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Background: Circular RNAs play an important role in the development of gastric cancer (GC). circ-low-density lipoprotein receptor class A domain containing 3 (LDLRAD3) has been confirmed to be related to GC progression. miR-137 is also a suppressor in GC. However, the impact of the interaction between circ-LDLRAD3 and miR-137 on the progression of GC remains unclear at present., Methods: The study identified expression level differences of circ-LDLRAD3, miR-137, and COL4A5 in GC pathological specimens compared to normal tissue samples. Furthermore, through in vitro experiments, including flow cytometry, cell counting kit-8 (CCK-8) assays, wound healing, Western blotting, and colony formation assays, we further explored the molecular regulatory mechanisms by which these factors promote the progression of GC., Results: In this study, circ-LDLRAD3 was confirmed to have higher expression, and miR-137 had lower expression in GC tissues and cell lines. circ-LDLRAD3 knockdown and miR-137 overexpression promoted apoptosis and inhibited proliferation, migration, and invasion in GC cell lines. Further experiments validated that COL4A5 had a positive relationship with GC and that circ-LDLRAD3 promoted the expression of COL4A5. circ-LDLRAD3 could be sponged and inhibited by miR-137 in GC cells. As a result, the promotional effect of circ-LDLRAD3 on COL4A5 was counteracted by miR-137., Conclusion: Our study showed that the knockdown of circ-LDLRAD3 suppressed the development of GC by regulating the miR-137/COL4A5 axis., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Metastasis is a major contributor to treatment failure and death in urological cancers, representing an important biomedical challenge at present. Metastases form as a result of cancer cells leaving the primary site, entering the vasculature and lymphatic vessels, and colonizing clones elsewhere in the body. However, the specific regulatory mechanisms of action underlying the metastatic process of urological cancers remain incompletely elucidated. With the deepening of research, circular RNAs (circRNAs) have been found to not only play a significant role in tumor progression and prognosis but also show aberrant expression in various tumor metastases, consequently impacting tumor metastasis through multiple pathways. Therefore, circRNAs are emerging as potential tumor markers and treatment targets. This review summarizes the research progress on elucidating how circRNAs regulate the urological cancer invasion-metastasis cascade response and related processes, as well as their role in immune microenvironment remodeling and circRNA vaccines. This body of work highlights circRNA regulation as an emerging therapeutic target for urological cancers, which should motivate further specific research in this regard., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Circular RNAs are a class of noncoding RNAs with covalently linked 5' and 3' ends that arise from backsplicing events. The absence of a 5' cap and a 3' poly(A) tail makes circular RNAs relatively more stable than their linear counterparts. They are evolutionary conserved and tissue-specific, and some show disease-specific expression patterns. Although their biological functions remain largely unknown, circular RNAs have been shown to play regulatory roles by acting as microRNA sponges, regulators of RNA-binding proteins, alternative splicing, and parental gene expression, and they could even encode proteins. Over the past few decades, circular RNAs have attracted wide attention in oncology owing to their implications in various tumors. Many circular RNAs have been characterized as key players in gastrointestinal cancers and influence cancer growth, progression, metastasis, and therapeutic resistance. Accumulating evidence reveals that their unique characteristics, coupled with their critical roles in tumorigenesis, make circular RNAs promising non-invasive clinical biomarkers for gastrointestinal cancers. In the present review, we summarized the biological roles of the emerging circular RNAs and their potential as biomarkers and therapeutic targets, which may help better understand their clinical significance in the management of gastrointestinal cancers., (© 2024 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Circular RNA (circRNA) has been found to mediate ulcerative colitis (UC) progression by regulating intestinal mucosal barrier function. However, the role of circSOD2 in UC process and its underlying molecular mechanism still need to be further elucidated., Methods: Lipopolysaccharide (LPS)-induced Caco2 cells were used to mimic UC cell models. CircSOD2, miR-378g, and Snail1 levels were determined by quantitative real-time PCR. Cell viability was detected using MTT assay, and inflammatory cytokine levels were measured using ELISA. The intestinal mucosal barrier function was evaluated by testing transepithelial electrical resistance and fluorescein isothiocyanate (FITC)-dextran permeability. Snail1 and tight junction-related markers (Zo-1 and Claudin2) protein levels were examined using western blot. The interaction between miR-378g and circSOD2 or Snail1 was confirmed by dual-luciferase reporter assay. Dextran sulfate sodium (DSS) was used to induce UC rat models in vivo., Results: CircSOD2 was overexpressed in UC patients, and its knockdown significantly increased cell viability, transepithelial electrical resistance, and tight junction-related protein expression, while reduced inflammation cytokine levels and the permeability of FITC-dextran in LPS-induced Caco2 cells. In terms of mechanism, circSOD2 sponged miR-378g to positively regulate Snail1 expression. MiR-378g inhibitor reversed the effect of circSOD2 knockdown on intestinal mucosal barrier injury and Snail1 expression in LPS-induced Caco2 cells. In DSS-induced UC rat models, circSOD2 knockdown also could repair the intestinal mucosal barrier injury through regulating miR-378g/Snail1 axis., Conclusion: CircSOD2 could destroy intestinal mucosal barrier function in LPS-induced Caco2 cells and DSS-induced UC rats by miR-378g/Snail1 axis., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Spinal cord injury (SCI) is a serious central nervous system disease with high disability and mortality rates and complex pathophysiologic mechanisms. MicroRNA (miRNA), as a kind of non-coding RNA, plays an important role in SCI. miRNA is involved in the regulation of inflammatory response, oxidative stress, axonal regeneration, and apoptosis after SCI, and interacts with long non-coding RNA (lncRNA) and circular RNA (circRNA) to regulate the pathophysiological process of SCI. This paper summarizes the changes in miRNA expression after SCI, and reviews the targeting mechanism of miRNA in SCI and the current research status of miRNA-targeted drugs to provide new targets and new horizons for basic and clinical research on SCI.

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck tumor that is influenced by a variety of molecular factors during its pathogenesis. Among these, the phosphatase and tensin homolog (PTEN) plays a crucial role in regulatory networks. This article systematically reviews the multifaceted functions of PTEN in NPC, including its roles in inhibiting cell proliferation, regulating migration and invasion, promoting autophagy and apoptosis, and influencing resistance to radiotherapy. Molecular factors such as long non-coding RNA, microRNA (miRNA), and circular RNA can modulate PTEN through various pathways, thereby impacting the biological behavior of NPC. In addition, PTEN is involved in regulating the tumor microenvironment of NPC, and its interaction with the Epstein-Barr virus has also recently become a focus of research. A comprehensive understanding of the PTEN regulatory network provides a foundation for future personalized and targeted therapeutic strategies. This study expands our understanding of the pathogenesis of NPC and suggests new directions in the field of tumor biology and NPC treatment., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Atherosclerosis (AS) is a chronic inflammatory vascular disease that begins with endothelial activation followed by a series of inflammatory responses, plaque formation, and finally rupture. An early event in endothelial dysfunction is activation of the nuclear factor-κB (NF-κB) signaling axis. Toll-like receptors (TLRs) in endothelial cells (ECs) play an essential role in recognizing pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and lifestyle-associated molecular patterns (LAMPs). Activation of the canonical NF-κB pathway stimulates the expression of cytokines, chemokines, and an array of additional genes which activate and amplify AS-associated inflammatory responses. In this review, we discuss the involvement of TLR2/4 and NF-κB signaling in ECs during AS initiation, as well as regulation of the inflammatory response during AS by noncoding RNAs, especially microRNA (miRNA) and circular RNA (circRNA)., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Background: The mechanotransduction mechanisms by which cells regulate tissue remodeling are not fully deciphered. Circular RNAs (circRNAs) are crucial to various physiological processes, including cell cycle, differentiation, and polarization. However, the effects of mechanical force on circRNAs and the role of circRNAs in the mechanobiology of differentiation and remodeling in stretched periodontal ligament stem cells (PDLSCs) remain unclear. This article aims to explore the osteogenic function of mechanically sensitive circular RNA protein kinase D3 (circPRKD3) and elucidate its underlying mechanotransduction mechanism., Materials and Methods: PDLSCs were elongated with 8% stretch at 0.5 Hz for 24 h using the Flexcell® FX-6000™ Tension System. CircPRKD3 was knockdown or overexpressed with lentiviral constructs or plasmids. The downstream molecules of circPRKD3 were predicted by bioinformatics analysis. The osteogenic effect of related molecules was evaluated by quantitative real-time PCR (qRT-PCR) and western blot., Results: Mechanical force enhanced the osteogenesis of PDLSCs and increased the expression of circPRKD3. Knockdown of circPRKD3 hindered PDLSCs from osteogenesis under mechanical force, while overexpression of circPRKD3 promoted the early osteogenesis process of PDLSCs. With bioinformatics analysis and multiple software predictions, we identified hsa-miR-6783-3p could act as the sponge of circPRKD3 to indirectly regulate osteogenic differentiation of mechanically stimulated PDLSCs., Conclusions: Our results first suggested that both circPRKD3 and hsa-miR-6783-3p could enhance osteogenesis of stretched PDLSCs. Furthermore, hsa-miR-6783-3p could sponge circPRKD3 to indirectly regulate RUNX2 during the periodontal tissue remodeling process in orthodontic treatment., (© 2024. The Author(s).)

