Circular RNA CDR1as Research Articles

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.

Abstract WP314: Post-Stroke Regulation of α-Synuclein by microRNA miR-7 and Circular RNA CDR1as

α-Synuclein (α-Syn) induced after stroke is a known mediator of ischemic brain damage. We currently evaluated the molecular mechanisms that regulate α-Syn expression in the post-ischemic brain. The miR-7 is an abundantly expressed miRNA in brain that targets α-Syn mRNA with high energy. In adult mice subjected to transient middle cerebral artery occlusion (MCAO), miR-7 levels were down-regulated in the cerebral cortex as early as 3h and late as 3 days of reperfusion which leads to derepression of α-Syn mRNA that facilitates α-Syn protein translation. Treating mice after transient MCAO with a miR-7 mimic significantly curtailed ischemic brain damage and promoted better motor function recovery. However, the pri-miR-7a and -7b levels were unaltered indicating that the post-ischemic reduction in miR-7 levels are not due to reduced expression of miR-7 gene. With bioinformatics, we observed that the circRNA CDR1as contains >70 binding sites with good affinity for miR-7. CDR1as is thought to sequester miR-7 to protect it from degradation and/or to transport it to the sites of its necessity. Transient MCAO also led to down-regulation of CDR1as expression between 3h and 3 days of reperfusion. When CDR1as levels were replenished in the post-ischemic mice with a CDR1as AAV9 vector, the miR-7 levels as well as binding of CDR1as to Ago2/miR-7 increased and α-Syn protein levels decreased significantly in the peri-infarct cortex. Furthermore, the CDR1as AAV9 treated mice showed decreased markers of inflammation and apoptosis, better motor function recovery and smaller infarcts. Our studies thus indicate that α-Syn in the post-ischemic brain is controlled by the mutual interaction of a miRNA (miR-7) and a circRNA (CDR1as). Thus, understanding noncoding RNA interactions and mechanisms might help to design better therapies to alleviate post-stroke neuronal damage.

Exosomes From IgE-Stimulated Mast Cells Aggravate Asthma-Mediated Atherosclerosis Through circRNA CDR1as-Mediated Endothelial Cell Dysfunction in Mice.

IgE has been known for mediating endothelial cell dysfunction and mast cell (MC) activation to fuel asthma-aggravated high-fat diet-induced atherosclerosis. However, it remains unclear for the mechanism of asthma-mediated atherosclerosis, especially the potential involvement of IgE in the exacerbation of asthma-mediated atherosclerosis with a standard laboratory diet, and the cross talk between endothelial cells and MCs. Asthma-mediated atherosclerosis mice models under a standard laboratory diet and FcεR1 knock-out mice were used to determine the role of IgE-FcεR1 signaling in asthma-mediated atherosclerosis, which was assessed by Oil Red O staining and immunohistochemistry. Various in vitro assays including nanoparticle tracking analysis and transmission electron microscopy were used to evaluate exosome characteristics. Immunofluorescence and fluorescent in situ hybridization approaches were used to evaluate the effect and mechanism of MC-secreted exosomes encapsulated circular RNA CDR1as (cerebellar degeneration-related 1 antisense) on endothelial cells in vivo and in vitro. Finally, cohort studies examined the plasma CDR1as levels in patients with atherosclerosis with or without allergies. Asthma mice with a standard laboratory diet showed increased atherosclerotic lesions and inflammatory infiltration depending on IgE-FcεR1 signal. FcεR1 knockout mice and blockage of IgE-FcεR1 signaling with IgE monoclonal antibody, omalizumab, all significantly alleviated asthma-mediated atherosclerosis and vascular inflammatory remodeling. Anti-inflammation with dexamethasone and stabilization of MC with cromolyn partially alleviated atherosclerotic lesions and mitigated the inflammatory infiltration in arteries. Mechanistically, IgE stimulation upregulates MC CDR1as expression in exosomes and upregulates the endothelial cell adhesive factors VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) via the CDR1as-FUS (fused in sarcoma)-phos-p65 axis. Knockdown of CDR1as in vivo significantly decreased the endothelial adhesion function and mitigated asthma-mediated atherosclerosis. Furthermore, a cohort study indicated higher plasma CDR1as levels in patients with atherosclerosis with allergies than in patients with atherosclerosis and healthy controls. Exosomes from IgE-stimulated MCs aggravated atherosclerosis through circular RNA CDR1as-mediated endothelial dysfunction, providing a novel insight into asthma-mediated atherosclerosis and potential diagnostic and therapeutic targets.

