Circular RNA circRNF169 functions as a miR-30c-5p sponge to promote cellular senescence.

Circular RNAs (circRNAs), characterized as single-stranded closed circular RNA molecules, have been established to exert pivotal functions in various biological or pathological processes. Nonetheless, the effects and underlying mechanisms concerning circRNAs on the aging and aging-related diseases remain elusive. We herein compared the expression patterns of circRNAs in young and senescent mouse embryonic fibroblasts (MEFs), and uncovered that circRNF169 was dramatically up-regulated in senescent MEFs compared with that in young MEFs. Therefore, we further digged into the role and potential mechanisms of circRNF169 in the senescence of MEFs. The results of senescence-associate-ß-galactosidase staining and BrdU incorporation assay showed that silencing of circRNF169 significantly delayed MEFs senescence and promoted cell proliferation, while ectopic expression of circRNF169 exhibited the opposite effects. Moreover, the dual-luciferase reporter assay confirmed that circRNF169 acted as an endogenous miR-30c-5p sponge, which accelerated cellular senescence by sequestering and inhibiting miR-30c-5p activity. Taken together, our results suggested that circRNF169 exerted a crucial role in cellular senescence through sponging miR-30c-5p and represented a promising target for aging intervention.

Association between ADAMTS7 TagSNPs and the risk of myocardialinfarction.

PURPOSE OF THE STUDY: Genome-wide association studies have revealed an association of ADAMTS7 polymorphisms with the risk of cardiovascular diseases. Nonetheless, the role of ADAMTS7 polymorphisms on myocardial infarction (MI) risk remains poorly understood. Here, we aim to evaluate the effect of ADAMTS7 tag single nucleotide polymorphisms (SNPs) on individual susceptibility to MI. STUDY DESIGN: Genotyping of the four tagSNPs (rs1994016, rs3825807, rs4380028 and rs7173743) was performed in 232 MI cases and 661 control subjects using PCR-ligase detection reaction (LDR) method. The association of these four tagSNPs with MI risk was performed with SPSS software. RESULTS: Multivariate logistic regression analysis showed that ADAMTS7 tagSNP rs3825807 exhibited a significant effect on MI risk. Compared with the TT homozygotes, the CT genotype (OR1.93, 95% CI1.30to 2.85, Pc=0.004) and the combined CC/CT genotypes (OR1.70, 95% CI1.16 to 2.50, Pc=0.028) were statistically significantly associated with the increased risk for MI. Further stratified analysis revealed a more significant association with MI risk among older subjects, hypertensives, non-diabetics and patients with hyperlipidaemia. Consistently, the haplotype rs1994016T-rs3825807C containing rs3825807 C allele exhibited increased MI risk (OR1.52, 95% CI1.10 to 2.10, p=0.010). However, we did not detect any association of the other three tagSNPs with MI risk. CONCLUSIONS: Our finding suggest that ADAMTS7 tagSNP rs3825807 contributes to MI susceptibility in the Chinese Han population. Further studies are necessary to confirm the general validity of our findings and to clarify the underlying mechanism for this association.

The emerging landscape of circular RNA in cardiovascular diseases.

Circular RNAs (circRNAs), a large novel type of endogenous transcripts, have become a new research hotspot in the field of RNA biology. CircRNAs are mainly generated from exons or introns via multiple mechanisms, and the majority of circRNAs are stable and conserved across different species. Recent studies have revealed that circRNAs can function as miRNA sponges, binding partners of proteins, regulators of transcription, or can even be translated into proteins. Growing evidence has demonstrated that circRNAs play important roles in a wide variety of biological processes such as cell proliferation, apoptosis and senescence, and may serve as potential diagnostic biomarkers or therapeutic targets for various cardiovascular diseases. Here, we review the biogenesis, properties and biological function of circRNAs, and summarize their roles in cardiovascular disorders.

The association between pre-miR-27a rs895819 polymorphism and myocardial infarction risk in a Chinese Han population.