The dynamic balance between bone formation and bone resorption is a critical process of bone remodeling. The imbalance of bone formation and bone resorption is closely associated with the occurrence and development of various bone-related diseases. Under both physiological and pathological conditions, non-coding RNAs (ncRNAs) play a crucial regulatory role in protein expression through either inhibiting mRNAs translation or promoting mRNAs degradation. Circular RNAs (circRNAs) are a type of non-linear ncRNAs that can resist the degradation of RNA exonucleases. There is accumulating evidence suggesting that circRNAs and microRNAs (miRNAs) serve as critical regulators of bone remodeling through their direct or indirect regulation of the expression of osteogenesis-related genes. Additionally, recent studies have revealed the involvement of the circRNAs-miRNAs regulatory network in the process by which mesenchymal stem cells (MSCs) differentiate towards the osteoblasts (OB) lineage and the process by which bone marrow-derived macrophages (BMDM) differentiate towards osteoclasts (OC). The circRNA-miRNA network plays an important regulatory role in the osteoblastic-osteoclastic balance of bone remodeling. Therefore, a thorough understanding of the circRNA-miRNA regulatory mechanisms will contribute to a better understanding of the regulatory mechanisms of the balance between osteoblastic and osteoclastic activities in the process of bone remodeling and the diagnosis and treatment of related diseases. Herein, we reviewed the functions of circRNA and microRNA. We also reviewed their roles in and the mechanisms of the circRNA-miRNA regulatory network in the process of bone remodeling. This review provides references and ideas for further research on the regulation of bone remodeling and the prevention and treatment of bone-related diseases., Competing Interests: 利益冲突　所有作者均声明不存在利益冲突, (© 2024《四川大学学报（医学版）》编辑部 版权所有Copyright ©2024 Editorial Board of Journal of Sichuan University (Medical Sciences).)

Problem: Preeclampsia (PE) is an obstetric disease involving multiple systems, which account for maternal and fetal complications and increased mortality. Circular RNAs (circRNAs) were recently deemed to associate with the pathogenesis of PE. This study aims to clarify the correlation between circRNA hsa_circ_0001326 and PE and explore its biological function in PE., Method of Study: The expression of hsa_circ_0001326 in PE placentas was detected by real-time quantitative PCR (qRT-PCR). After overexpressing or inhibiting hsa_circ_0001326 in trophoblast cells, the cell growth, migration, and invasion were evaluated by Cell Counting Kit-8 (CCK-8) and transwell assays. Western blot assay was applied to detect the epithelial-mesenchymal transition (EMT) proteins, E-cadherin and Vimentin. Furthermore, a dual-luciferase reporter assay was applied to verify the binding sites of hsa_circ_0001326, miR-145-5p, and transforming growth factor beta 2 (TGFB2)., Results: Hsa_circ_0001326 was found to be higher expressed in PE placentas than in normal placentas. Furthermore, hsa_circ_0001326 played a negative regulating role in trophoblast cell viability, migration, and invasion. Overexpression of hsa_circ_0001326 inhibited the viability, migration, and invasion of trophoblast cells, while inhibition of hsa_circ_0001326 showed opposite effects. Mechanistically, hsa_circ_0001326 sponged miR-145-5p to elevate TGFB2 expression in trophoblast cells., Conclusion: This study provided evidence that the up-regulated hsa_circ_0001326 in PE restrained trophoblast cells proliferation, migration, and invasion by sponging miR-145-5p to elevate TGFB2 expression. Our results might provide a novel insight into the role of hsa_circ_0001326 in the pathogenesis of PE., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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-β-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., (Copyright © 2022. Published by Elsevier Inc.)

CircRNA circ-PRDM5 (PR/SET domain 5) (circ-PRDM5) is overexpressed in age-related cataracts. Nevertheless, the biological role of circ-PRDM5 in posterior capsule opacities (PCO) (a common complication after cataract surgery) is unclear. Human lens epithelial cells SRA01/04 (LECs) were stimulated with TGF-β2 (transforming growth factor beta-2) to mimic the PCO model in vitro. Cell viability, migration, and invasion were determined by MTT, transwell, or wound-healing assays. Protein levels of EMT (epithelial-to-mesenchymal transition) markers and COL1A2 (collagen type I alpha 2 chain) were analyzed by western blotting (WB). Relative expression of circ-PRDM5, miR-92b-3p, and COL1A2 mRNA was analyzed by qRT-PCR. The targeting relationship was confirmed by dual-luciferase reporter and RIP assays. We observed that circ-PRDM5 and COL1A2 were upregulated in PCO tissues and TGF-β2-treated LECs, while miR-92b-3p was downregulated. Both circ-PRDM5 and COL1A2 knockdown impaired TGF-β2-induced LEC migration, invasion, and EMT. Also, circ-PRDM5 could adsorb miR-92b-3p to regulate COL1A2 expression. Furthermore, miR-92b-3p inhibitor offset circ-PRDM5 knockdown-mediated influence on migration, invasion, and EMT of LECs under TGF-β2 stimulation. Also, COL1A2 overexpression overturned the repressive influence of miR-92b-3p mimic on TGF-β2-induced LEC migration, invasion, and EMT. In summary, TGF-β2-induced circ-PRDM5 facilitated LEC migration, invasion, and EMT by adsorbing miR-92b-3p and increasing COL1A2 expression, offering new insights into the development of PCO., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

The SQUAMOSA promoter-binding protein-like (SPL) family play a key role in guiding the switch of plant growth from juvenile to adult phases. Populus euphratica Oliv. exhibit typical heterophylly, and is therefore an ideal model for studying leaf shape development. To investigate the role and regulated networks of SPLs in the morphogenesis of P. euphratica heteromorphic leaves. In this study, 33 P. euphratica SPL (PeuSPL) genes were identified from P. euphratica genome and transcriptome data. Phylogenetic analysis depicted the classification of these SPL genes into two subgroups. The expression profiles and regulatory networks of P. euphratica SPL genes analysis displayed that major P. euphratica SPL family members gradually increases from linear to broad-ovate leaves, and they were involved in the morphogenesis regulation, stress response, transition from vegetative to reproductive growth, photoperiod, and photosynthesis etc. 14 circRNAs, and 33 lncRNAs can promote the expression of 12 of the P. euphratica SPLs by co-decoying miR156 in heteromorphic leaf morphogenesis. However, it was found that the effect of PeuSPL2-4 and PeuSPL9 in leaf shape development was contrasting to their homologous genes of Arabidopsis. Therefore, it was suggested that the SPL family were evolutionarily conserved for regulation growth, but were varies in different plant for regulation of the organ development., (© 2022. The Author(s).)

