Role Of Circular RNAs Research Articles

Research Advances in the Roles of Circular RNAs in Pathophysiology and Early Diagnosis of Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) refers to different degrees of glucose tolerance abnormalities that occur during pregnancy or are discovered for the first time, which can have a serious impact on the mother and the offspring. The screening of GDM mainly relies on the oral glucose tolerance test (OGTT) at 24–28 weeks of gestation. The early diagnosis and intervention of GDM can greatly improve adverse pregnancy outcomes. However, molecular markers for early prediction and diagnosis of GDM are currently lacking. Therefore, looking for GDM-specific early diagnostic markers has important clinical significance for the prevention and treatment of GDM and the management of subsequent maternal health. Circular RNA (circRNA) is a new type of non-coding RNA. Recent studies have found that circRNAs were involved in the occurrence and development of malignant tumors, metabolic diseases, cardiovascular and cerebrovascular diseases, etc., and could be used as the molecular marker for early diagnosis. Our previous research showed that circRNAs are differentially expressed in serum of GDM pregnant women in the second and third trimester, placental tissues during cesarean delivery, and cord blood. However, the mechanism of circular RNA in GDM still remains unclear. This article focuses on related circRNAs involved in insulin resistance and β-cell dysfunction, speculating on the possible role of circRNAs in the pathophysiology of GDM under the current research context, and has the potential to serve as early molecular markers for the diagnosis of GDM.

Circular RNAs: novel regulators of resistance to systemic treatments in breast cancer.

Systematic treatments including chemotherapy, endocrine therapy, and HER2-targeted therapy are important therapeutic approaches to breast cancer. However, drug resistance is a major barrier to achieving a cure in breast cancer (BC) patients. Hence, it is urgent to gain insight into the drug-resistance mechanisms in order to improve the prognosis of BC patients. Genetic alternations, epigenetic alternations, and other non-genetic mechanisms such as BC stem-like cells, metabolic reprogramming, and tumor microenvironment contribute to drug resistance of BC. With the development of single-cell sequencing of circulating tumor cell and next-generation sequencing of matched pre- and post- progression tumor biopsies or ctDNA from BC patients with drug resistance, new mechanisms of resistance are being discovered. An increasing number of microRNAs and long non-coding RNAs have been found to be associated with the drug resistance of BC. However, there are few reports on the role of circular RNAs (circRNAs) as master regulators of drug resistance. Therefore, there is still much to say in the field of drug resistance-related circRNAs. In this review, we mainly focus on literature evidence for the detailed mechanisms associated with systematic treatments' resistance of BC and how circRNAs intensify or weaken drug resistance. Exogenous expression of tumor suppressive circRNAs or knockdown of oncogenic circRNAs has been verified to reverse drug resistance of BC cells, which highlights that circRNAs may function as potential biomarkers and/or therapeutic targets of BC. Treatment targeting abnormally expressed circRNAs alone or combined with other systemic treatments may be a promising approach to conquering drug resistance.

Role of Circular RNAs in the Pathogenesis of Malignant Melanoma.

Malignant melanoma is one of the most aggressive types of skin cancer. Thus, efficient diagnosis and treatment methods are crucial for advanced melanoma. Circular RNAs (circRNAs) have been regarded as a 'splicing noise' in the past decades. However, several circRNAs have been recently reported to be differentially expressed in melanoma, and the cell or tissue-specific expression makes these suitable candidate diagnostic or therapeutic biomarkers. In addition, emerging studies have confirmed that circular RNAs play pivotal roles in the proliferation, invasion, metastasis, and migration of malignant melanoma. However, specific pathogenic mechanisms between melanoma and circRNAs remain unclear. In the present study, it was summarized that circRNAs are associated with the pathogenesis of melanoma, including hsa_circ_0083444, hsa_circ_0005320, hsa_circ_0067531, hsa_circ_0084043, hsa_circ_0000082, hsa_circ_0016418, hsa_circ_0085533 and hsa_circ_0025039, hsa_circ_0001946, hsa_circ_0002770, hsa_circ_0079593, hsa_circ_0027247, hsa_circ_0017247, hsa_circ_0020710. These can provide potential diagnosis, treatment, and prognostication biomarkers for advanced melanoma in clinical applications.