Circular RNA Cdr1as inhibits proliferation and delays injury-induced regeneration of the intestinal epithelium.

Circular RNAs (circRNAs) are highly expressed in the mammalian intestinal epithelium, but their functions remain largely unknown. Here, we identified the circRNA Cdr1as as a repressor of intestinal epithelial regeneration and defense. Cdr1as levels increased in mouse intestinal mucosa after colitis and septic stress, as well as in human intestinal mucosa from patients with inflammatory bowel disease and sepsis. Ablation of the Cdr1as locus from the mouse genome enhanced renewal of the intestinal mucosa, promoted injury-induced epithelial regeneration, and protected the mucosa against colitis. We found approximately 40 microRNAs, including miR-195, differentially expressed between intestinal mucosa of Cdr1as-knockout (Cdr1as-/-) versus littermate mice. Increasing the levels of Cdr1as inhibited intestinal epithelial repair after wounding in cultured cells and repressed growth of intestinal organoids cultured ex vivo, but this inhibition was abolished by miR-195 silencing. The reduction in miR-195 levels in the Cdr1as-/- intestinal epithelium was the result of reduced stability and processing of the precursor miR-195. These findings indicate that Cdr1as reduces proliferation and repair of the intestinal epithelium at least in part via interaction with miR-195 and highlight a role for induced Cdr1as in the pathogenesis of unhealed wounds and disrupted renewal of the intestinal mucosa.

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.

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.

Retraction: The Circular RNA Cdr1as Act as an Oncogene in Hepatocellular Carcinoma through Targeting miR-7 Expression.

Retraction: The Circular RNA Cdr1as Act as an Oncogene in Hepatocellular Carcinoma through Targeting miR-7 Expression.

Splenic Serum Exosome Circular RNA Cdr1as Is Involved in Hepatocellular Carcinoma by Inducing Hepatic Precursor Cells EMT

Splenic Serum Exosome Circular RNA Cdr1as Is Involved in Hepatocellular Carcinoma by Inducing Hepatic Precursor Cells EMT

CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability

Transient focal ischemia decreased microRNA-7 (miR-7) levels, leading to derepression of its major target α-synuclein (α-Syn) that promotes secondary brain damage. Circular RNA CDR1as is known to regulate miR-7 abundance and function. Hence, we currently evaluated its functional significance after focal ischemia. Transient middle cerebral artery occlusion (MCAO) in adult mice significantly downregulated both CDR1as and miR-7 levels in the peri-infarct cortex between 3 and 72h of reperfusion. Interestingly, neither pri-miR-7a nor 7b was altered in the ischemic brain. Intracerebral injection of an AAV9 vector containing a CDR1as gene significantly increased CDR1as levels by 21days that persisted up to 4months without inducing any observable toxicity in both sham and MCAO groups. Following transient MCAO, there was a significant increase in miR-7 levels and CDR1as binding to Ago2/miR-7 in the peri-infarct cortex of AAV9-CDR1as cohort compared with AAV9-Control cohort at 1day of reperfusion. CDR1as overexpression significantly suppressed post-stroke α-Syn protein induction, promoted motor function recovery, decreased infarct size, and curtailed the markers of apoptosis, autophagy mitochondrial fragmentation, and inflammation in the post-stroke brain compared with AAV9-Control-treated cohort. Overall, our findings imply that CDR1as reconstitution is neuroprotective after stroke, probably by protecting miR-7 and preventing α-Syn-mediated neuronal death.