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder among reproductive-age women. The mechanism by which circular RNA (circRNA) drives PCOS development remains unclear. Thus, the study is designed to explore the role of a novel circRNA, circ_FURIN, in the PCOS cell model and the underlying mechanism., Methods: PCOS cell model was established by treating human ovarian granulosa-like tumor cells (KGN) with Testosterone (TTR). RNA expressions of circ_FURIN, microRNA-423-5p (miR-423-5p) and myotubularin 1 (MTM1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was checked by Western blot. Cell proliferation was investigated by a 5-Ethynyl-29-deoxyuridine assay, 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis for cell cycle. Apoptotic cells were quantified by flow cytometry analysis for cell apoptosis. The interplay between miR-423-5p and circ_FURIN or MTM1 was identified by dual-luciferase reporter and RNA pull-down assays., Results: Circ_FURIN and MTM1 expressions were significantly upregulated, whereas miR-423-5p was downregulated in the ovarian cortex tissues of PCOS patients and TTR-treated KGN cells compared with controls. Circ_FURIN depletion relieved TTR-induced proliferation inhibition and apoptosis promotion. Besides, knockdown of miR-423-5p, a target miRNA of circ_FURIN, rescued circ_FURIN knockdown-mediated effects under TTR treatment. MiR-423-5p remitted TTR-induced cell disorders by binding to MTM1. Moreover, circ_FURIN modulated MTM1 expression through miR-423-5p., Conclusion: Circ_FURIN silencing protected against TTR-induced dysfunction by the miR-423-5p/MTM1 pathway in human ovarian granulosa-like tumor cells., (© 2022. The Author(s).)

Acute myocardial infarction (AMI) is characterized by high morbidity and mortality rates. Circular RNAs collectively participate in the initiation and development of AMI. The purpose of this study was to investigate the role of circRbms1 in AMI. Ischemia-reperfusion (I/R) was performed to establish an AMI model. RT-qPCR and Western blotting were performed to detect mRNA and analyze protein expression, respectively. The interaction between miR-92a and circRbms1/BCL2L11 was confirmed by luciferase and RNA pull-down assays. circRbms1 is overexpressed in AMI. However, circRbms1 knockdown alleviated H9c2 cell apoptosis and reduced the release of reactive oxygen species. circRbms1 targeted miR-92a, the downregulation of which alleviated the effects of circRbms1 knockdown and increased oxidative stress and H9c2 cell apoptosis. Moreover, circRbms1 sponged miR-92a to upregulate BCL2L11, which modulated the expression of apoptosis-related genes. circRbms1 participated in myocardial I/R injury by regulating the miR-92a/BCL2L11 signaling pathway, which may provide a new strategy for the treatment of AMI.

Background: The role of estrogen receptor β (ERβ) in the pathogenesis and development of breast cancer (BC) is controversial, and it is currently considered to play contradictory roles in different phenotypes. ERβ2 is thought to promote the BC process, but its role in triple-negative breast cancer (TNBC) has not been reported., Methods: In this study, we collected tumor tissues from 15 patients with TNBC and obtained a variety of TNBC cell lines as research objects. The plasmid vectors and RNA interference techniques were used to change the level of target genes in cells, quantitative PCR and Western Blots were used to detect gene expression levels, CCK-8 and EdU assay were used to detect cell growth, and Transwell was used to detect cell migration and invasion. Dual-luciferase gene reports and RNA immunoprecipitation (RIP) were used to verify gene targeting relationships., Results: ERβ2 was up-regulated in TNBC tissues and promoted the growth, migration, and invasion of TNBC cells. ERβ2 regulated hsa_circ_0000732 expression by binding to SCARF1 promoter. Knockdown of hsa_circ_0000732 inhibited TNBC cell proliferation, migration, and invasion by upregulating miR-1184., Conclusion: Our present study found that ERβ2 is upregulated in some TNBC cells and promotes TNBC cell growth, migration and invasion by regulating hsa_circ_0000732 targeting miR-1184. The special role of ERβ2 in TNBC may be the breakthrough of a targeted treatment strategy for TNBC., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Circular RNAs (circRNAs) are non-coding RNAs with closed ends which makes them resistant to degrading enzyme RNAse R. These RNA molecules show cell, tissue or organ specific expression. Regulatory functions have been reported for a number of circRNAs. Particularly, they have been found to affect cell cycle and control cell proliferation. CircRNAs are involved in physiological processes like natural organ development. Their dysregulation in high-throughput technologies have been shown in a growing number of diseases especially many types of cancers such as renal cell carcinoma (RCC). Differentially expressed circRNAs in RCC tissues compared to normal tissues may affect carcinogenesis process. Overexpressed circRNAs promote tumorigenic functions of RCC cell lines while down-regulated transcripts repress them. Both dysregulated circRNAs are correlated with clinicopathological features, prognosis and survival in RCC patients which along with their acceptable diagnostic values suggest them as potential biomarkers in diagnosis or prediction of prognosis of RCC patients. In this review, we have assessed tumorigenic or tumor-suppressing effects of circRNAs and also their diagnostic and prognostic potentials in RCC., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Circular RNAs (circRNAs) are key regulators in the development of many cancers. The present study was aimed to investigate the mechanism by which circ_0007919 affected colorectal cancer (CRC) progression.The differentially expressed circRNA was screened out by analyzing the expression profile of circRNAs of CRC tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for detecting the expressions of circ_0007919, miR-942-5p, and ten-eleven translocation 1 (TET1) mRNA in CRC tissues and cell lines. Cell growth and migration were assessed by cell counting kit-8 (CCK-8) 5-bromo-2'-deoxyuridine (BrdU) and scratch assays. Bioinformatics analysis and dual-luciferase reporter assay were conducted to predict and validate the targeted relationships between circ_0007919 and miR-942-5p, as well as between miR-942-5p and TET1 mRNA. Besides, Western blot was conducted for detecting TET1 protein expression in CRC cells. It was revealed that, in CRC tissues and cell lines, circ_0007919 and TET1 expressions were reduced whereas miR-942-5p expression was enhanced. It was also revealed that circ_0007919 overexpression markedly suppressed CRC cell growth and migration. In addition, circ_0007919 could competitively bind with miR-942-5p to increase the expression of miR-942-5p's target gene TET1. Collectively, circ_0007919 inhibits CRC cell growth and migration via regulating the miR-942-5p/TET1 axis. This study helps to better understand the molecular mechanism of CRC progression., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Studies have confirmed that circular RNA (circRNA) has a stable closed structure, which plays an important role in the progression of tumors. Cancers with positive fusion genes can produce associated fusion circRNA (F-cirRNA). However, there are no reports concerning a role for F-circRNA of the echinoderm microtubule associated-protein like 4-anaplastic lymphoma kinase variant 1 (EML4-ALK1) in non-small cell lung cancer (NSCLC). Our study confirmed the existence of fusion circEA1 (F-circEA1) in NCI-H3122 cells (carrying the EML4-ALK1 gene), F-circEA1 was expressed both in the cytoplasm and nucleus as determined by fluorescence in situ hybridization (FISH) and Sanger sequencing. CCK8 and transwell assays showed that F-circEA1 was beneficial to cell proliferation, metastasis, and invasion. Overexpression of F-circEA1 can also promote cell proliferation, migration and invasion in A549 and SPCA1 cells (non-small cell lung cancer cell line not carrying the EML4-ALK1 gene). Interference with F-circEA1, induced cell cycle arrest and promoted apoptosis as determined by flow cytometry, and increased drug sensitivity to crizotinib in H3122 cells. F-circEA1 directly affected the expression of parental gene EML4-ALK1. Further research found that F-circEA1 can affect the downstream signaling pathway of ALK. In vivo, the growth rate of xenogeneic tumors was reduced and the protein expression level of EML4-ALK1 was significantly decreased in transplanted tumors measured by immunohistochemistry (IHC) after interference with F-circEA1. In conclusion, F-circEA1 can be considered as a proto-oncogene that regulates cell proliferation and apoptosis by affecting the expression of the parental gene EML4-ALK1 and its ALK downstream signaling pathway in non-small cell lung cancer., (© 2021. The Author(s).)