CircCHD2/miR-200b-3p/HLF Axis Promotes Liver Cirrhosis.

Inactivation of hepatic stellate cells (HSCs) slows down liver cirrhosis (LC) advancement. The role of circular RNAs (circRNAs) in LC is largely undiscovered. Here, we clarified the effect of circCHD2 on HSCs. LX-2 cells were stimulated with TGF-β1 to establish a cell model. The circCHD2, miR-200b-3p, and HLF were inspected using quantitative real-time PCR (qPCR). Cell counting kit-8, 5-Ethynyl-2'-deoxyuridine, together with colony formation assays were all conducted to analyze cell proliferation. α-SMA and Col1A1 were evaluated by qPCR and Western blot. The targets of circCHD2 and miR-200b-3p were verified by luciferase reporter assay. We found the circCHD2 was upregulated in the patients with LC and transforming growth factor beta 1 (TGF-β1)-stimulated LX-2 cells. Interfering of circCHD2 inhibited the proliferation induced by TGF-β1, downregulated α-SMA, and Col1A1. CircCHD2 served as a miR-200b-3p sponge, which directly targeted downstream HLF. Downregulated miR-200b-3p abrogated suppression on the cellular process, α-SMA and Col1A1 levels induced by knockdown of circCHD2. Enforced HLF reversed the effect induced by miR-200b-3p overexpression. Taken together, a loss of circCHD2/miR-200b-3p/HLF axis contributed to alleviate LC progression. The findings suggested that circCHD2 may have potential to be a therapeutic target of LC.

The role of circular RNA in Diabetic Nephropathy.

Diabetic nephropathy (DKD) is the most common chronic microvascular complication of diabetes. About 20%-40% of diabetics develop DKD, which eventually leads to chronic kidney failure. Although progress has been made in diagnosis and treatment tools, diabetic nephropathy is still a major clinical problem. In recent years, circular RNA (CircRNA) has become a research hotspot. CircRNA is a non-coding RNA formed by covalently closing the 5 'and 3' ends of the precursor RNA. CircRNA has powerful biological functions. CircRNA can regulate the expression of target genes through competitive binding with microRNA, thus playing the biological role of endogenous RNA (CeRNA). Many studies have shown that circRNAs plays an important role in malignant tumors, autoimmune system diseases, coronary heart disease and other diseases. More and more studies have shown that it can also be used as a biomarker of diabetes and diabetic nephropathy. This review summarizes the origin, classification, biogenesis and regulatory mechanisms of circRNAs. In addition, the pathogenesis and clinical significance of circRNAs as competing endogenous RNAs involved in diabetic nephropathy were also introduced. This will help us fully understand the pathological mechanism of diabetic nephropathy and develop new therapeutic targets or treatment options to improve the prognosis of patients with diabetic nephropathy.

CircRNAPTK2 Promotes Cardiomyocyte Apoptosis in Septic Mice by Competitively Binding to miR-29b-3p with BAK1

Objective: Sepsis is a predominant reason for the growing morbidity and mortality in the world. The role of circular RNAs (CircRNAs) is actively researched in sepsis. In this study, we attempt to find out the effect of CircRNA protein tyrosine kinase 2 (circPTK2) on cardiomyocyte apoptosis in septic mice. Methods: Septic mouse model was established by cecal ligation and puncture. Then circPTK2 expression was detected and the role of circPTK2 in myocardial damage was assessed after circPTK2 expression was silenced using Ad-sh-circHIPK3. The subcellular localization of circPTK2 was analyzed. Besides, the binding relation between circPTK2 and microRNA (miR)-29b-3p and between miR-29b-3p and BCL2 antagonist/killer 1 (BAK1) was verified. The expression of miR-29b-3p and BAK1 in the myocardium was detected. Functional rescue was conducted to evaluate the role of miR-29b-3p and BAK1 in cardiomyocyte apoptosis in septic mice. Results: CircPTK2 was highly expressed in the myocardium of septic mice, while circPTK2 silencing relieved the cardiac function and reduced inflammatory reaction and cardiomyocyte apoptosis of septic mice. Mechanically, circPTK2 competitively bound to miR-29b-3p to upregulate BAK1 mRNA level. Inhibition of miR-29b-3p and BAK1 overexpression could counteract the protective role of circPTK2 silencing in the myocardium of septic mice. Conclusion: CircPTK2 is overexpressed in the myocardium of septic mice. CircPTK2 competitively bound to miR-29b-3p to upregulate BAK1 mRNA level, to promote cardiomyocyte apoptosis, inflammatory response, and myocardial damage of the myocardium of septic mice.