Circular RNA Cdr1as modulates monocyte/macrophage function during cardiac injury and repair

Circular RNA Cdr1as modulates monocyte/macrophage function during cardiac injury and repair

Circular RNA CDR1as Alleviates Cisplatin-Based Chemoresistance by Suppressing MiR-1299 in Ovarian Cancer

Cisplatin (CDDP) chemoresistance seriously affects the prognosis and survival of patients with ovarian cancer (OC). Previous research has shown that circular RNA CDR1as is biologically associated with a large number of cancers. However, the molecular mechanism underlying the role of CDR1as in CDDP chemoresistance in OC remains unclear. Here, we investigated the mechanism of CDR1as in CDDP-resistant OC. First, we employed bioinformatics analysis and quantitative real-time PCR (qRT-PCR) to determine the expression of CDR1as and related RNAs in CDDP-sensitive and -resistant OC tissues and cells. Then, functional experiments were used to determine cell proliferation, invasion, migration, and apoptosis in CDDP chemoresistance and parent OC cells in vitro. The effect of CDR1as in CDDP chemoresistance OC progression was tested in nude mice in vivo. Moreover, dual-luciferase assays and RNA immunoprecipitation (RIP) were performed to confirm the interactions of CDR1as and related RNAs. Finally, we used Western blotting to determine protein expression levels. Our findings interpret the underlying mechanisms of the CDR1as/miR-1299/PPP1R12B axis and shed light on the clinical applications for CDDP-chemoresistant OC.

Circular RNA-CDR1as is involved in lung injury induced by long-term formaldehyde inhalation

Objective: Formaldehyde (FA) is known to induce lung injury, but the underlying molecular mechanism remains largely unclear. CDR1as is an important member of the circular RNAs (circRNAs) family and functions as miRNA sponges with gene-regulatory potential. Our earlier circRNA microarray data showed CDR1as was highly expressed in lung tissue exposed to FA. However, the mechanism of circRNA-CDR1as mediates the FA-exposed lung injury is still unclear. This study aimed to explore the role of CDR1as in lung injury. Materials and methods: In this study, FA was inhaled at doses of 0.5, 2.46, and 5 mg/m3, respectively. After exposure 8 weeks, lung histopathological examination, lung injury score, and IL-1β in bronchoalveolar lavage fluid (BALF) were determined. The expressions of CDR1as, rno-miR-7b and Atg7 were detected and the potential interaction of circRNA/miRNA/mRNA was predicted by bioinformatics analysis, including drawing circRNA/miRNA/mRNA interaction network, GO and KEGG analysis. Results: Our results indicated FA inhalation upregulated the expression of CDR1as in lung tissues in a dose-dependent manner while the expression of rno-miR-7b decreased and Atg7 increased. Moreover, the alteration of CDR1as was positively correlated with lung injury. Discussion and conclusions: CircRNA/miRNA/mRNA prediction further explained the possible effect mechanisms of CDR1as. These data implicated that CDR1as might be a critical regulator involved in lung injury induced by FA.

Circular RNA CDR1as Inhibits the Metastasis of Gastric Cancer through Targeting miR-876-5p/GNG7 Axis.

Circular RNA CDR1as has been demonstrated to participate in various cancer progressions as miRNA sponges. The exact underlying mechanisms of CDR1as on gastric cancer (GC) metastasis remain unknown. Here, we found that CDR1as knockdown facilitated GC cell migration and invasion while its overexpression inhibited the migration and invasion abilities of GC cells in vitro and in vivo. Moreover, epithelial-mesenchymal transition- (EMT-) associated proteins and MMP2 and MMP9 were downregulated by CDR1as. Bioinformatics analysis combined with dual-luciferase reporter gene assays, western blot, RT-qPCR analysis, and functional rescue experiments demonstrated that CDR1as served as a miR-876-5p sponge and upregulated the target gene GNG7 expression to suppress GC metastasis. In summary, our findings indicate that CDR1as suppresses GC metastasis through the CDR1as/miR-876-5p/GNG7 axis.