The type of myofiber is related to the quality of meat. The slow oxidized myofiber helps to increase the tenderness and juiciness of muscle. Numerous studies have shown that circRNA plays a key role in skeletal muscle development. However, the role of circRNA in porcine skeletal myofiber types is unclear. In this study, we performed high-throughput RNA sequencing to study the differential expression of circRNA in the longissimus dorsi and the soleus muscle. A total of 40,757 circRNAs were identified, of which 181 were significantly different. Interestingly, some circRNAs were involved in metabolism pathways, AMPK, FoxO, and PI3K-Akt signaling pathways. Besides, we focused on a novel circRNA-circMYLK4. By injecting circMYLK4-AAV into piglets, we found that circMYLK4 significantly increased the mRNA and protein levels of the slow muscle marker genes. In summary, our study laid an essential foundation for further research of circRNA in myofiber type conversion and higher meat quality., (© 2021. The Author(s).)

The discovery of introns over four decades ago revealed a new vision of genes and their interrupted arrangement. Throughout the years, it has appeared that introns play essential roles in the regulation of gene expression. Unique processing of excised introns through the formation of lariats suggests a widespread role for these molecules in the structure and function of cells. In addition to rapid destruction, these lariats may linger on in the nucleus or may even be exported to the cytoplasm, where they remain stable circular RNAs (circRNAs). Alternative splicing (AS) is a source of diversity in mature transcripts harboring retained introns (RI-mRNAs). Such RNAs may contain one or more entire retained intron(s) (RIs), but they may also have intron fragments resulting from sequential excision of smaller subfragments via recursive splicing (RS), which is characteristic of long introns. There are many potential fates of RI-mRNAs, including their downregulation via nuclear and cytoplasmic surveillance systems and the generation of new protein isoforms with potentially different functions. Various reports have linked the presence of such unprocessed transcripts in mammals to important roles in normal development and in disease-related conditions. In certain human neurological-neuromuscular disorders, including myotonic dystrophy type 2 (DM2), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) and Duchenne muscular dystrophy (DMD), peculiar processing of long introns has been identified and is associated with their pathogenic effects. In this review, we discuss different mechanisms involved in the processing of introns during AS and the functions of these large sections of the genome in our biology., (© 2021. The Author(s).)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Circular RNA FAT atypical cadherin 1 (circFAT1) has been reported to play vital roles in the progression of some cancers. However, the regulatory role and underlying mechanisms of circFAT1 in cervical cancer (CC) remain largely unknown. The expression of circFAT1, microRNA (miR)-409-3p and cyclin-dependent kinase 8 (CDK8) was detected using qRT-PCR and Western blot assays. Cell proliferation, apoptosis, migration and invasion in vitro were investigated using cell counting kit-8, colony formation, flow cytometry, and transwell assays, respectively. Western blot assay was used to determine the activation of ERK1/2 and p38 MAPK pathway. The interaction miR-409-3p and circFAT1 or CDK8 was confirmed by dual-luciferase reporter, pull-down or RIP assays. The effects of circFAT1 in vivo were determined using xenograft models. CircFAT1 was highly expressed in CC, and closely associated with poor prognosis. CircFAT1 knockdown resulted in the suppression of proliferation, migration and invasion, and promotion of apoptosis in CC cells via the inactivation of ERK1/2 and p38 MAPK pathway; also, circFAT1 silencing could inactivate this pathway and repressed CC tumor growth in vivo. Mechanistic analysis showed that circFAT1 directly sponged miR-409-3p and then relieved the repressive effect of miR-409-3p on its target CDK8. Furthermore, miR-409-3p inhibition reversed the effects of circFAT1 silencing on CC cells. Whereas, miR-409-3p overexpression impeded CC cell growth and motility, which was attenuated by CDK8. CircFAT1 promoted CC progression via activating ERK1/2 and p38 MAPK pathway through the miR-409-3p/CDK8 axis, suggesting a promising prognostic biomarker and therapeutic target for CC., (© 2021 Wiley Periodicals, LLC.)

Circular RNAs (circRNAs), emerging as a new type of non-coding RNAs, play important roles in cancers. Instead, the functions and mechanisms of circ_0011385 in cervical cancer (CC) are still inconclusive. Microarray data GSE102686 was downloaded from Gene Expression Omnibus (GEO) database, and were utilized to screen out circRNAs differently expressed in CC tissues. Circ_0011385, miR-149-5p, SRY-box transcription factor 4 (SOX4) mRNA expressions in CC tissues and cells were probed by quantitative real-time PCR (qRT-PCR). CC cell lines with circ_0011385 knockdown were constructed, and he multiplication, migration, invasion, and apoptosis of CC cells were evaluated by cell counting kit-8 (CCK-8) method, transwell assay, and flow cytometry. In addition, the targeting relationships between miR-149-5p and circ_0011385 or SOX4 mRNA 3'UTR were probed by dual-luciferase reporter gene assay and RNA pull-down assay. The regulatory function of circ_0011385 and miR-149-5p on SOX4 expression was studied with western blot. Expressions of circ_0011385 and SOX4 mRNA were raised in CC tissues and cells, while miR-149-5p expression was decreased. Knocking down circ_0011385 restrained the multiplication, migration, and invasion of CC cells and induced the apoptosis. Circ_0011385 directly targeted miR-149-5p, and SOX4 was the target of miR-149-5p, which could be positively regulated by circ_0011385. Circ_0011385 elevates SOX4 expression by targeting miR-149-5p, thus participating in promoting the malignant biological behaviors of CC cells., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background: During the transformation to dedifferentiated thyroid cancer (TC) types, the ability of papillary thyroid carcinomas (PTCs) to concentrate radioactive iodine might be lost, raising difficulty for the current therapy. circRNAs were proved to be implicated in the progression of various cancers. In this study, we aimed to investigate the functional role and mechanism of hsa_circ_0023990 in dedifferentiated TC., Methods: The expression pattern of genes were detected using quantitative PCR or western blot assays. Cell proliferation was determined by CCK8, colony formation, EdU, and cell-cycle assays. Glycolysis was assessed using glucose uptake and lactate production assays. Luciferase reporter assay was performed to examine the interactions between miR-485-5p and hsa_circ_0023990 or FOXM1. Xenograft assay was allowed for observation of tumor growth in vivo., Results: Hsa_circ_0023990 and FOXM1 were upregulated in dedifferentiated TC tissues and cell lines. The higher level of hsa_circ_0023900 could stimulate the proliferation and glycolysis of dedifferentiated TC cells via positively regulating FOXM1. Mechanistically, miR-485-5p was demonstrated to interact with hsa_circ_0023990 and FOXM1 and involved in the regulation of has_circ_0023990 and FOXM1 in TC biological processes., Conclusion: Our results discovered the functional network of hsa_circ_0023990 in dedifferentiated TC development by facilitating cell proliferation and glycolysis via miR-485-5p/FOXM1 axis, implying that hsa_circ_0023990 might be a potential therapeutic target for the dedifferentiated TC treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In recent years, circular RNA (circRNA) has been found to be involved in a variety of cancer processes. More and more attention has been paid to the research of circRNA in lung cancer. This study aims to investigate whether circ_0000517 affected the physiology of non-small cell lung cancer (NSCLC) and the underlying mechanism. The results demonstrated that circ_0000517 was highly expressed in lung cancer tissues and cells, and overexpression of circ_0000517 was negatively correlated with the prognosis of NSCLC patients. Silencing of circ_0000517 significantly inhibited the proliferation, glycolysis, and glutamine decomposition of NSCLC cells in vitro and repressed the growth of xenografted tumors in vivo. Moreover, knockdown of circ_0000517 attenuated the expression of PCNA, HK2, LDHA, ASCT2, and GLS1. Further study found that circ_0000517 targeted miR-330-5p and miR-330-5p targeted YY1. In addition, miR-330-5p inhibitor reversed inhibition of cancer cell proliferation, glycolysis, and glutamine decomposition induced by si-circ_0000517. In conclusion, our study revealed that silencing of circ_0000517 improved the progression of NSCLC through regulating miR-330-5p/YY1 axis., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Circular RNAs (circRNAs) feature prominently in regulating the malignant biological behaviors of colorectal cancer (CRC), including cell viability, cell cycle progression, apoptosis, migration, invasion, and so on. This study is performed to probe into the biological function and molecular mechanism of circ_0087862 in CRC. The expression profile of GSE138589 was available from Gene Expression Omnibus (GEO), and the differentially expressed circRNAs were analyzed by GEO2R. The expression of circ_0087862, miR-142-3p, and BACH1 mRNA in CRC tissues and cells was measured by qRT-PCR. CCK-8 assay was employed to determine the proliferation of CRC cells. Scratch wound healing and transwell assays were used to examine the migration and invasion of CRC cells. The targeting relationships between circ_0087862 and miR-142-3p, and between miR-142-3p and BACH1 3'UTR were verified by dual-luciferase reporter gene assay and RIP assay. BACH1 protein expression was probed by western blot. Circ_0087862 was highly expressed in CRC tissues and cell lines. Knocking down circ_0087862 significantly restrained the multiplication, migration and invasion of CRC cells. miR-142-3p inhibition weakened the impact of circ_0087862 knockdown on CRC cells. Circ_0087862 regulated BACH1 expressions by targeting miR-142-3p. Circ_0087862 regulates BACH1 expressions through sponging miR-142-3p, and promotes the proliferation, migration, and invasion of CRC cells., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Circular RNAs are considered to be associated with cancer resistance. This study aims to investigate the function and mechanism of circMYBL2 in paclitaxel (PTX) resistance of cervical cancer (CC). The expression of circMYBL2, miR-665 and epidermal growth factor receptor (EGFR) was investigated using quantitative real-time polymerase chain reaction assay. Cell viability, cell colony number, cell proliferation, apoptosis and lactate dehydrogenase (LDH) were detected by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, colony formation, 5-ethynyl-2'-deoxyuridine incorporation, flow cytometry and LDH release assays, respectively. The interaction between miR-665 and circMYBL2 or EGFR was confirmed by dual-luciferase reporter assay. The protein expression levels were quantified by western blot or immunohistochemistry assay. Mice xenograft models were constructed to investigate the effect of circMYBL2 on CC tumor growth. CircMYBL2 was upregulated in CC tissues and cells, especially in PTX-resistant CC tissues and cells, and it was a stable circRNA mainly distributed in the cytoplasm. CircMYBL2 could enhance the PTX resistance of CC cells in vitro and promote CC tumor growth in vivo. Mechanistically, circMYBL2 could inhibit the PTX sensitivity and promote cell malignant behaviors in PTX-sensitive and PTX-resistant CC cells via upregulating EGFR mediated by miR-665. CircMYBL2 played a positive role in the PTX resistance and malignant activities of PTX-sensitive and PTX-resistant CC cells by regulating the miR-665/EGFR network, providing a novel therapeutic strategy for the treatment of CC patients resistant to PTX., (© 2021 Wiley Periodicals, LLC.)