Role of circular RNAs in gastrointestinal tumors and drug resistance.

The incidence of gastrointestinal cancers has increased significantly over the past decade and gastrointestinal malignancies now rank among the leading causes of mortality globally. Although newer therapeutic strategies such as targeted therapies have greatly improved patient outcomes, their clinical success is limited by drug resistance, treatment failure and recurrence of metastatic disease. Therefore, there is an urgent need for further research identifying accurate and reliable biomarkers for precise treatment strategies. Circular RNAs (circRNAs) exhibit a covalently closed structure, high stability and biological conservation, and their expression is associated with the occurrence and development of gastrointestinal tumors. Moreover, circRNAs may significantly influence drug resistance of gastrointestinal cancers. In this article, we review the role of circRNAs in the occurrence and development of gastrointestinal cancer, their association with drug resistance, and potential application for early diagnosis, treatment and prognosis in gastrointestinal malignancies. Furthermore, we summarize characteristics of circRNA, including mechanism of formation and biological effects via mRNA sponging, chromatin replication, gene regulation, translational modification, signal transduction, and damage repair. Finally, we discuss whether circRNA-related noninvasive testing may be clinically provided in the future. This review provides new insights for the future development of diagnostics and therapeutics based on circRNAs in gastrointestinal tumors.

Ginsenoside Rg3 inhibits osteosarcoma progression by reducing circ_0003074 expression in a miR-516b-5p/KPNA4-dependent manner

BackgroundPrevious data have suggested that ginsenoside Rg3 (Rg3), isolated from the roots of Panax ginseng, plays a repressing role in multiple cancers, including osteosarcoma (OS). However, there is no any literature available about the role of circular RNA (circRNA) in Rg3-mediated OS development. The study aimed to explore the function of circ_0003074 in the anti-cancer effects of Rg3 on OS.MethodsRNA expression of circ_0003074, miR-516b-5p and karyopherin subunit alpha 4 (KPNA4) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was evaluated by Western blotting or immunohistochemistry assay. Cell viability, proliferation, apoptosis, migration and invasion were investigated by cell counting kit-8, 5-ethynyl-29-deoxyuridine (EdU), flow cytometry analysis, wound-healing and transwell invasion assays, respectively. Dual-luciferase reporter and/or RNA immunoprecipitation assay was performed to confirm the interplay between miR-516b-5p and circ_0003074 or KPNA4. Xenograft mouse model assay was conducted to reveal the effect of Rg3 treatment on tumor formation.ResultsCirc_0003074 and KPNA4 expression was significantly upregulated, while miR-516b-5p was downregulated in OS tissues and cells compared with controls. Rg3 treatment dramatically decreased circ_0003074 expression in OS cells. Rg3 treatment led to decreased cell proliferation, migration and invasion but increased cell apoptosis, which was attenuated after circ_0003074 overexpression. Besides, miR-516b-5p was a target miRNA of circ_0003074 and partially restored circ_0003074-mediated action under Rg3 treatment. Decreasing miR-516b-5p expression also promoted Rg3-treated OS cell malignancy through KPNA4, which was identified as a target mRNA of miR-516b-5p. Besides, circ_0003074 induced KPNA4 production owing to the decrease of miR-516b-5p expression. Furthermore, Rg3 treatment inhibited tumor formation by regulating circ_0003074 in vivo.ConclusionRg3 inhibited OS progression through circ_0003074/miR-516b-5p/KPNA4 axis, showing the potential of Rg3 as a therapeutic agent for OS.

Circular RNA circSNX6 promotes sunitinib resistance in renal cell carcinoma through the miR-1184/GPCPD1/ lysophosphatidic acid axis.