Circular RNA CDR1as disrupts the p53/MDM2 complex to inhibit Gliomagenesis

BackgroundInactivation of the tumor suppressor p53 is critical for pathogenesis of glioma, in particular glioblastoma multiforme (GBM). MDM2, the main negative regulator of p53, binds to and forms a stable complex with p53 to regulate its activity. Hitherto, it is unclear whether the stability of the p53/MDM2 complex is affected by lncRNAs, in particular circular RNAs that are usually abundant and conserved, and frequently implicated in different oncogenic processes.MethodsRIP-seq and RIP-qPCR assays were performed to determine the most enriched lncRNAs (including circular RNAs) bound by p53, followed by bioinformatic assays to estimate the relevance of their expression with p53 signaling and gliomagenesis. Subsequently, the clinical significance of CDR1as was evaluated in the largest cohort of Chinese glioma patients from CGGA (n = 325), and its expression in human glioma tissues was further evaluated by RNA FISH and RT-qPCR, respectively. Assays combining RNA FISH with protein immunofluorescence were performed to determine co-localization of CDR1as and p53, followed by CHIRP assays to confirm RNA-protein interaction. Immunoblot assays were carried out to evaluate protein expression, p53/MDM2 interaction and p53 ubiquitination in cells in which CDR1as expression was manipulated. After AGO2 or Dicer was knocked-down to inhibit miRNA biogenesis, effects of CDR1as on p53 expression, stability and activity were determined by immunoblot, RT-qPCR and luciferase reporter assays. Meanwhile, impacts of CDR1as on DNA damage were evaluated by flow cytometric assays and immunohistochemistry. Tumorigenicity assays were performed to determine the effects of CDR1as on colony formation, cell proliferation, the cell cycle and apoptosis (in vitro), and on tumor volume/weight and survival of nude mice xenografted with GBM cells (in vivo).ResultsCDR1as is found to bind to p53 protein. CDR1as expression decreases with increasing glioma grade and it is a reliable independent predictor of overall survival in glioma, particularly in GBM. Through a mechanism independent of acting as a miRNA sponge, CDR1as stabilizes p53 protein by preventing it from ubiquitination. CDR1as directly interacts with the p53 DBD domain that is essential for MDM2 binding, thus disrupting the p53/MDM2 complex formation. Induced upon DNA damage, CDR1as may preserve p53 function and protect cells from DNA damage. Significantly, CDR1as inhibits tumor growth in vitro and in vivo, but has little impact in cells where p53 is absent or mutated.ConclusionsRather than acting as a miRNA sponge, CDR1as functions as a tumor suppressor through binding directly to p53 at its DBD region to restrict MDM2 interaction. Thus, CDR1as binding disrupts the p53/MDM2 complex to prevent p53 from ubiquitination and degradation. CDR1as may also sense DNA damage signals and form a protective complex with p53 to preserve p53 function. Therefore, CDR1as depletion may play a potent role in promoting tumorigenesis through down-regulating p53 expression in glioma. Our results broaden further our understanding of the roles and mechanism of action of circular RNAs in general and CDR1as in particular, and can potentially open up novel therapeutic avenues for effective glioma treatment.

Association between Circular RNA CDR1as and Post-Infarction Cardiac Function in Pig Ischemic Heart Failure: Influence of the Anti-Fibrotic Natural Compounds Bufalin and Lycorine.