BACKGROUND: Accumulating evidences have shown that miRNAs are directly or indirectly involved in a variety of biological processes, and closely associated with diverse human diseases, including cardiovascular diseases. SNPs locating within pri/pre-miRNA can affect miRNA processing and binding ability of target genes. MiR-27a, miR-26a-1 miR-100, miR-126 and miR-218 were reported to be associated with pathogenesis of myocardial infarction (MI). Here we aimed to evaluate the potential association of five polymorphisms in these pri/pre-miRNAs with individual susceptibility to MI in a Chinese Han population. METHODS: Genotyping was performed in 287 MI cases and 646 control subjects using polymerase chain reaction-ligase detection reaction (PCR-LDR) method. The association of these SNPs with MI risk was performed with SPSS software. RESULTS: In a logistic regression analysis, we found that AG heterozygote (OR = 0.40, 95% CI = 0.21-0.76, Pa = 0.005) or AA homozygote (OR = 0.40, 95% CI = 0.22-0.75, Pa = 0.004) of pre-miR-27a rs895819 had a reduced susceptibility to MI in comparison with GG homozygote. Similarly, a reduced risk of MI was detected when the AG and AA genotypes were combined (OR = 0.40, 95% CI = 0.22-0.74, Pa = 0.003). However, no significant association between pri-miR-26a-1 pri-miR-100, pri-miR-126 and pri-miR-218 polymorphisms and MI risk was observed under the allelic and established genetic models. Further stratified analysis of pre-miR-27a rs895819 revealed a more significant association of AG + AA genotypes with MI risk among younger, male and smoking subjects. Interestingly, AG and AA genotypes of the rs895819 polymorphism conferred about 0.17 mmol/L and 0.18 mmol/L increase in HDL-C levels compared to GG genotype. CONCLUSIONS: Our findings suggest that the pre-miR-27a rs895819 polymorphism is associated with MI susceptibility in the Chinese Han population, which probably due to influence the HDL-C levels.

Long non-coding RNAs: An emerging powerhouse in the battle between life and death of tumor cells.

Long non-coding RNAs (lncRNAs) represent a class of non-protein coding transcripts longer than 200 nucleotides that have aptitude for regulating gene expression at the transcriptional, post-transcriptional or epigenetic levels. In recent years, lncRNAs, which are believed to be the largest transcript class in the transcriptomes, have emerged as important players in a variety of biological processes. Notably, the identification and characterization of numerous lncRNAs in the past decade has revealed a role for these molecules in the regulation of cancer cell survival and death. It is likely that this class of non-coding RNA constitutes a critical contributor to the assorted known or/and unknown mechanisms of intrinsic or acquired drug resistance. Moreover, the expression of lncRNAs is altered in various patho-physiological conditions, including cancer. Therefore, lncRNAs represent potentially important targets in predicting or altering the sensitivity or resistance of cancer cells to various therapies. Here, we provide an overview on the molecular functions of lncRNAs, and discuss their impact and importance in cancer development, progression, and therapeutic outcome. We also provide a perspective on how lncRNAs may alter the efficacy of cancer therapy and the promise of lncRNAs as novel therapeutic targets for overcoming chemoresistance. A better understanding of the functional roles of lncRNA in cancer can ultimately translate to the development of novel, lncRNA-based intervention strategies for the treatment or prevention of drug-resistant cancer.

MicroRNA-33 promotes the replicative senescence of mouse embryonic fibroblasts by suppressing CDK6.

MicroRNAs are a large class of tiny noncoding RNAs, which have emerged as critical regulators of gene expression, and thus are involved in multiple cellular processes, including cellular senescence. MicroRNA-33 has previously been established to exert crucial effect on cell proliferation, lipid metabolism and cholesterol metabolism. Nonetheless, the association between microRNA-33 and cellular senescence and its underlying molecular mechanism are far to be elucidated. The present study has attempted to probe into the effect of microRNA-33 on MEFs senescence. Our data unveiled that microRNA-33 was dramatically down-regulated in senescent MEFs compared to the young MEFs, and ectopic expression of microRNA-33 promoted MEFs senescence, while knock-down of microRNA-33 exhibited a protective effect against senescence phenotype. Moreover, we verified CDK6 as a direct target of microRNA-33 in mouse. Silencing of CDK6 induced the premature senescence phenotype of MEFs similarly as microRNA-33, while enforced expression of CDK6 significantly reverse the senescence-induction effect of microRNA-33. Taken together, our results suggested that microRNA-33 enhanced the replicative senescence of MEFs potentially by suppressing CDK6 expression.

The association of APOC4 polymorphisms with premature coronary artery disease in a Chinese Han population.