Sunitinib resistance is a major challenge in systemic therapy for renal cell carcinoma (RCC). The role of circular RNAs (circRNAs) in regulating sunitinib resistance of RCC is largely unknown. We established sunitinib-resistant RCC cell lines in vivo. Through RNA-sequencing, we identified circSNX6, whose expression is upregulated in sunitinib-resistant cells compared with their parental cells. High circSNX6 expression was correlated with sunitinib resistance and worse oncologic outcomes in a cohort of 81 RCC patients. In vitro and in vivo experiments confirmed that circSNX6 could promote sunitinib resistance in RCC. circSNX6 acts as a molecular "sponge" to relieve the suppressive effect of microRNA (miR)-1184 on its target gene, glycerophosphocholine phosphodiesterase 1 (GPCPD1), which increases intracellular lysophosphatidic acid (LPA) levels and, ultimately, promotes sunitinib resistance in RCC cells. Our findings demonstrated that the circSNX6/miR-1184/GPCPD1 axis had a critical role in regulation of intracellular LPA levels and sunitinib resistance in RCC; they also provide a novel prognostic indicator and promising therapeutic targets.

Hsa_Circ_0001860 Promotes Smad7 to Enhance MPA Resistance in Endometrial Cancer via miR-520h.

Background: Medroxyprogesterone acetate (MPA) is one of the most commonly prescribed progestin for the treatment of endometrial cancer (EC). Despite initial benefits, many patients ultimately develop progesterone resistance. Circular RNA (circRNA) is a kind of noncoding RNA, contributing greatly to the development of human tumor. However, the role of circular RNA in MPA resistance is unknown. Methods: We explored the expression profile of circRNAs in Ishikawa cells treated with (ISK/MPA) or without MPA (ISK) by RNA sequencing, and identified a key circRNA, hsa_circ_0001860. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to verify its expression in MPA-resistant cell lines and tissues. CCK8, Transwell, and flow cytometry were used to evaluate the functional roles of hsa_circ_0001860 in MPA resistance. The interaction between hsa_circ_0001860 and miR-520 h was confirmed by bioinformatics analysis, luciferase reporter assay, and RNA pull-down assay. Results: The expression of hsa_circ_0001860 was significantly downregulated in MPA-resistant cell lines and tissues, and negatively correlated with lymph node metastasis and histological grade of EC. Functional analysis showed that hsa_circ_0001860 knockdown by short hairpin RNA (shRNA) promoted the proliferation, inhibited the apoptosis of Ishikawa cells, and promoted the migration and invasion of Ishikawa cells treated with MPA. Mechanistically, hsa_circ_0001860 promoted Smad7 expression by sponging miR-520 h. Conclusion: Hsa_circ_0001860 plays an important role in the development of MPA resistance in EC through miR-520h/Smad7 axis, and it could be targeted to reverse the MPA resistance in endometrial cancer.

The Role of Circular RNAs in DNA Damage Response and Repair.

Simple SummaryThe role of non-coding RNA, and particularly of circular RNA, in the DNA damage response and repair network is underappreciated. Given the vital role of this network in preserving the genomic integrity and consequently cellular homeostasis, the constantly increasing numbers of discovered circular RNAs and the increasing implication of these molecules in the function of this network unravel a new important field that may open new therapeutic opportunities, but also require detailed investigation.Circular RNAs (circRNA) comprise a distinct class of non-coding RNAs that are abundantly expressed in the cell. CircRNAs have the capacity to regulate gene expression by interacting with regulatory proteins and/or other classes of RNAs. While a vast number of circRNAs have been discovered, the majority still remains poorly characterized. Particularly, there is no detailed information on the identity and functional role of circRNAs that are transcribed from genes encoding components of the DNA damage response and repair (DDRR) network. In this article, we not only review the available published information on DDRR-related circRNAs, but also conduct a bioinformatic analysis on data obtained from public repositories to uncover deposited, yet uncharacterized circRNAs derived from components of the DDRR network. Finally, we interrogate for potential targets that are regulated by this class of molecules and look into potential functional implications.

New perspectives on the roles of circular RNAs in osteoarthritis development and progression (Review).