Circular RNAs (circRNAs), a type of non-coding RNA, are single-stranded circularized molecules characterized by high abundance, evolutionary conservation and cell development- and tissue-specific expression. A large body of studies has found that circRNAs exert a wide variety of functions in diverse biological processes, including cell cycle. The cell cycle is controlled by the coordinated activation and deactivation of cell cycle regulators. CircRNAs exert mutifunctional roles by regulating gene expression via various mechanisms. However, the functional relevance of circRNAs and cell cycle regulation largely remains to be elucidated. Herein, we briefly describe the biogenesis and mechanistic models of circRNAs and summarize their functions and mechanisms in the regulation of critical cell cycle modulators, including cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors. Moreover, we highlight the participation of circRNAs in cell cycle-related signalling pathways and the clinical value of circRNAs as promising biomarkers or therapeutic targets in diseases related to cell cycle disorder., (© 2021 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.)

Bladder cancer is one of the most common types of urothelial carcinoma with a rising incidence rate worldwide. Circular RNAs (circRNAs) are involved in the development of numerous cancers, including bladder cancer. We aimed to uncover the role and associated mechanism of circMYLK in bladder cancer. The expression levels of circMYLK, miRNA-34a (miR-34a) and Cyclin D3 (CCND3) mRNA were investigated using real-time quantitative polymerase chain reaction. The protein level of CCND3 was investigated using western blot. In functional assays, flow cytometry assays were utilized for cell cycle analysis and cell apoptosis analysis. Transwell assays were used for cell migration and invasion analysis. Caspase-3 activity was examined to monitor cell apoptosis. The putative relationship between miR-34a and circMYLK or CCND3 was validated by dual-luciferase reporter assay and RNA immunoprecipitation assay. CircMYLK was highly expressed in bladder cancer tissues and cells. CircMYLK downregulation inhibited bladder cancer cell migration and invasion, and promoted cancer cell apoptosis and cell cycle arrest. MiR-34a, a target of circMYLK, was downregulated in bladder cancer tissues and cells. MiR-34a inhibition reversed the effects of circMYLK downregulation and then recovered bladder cell malignant behaviors. Further analysis showed that CCND3 was a downstream target of miR-34a, and CCND3 was upregulated in bladder cancer tissues and cells. MiR-34a overexpression blocked bladder cancer cell migration and invasion, and induced cell apoptosis and cycle arrest, while these effects were abolished by CCND3 overexpression. CircMYLK contributed to the malignant development of bladder cancer cells partly through the miR-34a/CCND3 regulatory network, showing the significance of circMYLK in bladder cancer pathogenesis., (© 2021 Wiley Periodicals LLC.)

Circular RNA (circRNA) is a large class of covalently closed circRNA. As a member of competitive endogenous RNA, it participates in the regulation of circRNA-miRNA-mRNA network and plays an important role in the regulation of physiology and pathology. CircRNA is produced by the reverse splicing of exon, intron or both, forming exon or intron circRNA. Studies have shown that circRNA is a ubiquitous molecule, which exceeds the linear mRNA distributed in human cells. Because of its covalent closed-loop structure, circRNA is resistant to RNase R, which is more stable than linear mRNA; circRNA is highly conserved in different species. It was found that circRNA competitively adsorbs miRNA, as a miRNA sponge, to involve in the expression regulation of a variety of genes and plays an important role in tumor development, invasion, metastasis and other processes. These molecules offer new potential opportunities for therapeutic intervention and serve as biomarkers for diagnosis. In this paper, the origin, characteristics and functions of circRNA and its role in tumor development, invasion and metastasis, diagnosis and prognosis are reviewed., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

MiR-143-3p is aberrantly expressed in patients with ischemic stroke and associated with ischemic brain injury. However, the underlying mechanisms are largely unknown. Here, we confirmed circ_0025984 and TET1 as a sponge and target of miR-143-3p, respectively, by luciferase reporter assay. In astrocytes, OGD significantly decreased circ_0025984 and TET1 levels but increased miR-143-3p levels, which was also observed in brains of mice with MCAO. Treatment with miR-143-3p inhibitor or circ_0025984 significantly decreased astrocyte apoptosis and autophagy, as well as cerebral injury and neuron loss in mice with MCAO. Notably, TET1 overexpression decreased astrocyte apoptosis and autophagy and induced promoter hypomethylation and expression of ORP150. Our results demonstrated for the first time that circ_0025984 protects astrocytes from ischemia-induced autophagy and apoptosis by targeting the miR-143-3p/TET1 pathway and might inhibit cerebral injury induced by ischemic stroke. Furthermore, our data revealed the important positive regulation of ORP150 by TET1, which could be associated with its neuroprotective role. Graphical abstract Model for signaling pathway of circ_0025984/miR-143-3p/TET1 inastrocytes cultured under OGD. In astrocytes, circ_0025984 acts as a sponge of miR-143-3p, which directly targets TET1 and decreases its expression (A). After translocatinginto the nucleus, TET1 binds to the promoter of ORP150, converts 5mC into 5hmC,leading to DNA demethylation and increased expression of ORP150 (B). In astrocytescultured under OGD, ER stress is induced and eventually leads to apoptosis andautophagy mediated by ATG7, which is regulated by circ_0025984 via ORP150 andGRP78 (C)., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Circular RNAs have participated in oncology progress. Nevertheless, the potential mechanisms are not completely understood. We intended to inspect the functions of hsa_circ_0088088 on breast malignancy, together with the possible mechanism(s). hsa_circ_0088088 expression in breast malignancy was studied using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). The overall survival was studied by the Kaplan-Meier curve. The biological functions of hsa_circ_0088088 aberrant expression on cell growth and metastasis were evaluated in MDA-MB-231 cells. Bioinformatics analysis, RNA immunoprecipitation (RIP), and qRT-PCR were accomplished to confirm the possible regulatory effects of eukaryotic initiation factor 4A3 (EIF4A3) on the biogenesis of hsa_circ_0088088. Furthermore, a dual-luciferase reporter assay, qRT-PCR, and RNA pull-down assay were used to confirm the association between the hsa_circ_0088088 and miR-135-5p in MDA-MB-231 cells. hsa_circ_0088088 was upregulated in the tumor tissues and cells, and higher expression presented an unfavorable prognosis. hsa_circ_0088088 overexpression promoted cell growth and metastasis in MDA-MB-231 cells. EIF4A3 was found to positively regulate hsa_circ_0088088. Furthermore, we confirmed that hsa_circ_0088088 sponges miR-135-5p and directly targets miR-135-5p with respect to the cell growth and metastasis in MDA-MB-231 cells. Our data suggest that EIF4A3-induced hsa_circ_0088088 stimulates the carcinogenic effects of breast tumors by sponging miR-135-5p., (© 2021 Wiley Periodicals LLC.)

