, CDR1as and their correlation with biochemical parameters in patients with T2DM, pre-diabetes and control subjects. METHODS AND RESULTS: The expression of circRNAs in peripheral blood was determined using QRT-PCR in 70 patients with T2DM, 60 pre-diabetes and in 69 age and sex matched healthy controls. Moreover, bioinformatics tools were applied to explore and predict the potential interactions between circRNAs and other non-coding RNAs (ncRNAs). Our analysis revealed that the expression level of CircHIPK3 was significantly elevated in T2DM patients compared to healthy participants (P < 0.001) and pre-diabetes subjects (P = 0.018). In addition, ROC analysis suggested that at the cutoff value of 0.24 and the sensitivity and specificity of 50% and 88.4%, respectively, CircHIPK3 could distinguish between T2DM patients and control subjects. Furthermore, it was observed that the expression level of CDR1as is higher in pre-diabetic individuals than healthy individuals (P = 0.004). Finally, Spearman correlation analysis showed that there was a significant correlation between CircHIPK3 and CDR1as expression levels and clinical and anthropometrical parameters such as BMI, systolic and diastolic blood pressure, HbA1c and fasting blood glucose (P < 0.005). CONCLUSIONS: The data of this study provided evidence that the expression levels of CircHIPK3, CDR1as increased in T2DM and pre-diabetes subjects, respectively.