Osteoarthritis (OA) is a common disease of the elderly, posing a major personal and socioeconomic burden. OA is characterized by painful degeneration of articular cartilage, and its prevention, diagnosis and treatment remain problematic. Circular RNAs (circRNAs) constitute a large family of non-coding RNAs that are widely distributed, stable, conserved and tissue-specific. circRNAs have been found to be closely associated with OA development and progression, and they may serve as targets for disease prevention and treatment. The aim of the present article was to review the roles of circRNAs in OA and discuss possible treatment strategies.

CircSOD2: A Novel Regulator for Smooth Muscle Proliferation and Neointima Formation.

Vascular smooth muscle cell (SMC) proliferation contributes to neointima formation following vascular injury. Circular RNA-a novel type of noncoding RNA with closed-loop structure-exhibits cell- and tissue-specific expression patterns. However, the role of circular RNA in SMC proliferation and neointima formation is largely unknown. The objective of this study is to investigate the role and mechanism of circSOD2 in SMC proliferation and neointima formation. Approach and Results: Circular RNA profiling of human aortic SMCs revealed that PDGF (platelet-derived growth factor)-BB up- and downregulated numerous circular RNAs. Among them, circSOD2, derived from back-splicing event of SOD2 (superoxide dismutase 2), was significantly enriched. Knockdown of circSOD2 by short hairpin RNA blocked PDGF-BB-induced SMC proliferation. Inversely, circSOD2 ectopic expression promoted SMC proliferation. Mechanistically, circSOD2 acted as a sponge for miR-206, leading to upregulation of NOTCH3 (notch receptor 3) and NOTCH3 signaling, which regulates cyclin D1 and CDK (cyclin-dependent kinase) 4/6. In vivo studies showed that circSOD2 was induced in neointima SMCs in balloon-injured rat carotid arteries. Importantly, knockdown of circSOD2 attenuated injury-induced neointima formation along with decreased neointimal SMC proliferation. CircSOD2 is a novel regulator mediating SMC proliferation and neointima formation following vascular injury. Therefore, circSOD2 could be a potential therapeutic target for inhibiting the development of proliferative vascular diseases.

Circ-SFMBT2 drives the malignant phenotypes of esophageal cancer by the miR-107-dependent regulation of SLC1A5

BackgroundIncreasing studies focused on the regulatory roles of circular RNAs (circRNAs) in diverse cancers. This study was to evaluate the function and mechanism of circRNA Scm-like with four malignant brain tumor domains 2 (circ-SFMBT2) in esophageal cancer (EC).MethodsThe circ-SFMBT2, microRNA-107 (miR-107) and solute-linked carrier family A1 member 5 (SLC1A5) levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was evaluated by 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) assay, colony formation assay and EdU assay. Cell apoptosis and invasion were detected by flow cytometry and transwell assay. Glutamine metabolism was assessed by the corresponding kits for glutamine consumption, α-ketoglutarate production and glutamate production. Western blot was used for protein quantification. The binding analysis was performed using dual-luciferase reporter assay, RNA immunoprecipitation (RIP) and pull-down assays. The functional research of circ-SFMBT2 in vivo was performed by xenograft tumor assay. Exosomes were identified by morphological observation and protein detection.ResultsCirc-SFMBT2 was overexpressed in EC samples and cells. Circ-SFMBT2 downregulation inhibited EC cell proliferation, invasion and glutamine metabolism. Circ-SFMBT2 targeted miR-107 and the regulation of circ-SFMBT2 was achieved by sponging miR-107. SLC1A5 was a target of miR-107, and it worked as an oncogene in EC cells. MiR-107 retarded the EC progression by downregulating SLC1A5. Circ-SFMBT2 could affect the SLC1A5 expression by targeting miR-107. Circ-SFMBT2 regulated EC progression in vivo by miR-107/SLC1A5 axis. Circ-SFMBT2 was transferred by exosomes in EC cells.ConclusionThese results suggested that circ-SFMBT2 upregulated the SLC1A5 expression to promote the malignant development of EC by serving as a miR-107 sponge.

Role of circular RNAs in osteoarthritis (Review).