Anti-fibrotic therapies are of increasing interest to combat cardiac remodeling and heart failure progression. Recently, anti-fibrotic circular RNAs (circRNAs) have been identified in human and rodent cardiac tissue. In vivo (rodent) experiments proved cardiac anti-fibrotic effects of the natural compounds bufalin and lycorine by downregulating miRNA-671-5p, associated with a theoretic increase in the tissue level of circRNA CDR1as. Accordingly, we hypothesized that both anti-fibrotic drugs may inhibit focal myocardial fibrosis of the remodeled left ventricle (LV) also in a translational large animal model of heart failure (HF). Domestic pigs were repeatedly treated with subcutaneous injections of either bufalin, lycorine, or saline, (n = 5/group) between days 7–21 post acute myocardial infarction (AMI). At the 2-month follow-up, both bufalin and lycorine led to significantly reduced cardiac fibrosis. Bufalin treatment additionally led to smaller end-diastolic volumes, higher LV ejection fraction (EF), and increased expression of CDR1as of the AMI region. Elevated tissue levels of the circRNA CDR1as in the AMI region of the pig heart correlated significantly with LV and right ventricular EF, LV stroke volume, and negatively with infarct size. In conclusion, we successfully identified the circRNA CDR1as in pig hearts and show a significant association with improved LV and RV function by anti-fibrotic therapies in a translational animal model of HF.

The Circular RNA CDR1as Regulates the Proliferation and Apoptosis of Human Cardiomyocytes Through the miR-135a/HMOX1 and miR-135b/HMOX1 Axes.

Background: Chronic heart failure (CHF) is a major health burden worldwide, but there are a lack of effective methods for its early diagnosis and prognostic evaluation. Circular RNAs (circRNA), as a class, have been found to regulate gene expression and are implicated in multiple types of diseases. The circRNA, CDR1as, is reported to regulate gene transcription by acting as a microRNA inhibitor. However, the role of CDR1as in CHF remains to be elucidated. The aim of this study was to investigate the role and mechanism of action of the circRNA, CDR1as, in CHF. Methods: A total of 30 patients with CHF and 30 healthy persons were included in the study. The levels of CDR1as, miR-135a, and miR-135b in the plasma of all subjects were quantified by qRT-PCR. ELISA was used to detect the level of HMOX1 in plasma. The effect of CDR1as was investigated in human cardiomyocytes, including HCMs and AC16 cells. Results: CDR1as was upregulated in the plasma of patients with CHF and is a potential diagnostic marker of CHF. The levels of miR-135a and miR-135b were downregulated in the plasma of patients with CHF. The plasma level of HMOX1 in patients with CHF was significantly higher compared with the control group and was highly correlated with cardiac function in CHF patients. CDR1as was shown to act as a sponge for miR-135a and miR-135b and regulated the proliferation and apoptosis of human cardiomyocytes through the miR-135a/HMOX1 and miR-135b/HMOX1 signaling axes. Conclusion: CDR1as is a potential biomarker of CHF that is mechanistically involved in the disease pathogenesis and participates in regulating the occurrence and development of CHF through the miR-135a/HMOX1 and miR-135b/HMOX1 signaling axes.

Circular RNA CDR1as Exerts Oncogenic Properties Partially through Regulating MicroRNA 641 in Cholangiocarcinoma.

It has been found that the circular RNA (circRNA) CDR1as is upregulated in cholangiocarcinoma (CCA) tissues. In this study, we tried to explore the roles of CDR1as in CCA. CDR1as was overexpressed or knocked down in human CCA cells to assess the effects of CDR1as on cell behaviors and tumor xenograft growth. In vitro, the CDR1as level was significantly increased in CCA cell lines. The results showed that CDR1as promoted the cell proliferation, migration, invasion, and activation of the AKT3/mTOR pathway in CCA cells. Moreover, miR-641, a predicted target microRNA (miRNA) of CDR1as, could partially reverse the effects of CDR1as on cell behaviors in CCA cells. Furthermore, CDR1as improved tumor xenograft growth, and it could be attenuated by miR-641 in vivo Additionally, CDR1as expression was inversely correlated with miR-641 in CCA cells, and miR-641 could directly bind with CDR1as and its target genes, the AKT3 and mTOR genes. Mechanistically, CDR1as could bind with miR-641 and accelerate miR-641 degradation, which possibly leads to the upregulation of the relative mRNA levels of AKT3 and mTOR in RBE cells. In conclusion, our findings indicated that CDR1as might exert oncogenic properties, at least partially, by regulating miR-641 in CCA. CDR1as and miR-641 could be considered therapeutic targets for CCA.