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease, but the molecular mechanisms of disease remain not very clear and there is no curative therapeutic strategy so far. This study was carried out to identify the expression profile of circular RNA (circRNA) in human DKD and explore circRNA regulatory function in glomeruli and tubuli simultaneously. As a result, a total of 40 upregulated and 23 downregulated differentially expressed circRNAs (DEcircRNAs) were detected. Six candidate DEcircRNAs were verified by quantitative real-time polymerase chain reaction in high glucose-treated human mesangial cells and human proximal renal tubular epithelial cells, respectively. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that both in glomeruli and in tubuli the DEcircRNAs-targeted genes participated in many pathophysiological processes of DKD. Correlation analysis with renal function showed that expression level of DEcircRNA-targeted hub gene was related to renal function. In conclusion, this is the first study to report expression profiles of circRNAs in kidney of DKD patients, and further analysis demonstrated that circRNA probably played a significant regulatory role, providing help for understanding the pathogenesis of DKD and investigating novel diagnostic and therapeutic strategy.

Background: Drug resistance is a major clinical drawback behind the failure of chemotherapy in non-small cell lung cancer (NSCLC). In this study, we undertook to identify the precise role of circular RNA (circRNA) circ_0058357 in the functional properties of DDP-resistant NSCLC cells., Methods: Circ_0058357, miR-361-3p and ATP-binding cassette (ABC) subfamily C member 1 (ABCC1) were quantified by qRT-PCR and western blot. Cell survival and viability were gauged by MTT assay. Cell proliferation, apoptosis, invasion and migration were measured by EdU, flow cytometry, transwell and wound-healing assays, respectively. The direct relationship between miR-361-3p and circ_0058357 or ABCC1 was validated by dual-luciferase reporter assay., Results: Our data showed that circ_0058357 was highly expressed in DDP-resistant NSCLC tissues and cells. Inhibition of circ_0058357 repressed cell growth, invasion, migration, and promoted DDP sensitivity and cell apoptosis of H1299/DDP and A549/DDP cells in vitro. Moreover, inhibition of circ_0058357 diminished the growth of A549/DDP cells and sensitized them to the cytotoxic effect of DDP in vivo. Mechanistically, circ_0058357 contained a miR-361-3p binding site and miR-361-3p was identified as a molecular mediator of circ_0058357 regulation. MiR-361-3p suppressed ABCC1 expression by binding to ABCC1 3'UTR, and miR-361-3p-mediated inhibition of ABCC1 affected the growth, invasion, migration, apoptosis and DDP sensitivity of H1299/DDP and A549/DDP cells. Furthermore, circ_0058357 regulated ABCC1 expression by competitively binding to shared miR-361-3p., Conclusions: Our findings identified that inhibition of circ_0058357 suppresses the growth and metastasis of H1299/DDP and A549/DDP cells and sensitizes them to DDP therapy partially by targeting the miR-361-3p/ABCC1 axis., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Oesophageal squamous cell carcinoma (OSCC) is a prevalent malignancy with high morbidity and mortality as a result of early metastasis and poor prognosis. Metastasis is a multistep process, involving various signalling pathways. Circular RNAs (circRNAs) are a class of covalently closed noncoding RNAs, the aberrant expression of which is reported to be involved in several biological events, including cell transformation, proliferation, migration, invasion, apoptosis and metastasis. Several studies have reported interactions between circRNAs and metastasis-associated signalling pathways. The abundance, stability and highly specific expression of candidate circRNAs make them potential biomarkers and therapeutic targets in OSCC. In this review article, we comprehensively describe metastasis-related circRNAs and their interactions with epithelial-mesenchymal transition-associated molecules. We also describe the molecular mechanisms and clinical relevance of circRNAs in OSCC progression and metastasis., (© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose : Circular RNAs (circRNAs) are essential regulators in tumorigenesis and development. In this study, we focused on the functions of circRNA muskelin 1 (circMKLN1) in retinoblastoma (RB) progression. Materials and Methods : Quantitative real-time polymerase chain reaction (qRT-PCR) assay was conducted to determine the levels of circMKLN1, microRNA-425-5p (miR-425-5p) and programmed cell death 4 (PDCD4). The characteristic of circMKLN1 was analyzed using RNase R assay. Cell Counting Kit-8 (CCK-8) assay and colony formation assay were employed to explore cell proliferation ability. The transwell assay was utilized for cell migration and invasion. A Western blot assay was performed for protein levels. The dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to demonstrate the relationships among circMKLN1, miR-425-5p and PDCD4. Murine xenograft model assay was adopted to investigate the role of circMKLN1 in vivo . Results : CircMKLN1 was downregulated in RB tissues and cells. High levels of circMKLN1 were related to a favorable outcome of RB patients. CircMKLN1 was resistant to RNase R digestion and circMKLN1 overexpression repressed RB cell proliferation, migration and invasion in vitro . MiR-425-5p was identified as the target of circMKLN1 and miR-425-5p elevation reversed the effects of circMKLN1 overexpression on RB cell malignant behaviors. Furthermore, as the target gene of miR-425-5p, PDCD4 silencing could ameliorate the suppressive roles of circMKLN1 in RB cell growth and metastasis. Additionally, circMKLN1 overexpression hampered tumor growth in vivo . Conclusions : CircMKLN1 overexpression decelerated the progression of RB through sponging miR-425-5p and elevating PDCD4.

Circular RNAs (circRNAs) have been documented to be aberrantly expressed in many types of malignancies and involved in cancer progression. However, their role in thyroid cancer (TC) remains largely unknown. Our study aimed to explore the role and mechanism of circUBAP2 in TC. The differentially expressed circRNAs in TC tissues were identified using GSE18105 from gene expression omnibus (GEO) database. CircUBAP2 and miR-370-3p expression was analyzed using qRT-PCR. The stability of circUBAP2 was confirmed by actinomycin D and RNase R. The subcellular localization of circUBAP2 was detected using cell fractionation assay. Cell proliferation, apoptosis, and invasion were evaluated using MTT, flow cytometry analysis, and Transwell invasion assay, respectively. The interaction between circUBAP2 and miR-370-3p was predicted using bioinformatics analysis and validated by luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation. CircUBAP2 was upregulated and miR-370-3p was downregulated in TC tissues and cells. CircUBAP2 was highly stable, resistant to RNase R digestion, and predominantly localized in the cytoplasm. CircUBAP2 knockdown inhibited cell proliferation and invasion and triggered apoptosis in TC cells. Bioinformatics analysis showed that circUBAP2 contained putative binding sites of miR-370-3p. CircUBAP2 acted as a sponge to inhibit miR-370-3p expression. Mechanistically, miR-370-3p inhibition abolished the effects of circUBAP2 on proliferation, apoptosis, and invasion in TC cells. Taken together, CircUBAP2 knockdown impeded the proliferation and invasion and induced apoptosis in TC cells via sponging miR-370-3p., (© 2021. Japan Human Cell Society.)