Osteoarthritis (OA) is a chronic bone and joint disease characterized by articular cartilage degeneration and joint inflammation. OA is the most common form of arthritis, and the major clinical manifestations of OA are chronic pain and joint activity disorder, which severely affect patients' quality of life. Circular RNA (circRNA) is a type of non-coding RNA that is ubiquitous in eukaryotic cells. Unlike standard linear RNAs, they form a covalently closed continuous loop without 5' or 3' polarity. They are usually considered as byproducts of mis-splicing or mRNA processing. CircRNAs have been detected and identified in numerous species. Various studies have confirmed that certain circRNAs are differentially expressed in OA cartilage and are closely associated with a variety of pathological processes of OA, including extracellular matrix degradation, inflammation and apoptosis. The present study reviewed the latest research on circRNAs in the pathogenesis of OA, providing a novel direction for the prevention, diagnosis and treatment of OA.

Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription

Intrahepatic cholangiocarcinoma (ICC) is a primary liver cancer with high aggressiveness and extremely poor prognosis. The role of circular RNAs (circRNAs) in ICC carcinogenesis and progression remains to be determined. CircRNA microarray was performed to screen significantly upregulated circRNAs in paired ICC and non-tumor tissues. Colony formation, transwell, and xenograft models were used to examine the role of circRNAs in ICC proliferation and metastasis. RNA pulldown, mass spectrometry, chromatin immunoprecipitation, RNA-binding protein immunoprecipitation, chromatin isolation by RNA purification, electrophoretic mobility shift assay, and luciferase reporter assays were used to explore the molecular sponge role of the circRNA (via miRNA binding), and the interaction between circRNA and RNA-binding proteins. Hsa_circ_0050898, which originated from exon 1 to exon 20 of the ACTN4 gene (named circACTN4), was significantly upregulated in ICC. High circACTN4 expression was associated with enhanced tumor proliferation and metastasis invitro and invivo, as well as a worse prognosis following ICC resection. In addition, circACTN4 upregulated Yes-associated protein 1 (YAP1) expression by sponging miR-424-5p. More importantly, circACTN4 also recruited Y-box binding protein 1 (YBX1) to stimulate Frizzled-7 (FZD7) transcription. Furthermore, circACTN4 overexpression in ICC cells enhanced the interaction between YAP1 and β-catenin, which are the core components of the Hippo and Wnt signaling pathways, respectively. CircACTN4 was upregulated in ICC and promoted ICC proliferation and metastasis by acting as a molecular sponge of miR-424-5p, as well as by interacting with YBX1 to transcriptionally activate FZD7. These results suggest that circACTN4 is a potential prognostic marker and therapeutic target for ICC. Intrahepatic cholangiocarcinoma is a primary liver cancer associated with aggressiveness and extremely poor prognosis. It is essential for therapeutic development that we uncover relevant pathogenic pathways. Herein, we showed that a circular RNA (circACTN4) was highly expressed in intrahepatic cholangiocarcinoma and was positively associated with tumor growth and metastasis through key developmental signaling pathways. Thus, circACTN4 could be a prognostic biomarker and therapeutic target for intrahepatic cholangiocarcinoma.

CircRNA pappalysin 1 facilitates prostate cancer development through miR-515-5p/FKBP1A axis.

The role of circular RNA (circRNA) pappalysin 1 (circ-PAPPA; hsa_circ_0088233) in prostate cancer (PCa) cells was explored in the current study. Circ-PAPPA abundance was markedly enhanced in PCa. Circ-PAPPA interference restrained cell viability, proliferation, motility and glycolysis while elevated the apoptosis rate of PCa cells. Circ-PAPPA negatively regulated microRNA-515-5p (miR-515-5p) abundance. MiR-515-5p silencing largely diminished circ-PAPPA knockdown-mediated effects in PCa cells. MiR-515-5p directly bound to FKBP prolyl isomerase 1A (FKBP1A). MiR-515-5p overexpression-mediated impacts were partly counteracted by FKBP1A overexpression. Circ-PAPPA silencing reduced FKBP1A protein level partly by elevating miR-515-5p expression. Circ-PAPPA knockdown significantly restrained the tumour growth in vivo. Circ-PAPPA elevated the malignant phenotypes of PCa cells by sequestering miR-515-5p to induce the expression of FKBP1A.