Circular RNA CDR1as promotes adipogenic and suppresses osteogenic differentiation of BMSCs in steroid-induced osteonecrosis of the femoral head.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a common debilitating orthopedic disease. The bone marrow mesenchymal stem cells (BMSCs) are a type of mesenchymal stem cells which play crucial roles in bone repair. The adipogenic/osteogenic differentiation disorder of BMSCs has been widely perceived contributing to SONFH. However, the regulatory mechanism of BMSCs differentiation disorder still remains unclear. Circular RNA (circRNA), a kind of stable ncRNA, plays important roles in regulating gene expression via various ways. To date, there are no studies to uncover the circRNA expression profile and screen out the key circRNAs playing crucial roles in adipogenic/osteogenic differentiation disorder of SONFH-BMSCs. In present study, we detected the circRNA expression profiles in SONFH-BMSCs for the first time. A total of 820 circRNAs were differentially expressed in SONFH-BMSCs, including 460 up- and 360 down-regulated circRNAs. Bioinformatics analysis indicates circRNA CDR1as, one up-regulated circRNA, may play crucial role in adipogenic/osteogenic differentiation disorder of SONFH-BMSCs via CDR1as-miR-7-5p-WNT5B axis. Knocking-down CDR1as resulted in increasing of osteogenic differentiation and decreasing of adipogenic differentiation of BMSCs, while over-expressing CDR1as resulted in decreasing of osteogenic differentiation and increasing of adipogenic differentiation of BMSCs. The miR-7-5p binding sites of CDR1as and WNT5B were verified by luciferase reporter gene assay. Our study may provide new insights into the molecular mechanisms of osteogenic/adipogenic differentiation disorder of SONFH-BMSCs and new biomarkers for the diagnosis and treatment of SONFH.

Circular RNA CDR1-AS contributes to pemetrexed and cisplatin chemoresistance through EGFR/PI3K signaling pathway in lung adenocarcinoma

Recent studies found circRNAs were involved in tumorigenesis and became new tumor biomarkers and therapeutic targets in lung adenocarcinoma (LUAD), which played a critical role in various biological processes and had been implicated in resistance to chemotherapeutic drugs. However, the role of CDR1-AS in chemoresistance of LUAD to pemetrexed (PTX) and cisplatin (CDDP) is poorly understood. Here, we found that CDR1-AS was up-regulated in LUAD tissues and cell lines, its high-expression was relevant to smoking history, T stage and neoadjuvant chemotherapy (PTX and CDDP) of LUAD patients. CDR1-AS was an independent prognostic biomarker for LUAD patients. CDR1-AS was highly expressed in PTX and CDDP resistant LUAD tissues and cell line (A549/CR). Silence of CDR1-AS re-sensitized A549/CR cells to PTX and CDDP. CDR1-AS was closely related with EGFR/PI3K signaling pathway in A549/CR cells. The activating of EGFR/PI3K pathway mostly restored the effecting of CDR1-AS silence on PTX and CDDP sensitivity in A549/CR cells, CDR1-AS contributed to PTX and CDDP chemoresistance through EGFR/PI3K signaling pathway in LUAD. In conclusion, the CDR1-AS is high-expressed in LUAD and is an independent prognostic biomarker for LUAD patients. The high-expression of CDR1-AS is related with the PTX and CDDP insensitivity of LUAD patients, CDR1-AS promotes PTX and CDDP chemoresistance through EGFR/PI3K signaling pathway in LUAD.