Gemcitabine is the first-line treatment for patients with pancreatic cancer (PC), yet most patients develop resistance to gemcitabine. Recent studies showed that circular RNAs (circRNAs) have important regulatory roles in PC progression and chemoresistance. In this study, the ability of circRNA circ_0092367 to enhance gemcitabine efficacy was tested and the underlying molecular mechanism of circ_0092367 was investigated. The expression levels of circ_0092367, miR-1206, and ESRP1 were measured using qRT-PCR experiments. The effects of circ_0092367, miR-1206, and ESRP1 on PC cell lines exposed to gemcitabine were examined by CCK-8 assays. We performed luciferase assays to determine the relationship between circ_0092367 and miR-1206 and between miR-1206 and ESRP1. We demonstrated that circ_0092367 was significantly downregulated in PC tissues and cell lines, and a high expression of circ_0092367 was associated with improved survival in patients with PC. Gain- and loss-of-function assays revealed that circ_0092367 inhibited epithelial-mesenchymal transition (EMT) phenotypes and sensitized PC cells to gemcitabine treatment in vitro and in vivo. Cytoplasmic circ_0092367 could directly repress the levels of miR-1206 and thus upregulate the expression of ESRP1, thereby inhibiting EMT and enhancing the sensitivity of PC cells to gemcitabine treatment. Our findings show that circ_0092367 plays a crucial role in sensitizing PC cells to gemcitabine by modulating the miR-1206/ESRP1 axis, highlighting its potential as a valuable therapeutic target in PC patients.

Circular RNA (circRNA) is a type of endogenous, high‑stability, noncoding RNA. circRNAs exhibit various biological functions, and are involved in physiological and pathological processes occurring in various diseases, including cancers. They can not only act as microRNA and protein sponges, but also interact with proteins, translated peptides, and transcriptional and translational regulators, and compete with pre‑mRNA splicing. Chemotherapy is one of the most important types of cancer treatment. However, the resistance of cancer cells to chemotherapy is a leading reason for the failure of chemotherapy. It has been reported that circRNAs play important roles in cancer resistance via a number of mechanisms. The functions of the circRNAs provide insight into their roles in chemoresistance pathways. In addition, some circRNAs may serve as novel biomarkers for the diagnosis and prognosis of cancer resistance. Obtaining improved understanding of the molecular regulatory networks featuring circRNAs in tumors and searching for markers for the diagnosis and treatment of cancer resistance are leading issues in circRNA research. The present review introduced the functions of circRNAs, illustrated the mechanisms underlying drug resistance in cancer, described the contributions of circRNAs to this resistance and discussed the potential application of circRNAs in the treatment of drug‑resistant cancer. In particular, the review aimed to reveal the main mechanisms of circRNAs in cancer drug resistance, including mechanisms involving drug transport and metabolism, alterations of drug targets, DNA damage repair, downstream resistance mechanisms, adaptive responses and the tumor microenvironment. The findings may provide novel therapeutic targets for clinical treatment of cancer chemoresistance.

Senile cataract is a common age-related disease in ophthalmology. Hsa_circ_0004058 has been reported to be down-regulated in the lens epithelial cells of senile cataract patients, suggesting that hsa_circ_0004058 is associated with senile cataract. However, the underlying mechanism is still unknown. This study attempted to determine the functional role of hsa_circ_0004058 in senile cataract. We treated human lens epithelial cells (SRA01/04) with H 2 O 2 as senile cataract model, and found that cell viability and autophagy of SRA01/04 cells were severely decreased by H 2 O 2 treatment. Hsa_circ_0004058 was notably down-regulated in H 2 O 2 -treated SRA01/04 cells. Moreover, hsa_circ_0004058 overexpression reduced apoptotic cells and the expression of Cleaved-caspase-3 and Bax, and enhanced Bcl-2 expression in H 2 O 2 -treated SRA01/04 cells. However, hsa_circ_0004058 silencing caused the opposite results. Hsa_circ_0004058 up-regulation accelerated the expression of autophagy-related proteins LC3-II/LC3-I and Beclin-1 in H 2 O 2 -treated SRA01/04 cells, which was partly abolished by 3-Methyladenine (autophagy inhibitor). Additionally, hsa_circ_0004058 functioned as a competing endogenous RNA to competitive binding miR-186, and thus accelerated the expression of its down-stream target, ATG7. Hsa_circ_0004058 promoted autophagy of SRA01/04 cells by regulating miR-186/ATG7 axis. In conclusion, these data demonstrates that hsa_circ_0004058 inhibits apoptosis of SRA01/04 cells by promoting autophagy, which attributes to regulate miR-186/ATG7 axis. Thus, hsa_circ_0004058 may be a potential target for senile cataract treatment., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Pancreatic cancer is one of the malignant tumors with poor prognosis. The molecular mechanisms of pancreatic oncogenesis and malignant progression are not fully elucidated. Several key signaling pathways, such as Notch, Wnt and hedgehog pathways, are important to drive pancreatic carcinogenesis. Recently, noncoding RNAs, especially circular RNAs (circRNAs), have been characterized to participate into pancreatic cancer development. Therefore, in this review article, we describe the association between circRNAs and pancreatic cancer prognosis. Moreover, we discuss how circRNAs are involved in regulation of cellular processes in pancreatic cancer, including proliferation, apoptosis, cell cycle, migration, invasion, EMT, metastasis, angiogenesis, drug resistance and immune escape. Furthermore, we mention that several compounds could regulate the expression of circRNAs, indicating that targeting circRNAs by compounds might be helpful for treating pancreatic cancer patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Gastric cancer (GC) is one of the most common digestive system tumors in the world. Many circular RNAs (circRNAs) are involved in the progression of GC. The purpose of this study was to delve into the expression characteristics and biological functions of circ_0000064 in GC, and further study its mechanisms. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect circ_0000064 expression in 61 GC tissues and cell lines. Circ_0000064 knockdown was successfully modeled with siRNA. The effects of circ_0000064 on the biological functions of GC cells were analyzed by CCK-8, BrdU, and Transwell assays. Bioinformatics and dual-luciferase reporter gene assay were adopted to explore the relations between circ_0000064 and microRNA-621 (miR-621). Western blot was used to examine the regulatory function of circ_0000064 and miR-621 on SYF2 pre-mRNA splicing factor 2. Cric_0000064 expression was elevated in GC tissues and cell lines. Knocking down cric_0000064 could inhibit the viability, migration, and invasion of GC cells. Dual-luciferase reporter gene assay showed that miR-621 could bind circ_0000064 and SYF2 3'UTR; in addition, miR-621 overexpression or SYF2 knockdown could partially weaken the cancer-promoting effect of circ_0000064 on GC cells. Circ_0000064 expression was negatively correlated with miR-621 expression in GC tissues while positively with SYF2 expression. Circ_0000064 can participate in the GC progression via modulating miR-621/SYF2 axis. This implies that circ_0000064 may be a new diagnosed biomarker or a new therapeutic target of GC., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Liver tumor-initiating cells (TICs) are involved in liver tumorigenesis, metastasis, drug resistance, and relapse, but the regulatory mechanisms of liver TICs are largely unknown. Here, we have identified a functional circular RNA, termed circRNA activating MAFF (cia-MAF), that is robustly expressed in liver cancer and liver TICs. cia-MAF-KO primary cells and cia-maf-KO liver tumors harbor decreased ratios of TICs, and display impaired liver tumorigenesis, self-renewal, and metastatic capacities. In contrast, cia-MAF overexpression drives liver TIC propagation, self-renewal, and metastasis. Mechanistically, cia-MAF binds to the MAFF promoter, recruits the TIP60 complex to the MAFF promoter, and finally promotes MAFF expression. Loss of cia-MAF function attenuates the combination between the TIP60 complex and the MAFF promoter. MAFF is highly expressed in liver tumors and liver TICs, and its antisense oligo (ASO) has therapeutic potential in treating liver cancer without MAFA/MAFG gene copy number alterations (CNAs). This study reveals an additional layer for liver TIC regulation as well as circRNA function, and provides an additional target for eliminating liver TICs, especially for liver tumors without MAFA/MAFG gene CNAs.