Spatiotemporal Regulation and Functional Analysis of Circular RNAs in Skeletal Muscle and Subcutaneous Fat during Pig Growth

Simple SummaryThis study provides a clear and accurate dynamic profile of circRNAs in skeletal muscle and subcutaneous fat of Ningxiang pig. The results include high-quality genomic data, and help to elucidate the roles of circRNAs in regulation of protein and lipid synthesis and metabolism providing new ideas for further understanding of the molecular mechanisms governing pork quality traits. Recently, thousands of circular RNAs have been reported in different pig breeds. However, researches on the temporal and spatial expression patterns of circRNA over the period of animal growth are limited. Here, we systematically analyzed circRNAs in skeletal muscle and subcutaneous fat in four growth time points (30 days, 90 days, 150 days and 210 days after birth) of a Chinese native pig breed, Ningxiang pigs. A total of 1171 differentially expressed (DE) circRNAs between muscle and fat were identified, including 562 upregulated and 609 downregulated circRNAs. KEGG pathway enrichment analysis of these DE circRNAs revealed that host genes were mainly involved in glycogen metabolism signaling pathways, muscle development signaling pathways such as ErbB pathway and adipocytokine signaling pathways and AMPK signaling pathways and fatty acid biosynthesis. The circRNAs have striking spatiotemporal specificity in the form of dynamic expression at 90 d. Short Time-Series Expression Miner analysis showed multiple model spectra that are significantly enriched with time changes in muscle and fat. Our findings provide new ideas and perspectives about the role of circular RNAs and their targeting relations with mRNA and miRNA in skeletal muscle and fat tissue during pig growth.

Roles of circular RNAs in the pathogenesis of intervertebral disc degeneration (Review).

Lower back pain (LBP) is an extremely common symptom and is recognized as a leading contributor to disability and disease burden globally. Intervertebral disc degeneration (IDD) represents a major cause of LBP. However, the molecular mechanisms involved in the pathogenesis of IDD remain unclear, and currently available treatments, including conservative and surgical options, fail to effectively delay, stop or reverse the progression of IDD. Circular RNAs (circRNAs) are a newly discovered group of covalently closed, single-stranded and endogenous non-coding RNAs. A growing body of research has revealed that a number of circRNAs are widely and aberrantly expressed in IDD tissues. Furthermore, they play important roles in the pathogenesis of IDD, including proliferation, apoptosis, senescence, mitophagy, inflammation and extracellular matrix metabolism, mainly by acting as sponges for microRNAs. The present review aims to summarize the current understanding on the mechanisms of circRNA-mediated regulation in IDD.

The Role of Circular RNAs in Keratinocyte Carcinomas.

Simple SummaryKeratinocyte carcinomas include BCC and cSCC and represent the most frequent cancer among fair-skinned people. Tumor development is associated with mutations and dysregulation of many genes involved in biological processes such as cell proliferation, differentiation and apoptosis. The expression of these genes is controlled in many ways, including transcriptional and post-transcriptional control by circular RNAs. In recent studies, a number of circular RNAs have been identified that are dysregulated in BCC and cSCC. Biological functions relevant to tumor development were shown for some of these circRNAs, which may represent biomarkers for disease progression and targets for novel treatment approaches.Keratinocyte carcinomas (KC) include basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC) and represents the most common cancer in Europe and North America. Both entities are characterized by a very high mutational burden, mainly UV signature mutations. Predominately mutated genes in BCC belong to the sonic hedgehog pathway, whereas, in cSCC, TP53, CDKN2A, NOTCH1/2 and others are most frequently mutated. In addition, the dysregulation of factors associated with epithelial to mesenchymal transition (EMT) was shown in invasive cSCC. The expression of factors associated with tumorigenesis can be controlled in several ways and include non-coding RNA molecules, such as micro RNAs (miRNA) long noncoding RNAs (lncRNA) and circular RNAs (circRNA). To update findings on circRNA in KC, we reviewed 13 papers published since 2016, identified in a PubMed search. In both BCC and cSCC, numerous circRNAs were identified that were differently expressed compared to healthy skin. Some of them were shown to target miRNAs that are also dysregulated in KC. Moreover, some studies confirmed the biological functions of individual circRNAs involved in cancer development. Thus, circRNAs may be used as biomarkers of disease and disease progression and represent potential targets of new therapeutic approaches for KC.