BACKGROUND: Hypercholesterolemia arising from abnormal lipid metabolism is one of the critical risk factors for coronary artery disease (CAD), however the roles of genetic variants in lipid metabolism-related genes on premature CAD (≤ 60 years old) development still require further investigation. We herein genotyped four single nucleotide polymorphisms (SNPs) in lipid metabolism-related genes (rs1132899 and rs5167 in APOC4, rs1801693 and rs7765781 in LPA), aimed to shed light on the influence of these SNPs on individual susceptibility to early-onset CAD. METHODS: Genotyping of the four SNPs (rs1132899, rs5167, rs1801693 and rs7765781) was performed in 224 premature CAD cases and 297 control subjects (≤ 60 years old) using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. The association of these SNPs with premature CAD was performed with SPSS software. RESULTS: Multivariate logistic regression analysis showed that C allele (OR = 1.50, P = 0.027) and CC genotype (OR = 2.84, P = 0.022) of APOC4 rs1132899 were associated with increased premature CAD risk, while the other three SNPs had no significant effect. Further stratified analysis uncovered a more evident association with the risk of premature CAD among male subjects (C allele, OR = 1.65, and CC genotype, OR = 3.33). CONCLUSIONS: Our data provides the first evidence that APOC4 rs1132899 polymorphism was associated with an increased risk of premature CAD in Chinese subjects, and the association was more significant among male subjects.

LincRNA-p21: Implications in Human Diseases.

Long noncoding RNAs (lncRNAs), which lack significant protein-coding capacity, regulate various biological processes through diverse and as yet poorly understood molecular mechanisms. However, a number of studies in the past few years have documented important functions for lncRNAs in human diseases. Among these lncRNAs, lincRNA-p21 has been proposed to be a novel regulator of cell proliferation, apoptosis and DNA damage response, and involved in the initiation and progression of human diseases. In this review, we summarize the current knowledge of lincRNA-p21, mainly focus on the known biological functions and its underlying mechanisms. Moreover, we highlight the growing body of evidences for the importance of lincRNA-p21 in diverse human diseases, which indicate lincRNA-p21 as a potential diagnostic marker and/or a valuable therapeutic target for these diseases.

A genetic variant in pre-miR-27a is associated with a reduced cervical cancer risk in southern Chinese women.

OBJECTIVE: MicroRNAs (miRNAs) play critical roles in cervical carcinogenesis. Common single nucleotide polymorphisms (SNPs) in pre/pri-miRNAs may change their property through altering miRNAs expression and/or maturation. Here we aimed to investigate the influence of three common SNPs in pre/pri-miRNAs (pri-miR-26a-1 rs7372209, pre-miR-27a rs895819 and pri-miR-100 rs1834306) on individual susceptibility to cervical cancer. METHODS: We genotyped these three polymorphisms in 103 cervical cancer cases and 417 cancer-free female subjects using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. Unconditional logistic regression analysis was utilized to estimate the association between these polymorphisms and the risk of cervical cancer. RESULTS: In a logistic regression analysis, we found that the rs895819 polymorphism in pre-miR-27a exhibited a significant effect on cervical cancer risk; T allele (OR = 0.68, 95% CI = 0.49-0.95, P = 0.025), and CT (OR = 0.33, 95% CI = 0.15-0.74, P = 0.007) or TT (OR = 0.33, 95% C I= 0.15-0.72, P = 0.006) genotype were associated with the decreased risk, compared to C and CC respectively. As we used further genotype association models, we found a similar trend of the association in additive (OR = 0.70, P = 0.041) and recessive model (OR = 0.33, P = 0.004). We did not detect any association of the other two SNPs in pri-miR-26a-1 (rs7372209) and pri-miR-100 (rs1834306) with cervical cancer risk. CONCLUSION: Our study provides the first evidence that the miR-27a rs895819 polymorphism is associated with a decreased risk of cervical cancer in southern Chinese women.

A common variant in pre-miR-146 is associated with coronary artery disease risk and its mature miRNA expression.

miRNAs are small non-coding RNAs that play an important role in numerous physiological processes. Common single nucleotide polymorphisms (SNPs) in pre-miRNAs may change their property through altering miRNAs expression and/or maturation, resulting in diverse functional consequences. To date, the role of genetic variants in pre-miRNAs on coronary artery disease (CAD) risk remains poorly understood. Here we aimed to evaluate the influence of three common SNPs in pre-miRNAs (miR-146a rs2910164 G>C, miR-196a2 rs11614913 C>T, miR-499 rs3746444 T>C) on individual susceptibility to CAD in a Chinese population of 295 CAD patients and 283 controls. Genotyping was performed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method. In a logistic regression analysis, we detected an association of rs2910164 in pre-miR-146a with the CAD risk; compared with the GG homozygotes, the GC heterozygotes [odds ratio (OR)=1.89, 95% confidence interval (CI)=1.06-3.36, P=0.029] and the CC homozygotes (OR=1.83, 95% CI=1.01-3.32, P=0.046) genotype were statistically significantly associated with the increased risk for CADs. As we used further genotype association models, we found a similar trend of the association in recessive model (OR=1.86, 95% CI=1.09-3.19, P=0.023). We also found that the genotypes of miR-146a rs2910164 were associated with its mature miRNA expression by analyzing 23 PBMC samples from CAD patients. Individuals carrying rs11614913 GC or CC genotypes showed 3.2-fold higher expression compared to GG genotype carriers (P<0.05). We observed no association of the other two SNPs in miR-196a2 (rs11614913) and miR-499 (rs3746444) with the CAD incidence. Our data provide the first evidence that the miR-146a rs2910164 polymorphism is associated with increased risk of CAD in Chinese Han population, which may be through influencing the expression levels of the miRNA.