Background: Circular RNAs (circRNAs) have an important role in the development and progression of human tumors, including lung cancer. Yet, their role in lung cancer induced by benzo(a)pyrene (B[a]P) remains unclear. In this study, circRNA chips and qRT-PCR were used to examine downregulated circRNAs in malignantly transformed 16HBE cells (16HBE-T) induced by B[a]P. Five down-regulated circRNAs were found, among which hsa_circ_0004552 (circ_CARM1) had the most significant downregulation. Consequently, the role of circ_CARM1 on 16HBE-T cells biological behavior was further examined using several in vitro experiments., Materials and Methods: Detecting RNA expression via qRT-PCR. Fluorescence in situ hybridization (FISH) was used to identify the localization of circ_CARM1 in 16HBE-T. The effect of circ_CARM1 on cell behavior (cell migration, proliferation, and apoptosis) was explored by transfecting cells with a vector carrying an overexpression and then using wound healing, transwell migration assay, and flow cytometry. Also, the regulation mechanism for circ_CARM1, miR-1288-3p, and CTNNBIP1 was studied by Dual-Luciferase® Reporter (DLR™) Assay System and western blotting., Results: Reduced expression of circ_CARM1 is observed in 16HBE-T. The overexpression of circ_CARM1 further inhibited the migration of 16HBE-T cells but did not affect cell proliferation and apoptosis. Furthermore, bioinformatic analysis and Dual-Luciferase® Reporter (DLR™) Assay System showed that the competitive binding of circ_CARM1 and miR-1288-3p enhanced the expression of CTNNBIP1, thereby inhibiting the migration of 16HBE-T cells., Conclusion: Downregulation of circ_CARM1 can stimulate the expression of miR-1288-3p, thereby reducing the expression of CTNNBIP1, spurring cell migration., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Inflammation events have been found to aggravate brain injury and blood-brain barrier (BBB) damage following subarachnoid hemorrhage (SAH). This study probed the role and mechanism of a novel circRNA, circARF3, in regulating the BBB injury in SAH rats and hypoxia-induced vascular endothelial cell (VEC) injury in vitro . Levels of circARF3 and miR-31-5p were monitored by RT-PCR. The expression of inflammatory factors IL-1β and TNF-α was verified by ELISA. In vivo SAH model was constructed in Sprague Dawley (SD) rats. The BBB integrity and cerebral edema, as well as the neurological functions of the rats were evaluated. The apoptotic neurons and microglia in brain lesions were examined by immunohistochemistry (IHC). The MyD88/NF-κB pathway was tested by Western blot. Furthermore, gain-of functional assay were constructed to explore the effects of circARF3 and miR-31-5p in primary cultured brain microvascular endothelial cell (BMEC) injury and microglial inflammation induced by oxygen and glucose deprivation (OGD). circARF3 was significantly down-regulated in plasma and CSF in SAH patients with higher Fisher stages. In the SAH rat model, overexpressing circARF3 improved BBB integrity and neurological score, decreased neuronal apoptosis and microglial activation in ipsilateral basal cortex, with declined miR-31-5p expression and MyD88-NF-κB activation. In vitro , overexpressing circARF3 attenuated OGD-mediated integrity destruction of BMECs and microglial induced neuroinflammation, while overexpressing miR-31-5p had opposite effects. Mechanistically, circARF3 sponged miR-31-5p as an endogenous competitive RNA and dampens its expression, thus inactivating MyD88-NF-κB pathway. CircARF3 attenuates BBB destruction in SAH rats by regulating the miR-31-5p-activated MyD88-NF-κB pathway.

Objective: Provide a reference to elucidate the mechanism of circRNAs regulating osteoarthritis (OA) and the clinical treatment., Methods: Herein, articles about circRNAs (hsa-circ) and osteoarthritis in the recent 5 years have been reviewed and the differential expression and regulatory effect of circRNAs in OA deduced. Based on these conclusions and Protein-Protein Interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the acquired circRNAs, the potential functions and interactions of circRNAs in OA and the involved signaling pathways are discussed., Results: A total of 33 studies meeting the inclusion criteria were included in this study, and 27 circRNAs were upregulated and 8 circRNAs were downregulated in OA. A total of 31 circRNAs were finally included in the PPI, GO, and KEGG analyses. From PPI, 12 map nodes and 7 map edges were interrelated. VWF had the biggest node and edge size. From GO, VWF showed a majority of the functions. From KEGG, circRNAs are enriched in PI3K/AKT, human papillomavirus infection (HPI), and focal adhesion (FA) pathways, and VWF was involved in major pathways., Conclusion: We found that most articles about circRNAs regulating OA in the recent 5 years focused on the mechanism, especially the absorption effect of circ-miRNA as sponges in the recent 2 years, while most of the articles about their functions addressed ECM and PI3K, AKT, and mTOR signaling pathways. Future studies might focus on the functions of circRNAs, and circRNA VWF, with preferable functions, interactions, and involvement, can be used as a biological indicator to detect OA in clinical practice., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Wei Wu and Jun Zou.)

Background: Circular RNAs (circRNAs) crucially regulate tumor progression. In this study, we examined the functional roles and mechanisms of hsa_circ_0003489 in multiple myeloma (MM)., Methods: Upon altering the expressions of hsa_circ_0003489, miR-874-3p, and/or histone deacetylase 1 (HDAC1) in MM1.R cells and treating them with bortezomib (BTZ), cell viability was examined by CCK-8 assay; cell proliferation by Ki-67 immunofluorescence; apoptosis by TUNEL staining, flow cytometry, and western blot; and autophagy by electron microscopy and western blot. The interaction between hsa_circ_0003489 and miR-874-3p as well as that between miR-874-3p and HDAC1 was examined by expressional analysis, dual luciferase reporter assay, and RNA immunoprecipitation. The in vivo impacts of hsa_circ_0003489 on MM growth and sensitivity to BTZ were examined using an MM xenograft mouse model., Results: Knocking down hsa_circ_0003489 significantly inhibited the viability, cell proliferation, and autophagy, while promoting the apoptosis of MM cells in vitro and MM xenograft in vivo. Suppressing hsa_circ_0003489 also further boosted the cytotoxic effects of BTZ in MM cells and reversed its promoting effect on autophagy. Mechanically, hsa_circ_0003489 acted as a sponge of miR-874-3p and positively regulated the expression of miR-874-3p target, HDAC1. MiR-874-3p and HDAC1 essentially mediated the effects of hsa_circ_0003489 on cell viability, proliferation, apoptosis, and autophagy., Conclusion: The hsa_circ_0003489/miR-874-3p/HDAC1 axis critically regulates the balance between apoptosis and autophagy. Silencing hsa_circ_0003489 sensitizes MM cells to BTZ by inhibiting autophagy and thus may boost the therapeutic effects of BTZ., (© 2021 John Wiley & Sons, Ltd.)

Circular RNAs (circRNAs) have been shown to be involved in the progression of many diseases, including cancer. However, the role of circ_0101802 in the proliferation, migration and invasion of colorectal cancer (CRC) has not been studied. Our results showed that circ_0101802 was highly expressed in CRC tumor tissues and cells. Functional experiments suggested that circ_0101802 knockdown could inhibit the proliferation, migration and invasion of CRC cells in vitro and CRC tumorigenesis in vivo. In the terms of mechanism, we discovered that circ_0101802 could act as a sponge of miR-1236-3p, and miR-1236-3p could target MACC1. The rescue experiments revealed that miR-1236-3p inhibitor could reverse the inhibition effect of circ_0101802 silencing on CRC proliferation, migration and invasion, and MACC1 overexpression also could abolish the negative regulation of miR-1236-3p on CRC proliferation, migration and invasion. More important, our data confirmed that circ_0101802 sponged miR-1236-3p to positively regulate MACC1. In summary, our results revealed that circ_0101802 functioned as a tumor promoter in CRC, which could facilitate CRC proliferation, migration and invasion via regulating the miR-1236-3p/MACC1 axis., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)