The LRP6 rs2302685 polymorphism is associated with increased risk of myocardial infarction.

BACKGROUND: Abnormal lipids is one of the critical risk factors for myocardial infarction (MI), however the role of genetic variants in lipid metabolism-related genes on MI pathogenesis still requires further investigation. We herein genotyped three SNPs (LRP6 rs2302685, LDLRAP1 rs6687605, SOAT1 rs13306731) in lipid metabolism-related genes, aimed to shed light on the influence of these SNPs on individual susceptibility to MI. METHODS: Genotyping of the three SNPs (rs2302685, rs6687605 and rs13306731) was performed in 285 MI cases and 650 control subjects using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. The association of these SNPs with MI and lipid profiles was performed with SPSS software. RESULTS: Multivariate logistic regression analysis showed that C allele (OR = 1.62, P = 0.039) and the combined CT/CC genotype (OR = 1.67, P = 0.035) of LRP6 rs2302685 were associated with increased MI risk, while the other two SNPs had no significant effect. Further stratified analysis uncovered a more evident association with MI risk among younger subjects (≤60 years old). Fascinatingly, CT/CC genotype of rs2302685 conferred increased LDL-C levels compared to TT genotype (3.0 mmol/L vs 2.72 mmol/L) in younger subjects. CONCLUSIONS: Our data provides the first evidence that LRP6 rs2302685 polymorphism is associated with an increased risk of MI in Chinese subjects, and the association is more evident among younger individuals, which probably due to the elevated LDL-C levels.

Targeting DDX11 promotes PARP inhibitor sensitivity in hepatocellular carcinoma by attenuating BRCA2-RAD51 mediated homologous recombination.

Homologous recombination (HR) is a major DNA double-strand break (DSB) repair pathway of clinical interest because of treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). Cooperation between RAD51 and BRCA2 is pivotal for DNA DSB repair, and its dysfunction induces HR deficiency and sensitizes cancer cells to PARPi. The depletion of the DEAD-box protein DDX11 was found to suppress HR in hepatocellular carcinoma (HCC) cells. The HR ability of HCC cells is not always dependent on the DDX11 level because of natural DDX11 mutations. In Huh7 cells, natural DDX11 mutations were detected, increasing the susceptibility of Huh7 cells to olaparib in vitro and in vivo. The HR deficiency of Huh7 cells was restored when CRISPR/Cas9-mediated knock-in genomic editing was used to revert the DDX11 Q238H mutation to wild type. The DDX11 Q238H mutation impeded the phosphorylation of DDX11 by ATM at serine 237, preventing the recruitment of RAD51 to damaged DNA sites by disrupting the interaction between RAD51 and BRCA2. Clinically, a high level of DDX11 correlated with advanced clinical characteristics and a poor prognosis and served as an independent risk factor for overall and disease-free survival in patients with HCC. We propose that HCC with a high level of wild-type DDX11 tends to be more resistant to PARPi because of enhanced recombination repair, and the key mutation of DDX11 (Q238H) is potentially exploitable.

Identification of FAM96B as a novel prelamin A binding partner.

Prelamin A accumulation causes nuclear abnormalities, impairs nuclear functions, and eventually promotes cellular senescence. However, the underlying mechanism of how prelamin A promotes cellular senescence is still poorly understood. Here we carried out a yeast two-hybrid screen using a human skeletal muscle cDNA library to search for prelamin A binding partners, and identified FAM96B as a prelamin A binding partner. The interaction of FAM96B with prelamin A was confirmed by GST pull-down and co-immunoprecipitation experiments. Furthermore, co-localization experiments by fluorescent confocal microscopy revealed that FAM96B colocalized with prelamin A in HEK-293 cells. Taken together, our data demonstrated the physical interaction between FAM96B and prelamin A, which may provide some clues to the mechanisms of prelamin A in premature aging.

Emerging Role and Mechanism of the FTO Gene in Cardiovascular Diseases.

The fat mass and obesity-associated (FTO) gene was the first obesity-susceptibility gene identified through a genome-wide association study (GWAS). A growing number of studies have suggested that genetic variants of FTO are strongly associated with the risk of cardiovascular diseases, including hypertension and acute coronary syndrome. In addition, FTO was also the first N6-methyladenosine (m6A) demethylase, suggesting the reversible nature of m6A modification. m6A is dynamically deposited, removed, and recognized by m6A methylases, demethylases, and m6A binding proteins, respectively. By catalyzing m6A demethylation on mRNA, FTO may participate in various biological processes by modulating RNA function. Recent studies demonstrated that FTO plays a pivotal role in the initiation and progression of cardiovascular diseases such as myocardial fibrosis, heart failure, and atherosclerosis and may hold promise as a potential therapeutic target for treating or preventing a variety of cardiovascular diseases. Here, we review the association between FTO genetic variants and cardiovascular disease risk, summarize the role of FTO as an m6A demethylase in cardiovascular disorders, and discuss future research directions and possible clinical implications.

Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Vasculopathies and Angiogenesis: Therapeutic Applications and Optimization.

Extracellular vesicles (EVs), as part of the cellular secretome, have emerged as essential cell-cell communication regulators in multiple physiological and pathological processes. Previous studies have widely reported that mesenchymal stromal cell-derived EVs (MSC-EVs) have potential therapeutic applications in ischemic diseases or regenerative medicine by accelerating angiogenesis. MSC-EVs also exert beneficial effects on other vasculopathies, including atherosclerosis, aneurysm, vascular restenosis, vascular calcification, vascular leakage, pulmonary hypertension, and diabetic retinopathy. Consequently, the potential of MSC-EVs in regulating vascular homeostasis is attracting increasing interest. In addition to native or naked MSC-EVs, modified MSC-EVs and appropriate biomaterials for delivering MSC-EVs can be introduced to this area to further promote their therapeutic applications. Herein, we outline the functional roles of MSC-EVs in different vasculopathies and angiogenesis to elucidate how MSC-EVs contribute to maintaining vascular system homeostasis. We also discuss the current strategies to optimize their therapeutic effects, which depend on the superior bioactivity, high yield, efficient delivery, and controlled release of MSC-EVs to the desired regions, as well as the challenges that need to be overcome to allow their broad clinical translation.

A single nucleotide polymorphism in EXO1 gene is associated with cervical cancer susceptibility in Chinese patients.

OBJECTIVE: The aim of this study was to investigate the association of Exonuclease1 (EXO1) genetic polymorphism and the development of cervical carcinoma. METHODS: This study was conducted with 126 patients diagnosed with cervical cancer and 278 people with no cancer history. The polymerase chain reaction-based restriction fragment length polymorphism was used to evaluate the K589E and C908G gene polymorphisms. Unconditional logistic regression analysis was used to estimate the association between the genotypes and the risk for cervical cancer. RESULTS: This is the first study on the role of EXO1 K589E (rs1047840) and EXO1 C908G (rs10802996) polymorphisms in cervical cancer in a Chinese population. Our results indicated that the EXO1 K589G polymorphism were significantly associated with the risk for cervical cancer. Compared with the G allele EXO1 K589E, the A allele increased the risk for cervical cancer (adjusted odds ratio, 1.67; 95% confidence interval, 1.13-2.45). By contrast, we have not found a significant association between the EXO1 C908G polymorphism and cervical cancer risk (P = 0.791). CONCLUSION: These findings indicate that the SNPs of EXO1 K589E may contribute to cervical cancer carcinogenesis in Chinese populations. A larger population study will need to be carried out to further validate the potential association of EXO1 genetic polymorphism and cervical carcinoma.

The MBD4 Glu346Lys polymorphism is associated with the risk of cervical cancer in a Chinese population.

OBJECTIVE: Methyl-CpG binding domain 4 (MBD4) protein functions as a DNA repair enzyme and plays an important role in maintaining genome integrity and carcinogenesis. The polymorphisms in the MBD4 gene may be associated with differences in DNA repair capacity and thereby influence an individual's susceptibility to cervical cancer. To verify this hypothesis, we examined the potential association between the MBD4 Glu346Lys polymorphism (rs140693, G>A) and the risk of cervical cancer in a Chinese population. METHODS: We genotyped the MBD4 Glu346Lys polymorphism in 146 cervical cancer cases and 320 healthy female subjects using polymerase chain reaction-based restriction fragment length polymorphism method. Unconditional logistic regression analysis was used to estimate the association between the genotypes and the risk of cervical cancer. RESULTS: We observed a significantly decreased risk of cervical cancer associated with the heterozygous Lys/Glu genotype (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.36-0.99; P = 0.046) and the homozygous Glu/Glu genotype (OR, 0.52; 95% CI, 0.30-0.89; P = 0.018), compared with the Lys/Lys homozygotes. Moreover, the reduced cervical cancer risk was more predominant among younger subjects or human papillomavirus-positive individuals carrying Glu/Glu genotypes (OR, 0.33; 95% CI, 0.14-0.78, P = 0.011; and OR, 0.27; 95% CI, 0.09-0.75, P = 0.013, respectively). CONCLUSIONS: The MBD4 codon 346 polymorphism may play a role in cervical cancer susceptibility in the Chinese population. Further larger case-control and functional studies are needed to validate these findings.

A circular intronic RNA ciPVT1 delays endothelial cell senescence by regulating the miR-24-3p/CDK4/pRb axis.

Circular RNAs (circRNAs) have been established to be involved in numerous processes in the human genome, but their function in vascular aging remains largely unknown. In this study, we aimed to characterize and analyze the function of a circular intronic RNA, ciPVT1, in endothelial cell senescence. We observed significant downregulation of ciPVT1 in senescent endothelial cells. In proliferating endothelial cells, ciPVT1 knockdown induced a premature senescence-like phenotype, inhibited proliferation, and led to an impairment in angiogenesis. An in vivo angiogenic plug assay revealed that ciPVT1 silencing significantly inhibited endothelial tube formation and decreased hemoglobin content. Conversely, overexpression of ciPVT1 in old endothelial cells delayed senescence, promoted proliferation, and increased angiogenic activity. Mechanistic studies revealed that ciPVT1 can sponge miR-24-3p to upregulate the expression of CDK4, resulting in enhanced Rb phosphorylation. Moreover, enforced expression of ciPVT1 reversed the senescence induction effect of miR-24-3p in endothelial cells. In summary, the present study reveals a pivotal role for ciPVT1 in regulating endothelial cell senescence and may have important implications in the search of strategies to counteract the development of age-associated vascular pathologies.

Circular RNA: an important player with multiple facets to regulate its parental gene expression.

Circular RNAs (circRNAs), a novel type of endogenous RNAs with covalently closed-loop structures, have become a new research hotspot in the RNA world. Their diversity, stability, evolutionary conservation, and cell type- or tissue-specific expression patterns endow circRNAs with various important biological functions. As a consequence, circRNAs are emerging as important regulators of physiological development and disease pathogenesis. Growing evidence has shown that circRNAs can regulate parental gene expression through diverse mechanisms, such as transcription and splicing regulation, microRNA (miRNA) sponges, mRNA traps, translational modulation, and post-translational modification. The study of circRNAs and how circRNAs regulate the expression of parental genes will facilitate a deeper understanding of their biological functions and provide new perspectives on their clinical application. Herein, we review the biogenesis of circRNAs, with a particular focus on the molecular mechanisms of circRNAs regulating their parental gene expression and the biological significance of such regulation.

Circular RNAs as Competing Endogenous RNAs in Cardiovascular and Cerebrovascular Diseases: Molecular Mechanisms and Clinical Implications.

Circular RNAs (circRNAs) represent a novel class of widespread and diverse endogenous RNA molecules. This unusual class of RNA species is generated by a back-splicing event of exons or introns, resulting in a covalently closed circRNA molecule. Accumulating evidence indicates that circRNA plays an important role in the biological functions of a network of competing endogenous RNA (ceRNA). CircRNAs can competitively bind to miRNAs and abolish the suppressive effect of miRNAs on target RNAs, thus regulating gene expression at the posttranscriptional level. The role of circRNAs as ceRNAs in the pathogenesis of cardiovascular and cerebrovascular diseases (CVDs) has been recently reported and highlighted. Understanding the underlying molecular mechanism could aid the discovery of therapeutic targets or strategies against CVDs. Here, we review the progress in studying the role of circRNAs as ceRNAs in CVDs, with emphasis on the molecular mechanism, and discuss future directions and possible clinical implications.