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Zhou L, Wang Q, Hou J, Wu X, Wang L, Chen X. Upregulation of hsa_circ_0002003 promotes hepatocellular carcinoma progression. BMC Cancer 2023; 23:611. [PMID: 37400785 PMCID: PMC10316602 DOI: 10.1186/s12885-023-11086-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 06/19/2023] [Indexed: 07/05/2023] Open
Abstract
BACKGROUND Circular RNAs (circRNAs), which are involved in various human malignancies, have emerged as promising biomarkers. The present study aimed to investigate unique expression profiles of circRNAs in hepatocellular carcinoma (HCC) and identify novel biomarkers associated with HCC development and progression. METHODS CircRNA expression profiles of HCC tissues were jointly analyzed to identify differentially expressed circRNAs. Overexpression plasmid and siRNA targeting candidate circRNAs were used in functional assays in vitro. CircRNA-miRNA interactions were predicted using miRNAs expressed in the miRNA-seq dataset GSE76903. To further screen downstream genes targeted by the miRNAs, survival analysis and qRT-PCR were conducted to evaluate their prognostic role in HCC and construct a ceRNA regulatory network. RESULTS Three significantly upregulated circRNAs, hsa_circ_0002003, hsa_circ_0002454, and hsa_circ_0001394, and one significantly downregulated circRNA, hsa_circ_0003239, were identified and validated by qRT-PCR. Our in vitro data indicated that upregulation of hsa_circ_0002003 accelerated cell growth and metastasis. Mechanistically, DTYMK, DAP3, and STMN1, which were targeted by hsa-miR-1343-3p, were significantly downregulated in HCC cells when hsa_circ_0002003 was silenced and were significantly correlated with poor prognosis in patients with HCC. CONCLUSION Hsa_circ_0002003 may play critical roles in HCC pathogenesis and serve as a potential prognostic biomarker for HCC. Targeting the hsa_circ_0002003/hsa-miR-1343-3p/STMN1 regulatory axis could be an effective therapeutic strategy in patients with HCC.
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Affiliation(s)
- Lisha Zhou
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Department of Immunology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing University, Nanjing, China
| | - Qianwen Wang
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Department of Immunology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Jun Hou
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Department of Immunology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Xiangwei Wu
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Lianghai Wang
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
- Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
| | - Xueling Chen
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
- Department of Immunology, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
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2
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Zhang Y, Tian Z, Ye H, Sun X, Zhang H, Sun Y, Mao Y, Yang Z, Li M. Emerging functions of circular RNA in the regulation of adipocyte metabolism and obesity. Cell Death Dis 2022; 8:268. [PMID: 35595755 PMCID: PMC9122900 DOI: 10.1038/s41420-022-01062-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 05/04/2022] [Accepted: 05/10/2022] [Indexed: 02/08/2023]
Abstract
As noncoding RNAs, circular RNAs (circRNAs) are covalently enclosed endogenous biomolecules in eukaryotes that have tissue specificity and cell specificity. circRNAs were once considered a rare splicing byproduct. With the development of high-throughput sequencing, it has been confirmed that they are expressed in thousands of mammalian genes. To date, only a few circRNA functions and regulatory mechanisms have been verified. Adipose is the main tissue for body energy storage and energy supply. Adipocyte metabolism is a physiological process involving a series of genes and affects biological activities in the body, such as energy metabolism, immunity, and signal transmission. When adipocyte formation is dysregulated, it will cause a series of diseases, such as atherosclerosis, obesity, fatty liver, and diabetes. In recent years, many noncoding RNAs involved in adipocyte metabolism have been revealed. This review provides a comprehensive overview of the basic structure and biosynthetic mechanism of circRNAs, and further discusses the circRNAs related to adipocyte formation in adipose tissue and liver. Our review will provide a reference for further elucidating the genetic regulation mechanism of circRNAs involved in adipocyte metabolism.
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Affiliation(s)
- Yuanyuan Zhang
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, 225009, Yangzhou, Jiangsu, China.,Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu province, College of Animal Science and Technology, Yangzhou University, 225009, Yangzhou, Jiangsu, China
| | - Zhichen Tian
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, 225009, Yangzhou, Jiangsu, China.,Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu province, College of Animal Science and Technology, Yangzhou University, 225009, Yangzhou, Jiangsu, China
| | - Haibo Ye
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, 225009, Yangzhou, Jiangsu, China.,Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu province, College of Animal Science and Technology, Yangzhou University, 225009, Yangzhou, Jiangsu, China
| | - Xiaomei Sun
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, 225009, Yangzhou, Jiangsu, China.,Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu province, College of Animal Science and Technology, Yangzhou University, 225009, Yangzhou, Jiangsu, China
| | - Huiming Zhang
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, 225009, Yangzhou, Jiangsu, China.,Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu province, College of Animal Science and Technology, Yangzhou University, 225009, Yangzhou, Jiangsu, China
| | - Yujia Sun
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, 225009, Yangzhou, Jiangsu, China.,Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu province, College of Animal Science and Technology, Yangzhou University, 225009, Yangzhou, Jiangsu, China
| | - Yongjiang Mao
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, 225009, Yangzhou, Jiangsu, China.,Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu province, College of Animal Science and Technology, Yangzhou University, 225009, Yangzhou, Jiangsu, China
| | - Zhangping Yang
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, 225009, Yangzhou, Jiangsu, China. .,Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu province, College of Animal Science and Technology, Yangzhou University, 225009, Yangzhou, Jiangsu, China.
| | - Mingxun Li
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, 225009, Yangzhou, Jiangsu, China. .,Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu province, College of Animal Science and Technology, Yangzhou University, 225009, Yangzhou, Jiangsu, China.
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3
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Cai Y, Jia Y. Circular RNA SOX5 promotes the proliferation and inhibits the apoptosis of the hepatocellular carcinoma cells by targeting miR-502-5p/synoviolin 1 axis. Bioengineered 2022; 13:3362-3370. [PMID: 35048790 PMCID: PMC8973662 DOI: 10.1080/21655979.2022.2029110] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
We aimed to explore the role of circ-SOX5 in the pathogenesis of hepatocellular carcinoma (HCC). The circRNAs in HCC were screened using the GEO database. RT-qPCR was used to detect mRNA expression. Targeting relationships were confirmed by dual luciferase reporter assay and RNA pull-down assay. CCK-8 and EDU staining were used to measure cell viability and proliferation, respectively. Cell apoptosis was determined using flow cytometry. Protein expression was determined by Western blotting. Circ-SOX5 expression was increased in HCC tissues. Inhibition of circ-SOX5 expression reduced the viability, proliferation, and colony formation, and increased the apoptosis of HCC cells. However, miR-502-5p inhibition or overexpression of synoviolin 1 (SYVN1) can reverse the effects of circ-SOX5 knockdown on proliferation and apoptosis. This study demonstrated that the circ-SOX5/miR-502-5p/SYVN1 axis promotes the development of HCC by regulating cell apoptosis. Therefore, circ-SOX5 may be a potential biomarker of HCC.
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Affiliation(s)
- Yu Cai
- Department of General Surgery, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi, China
| | - Yuanyuan Jia
- Department of Faculty Development and Teaching Evaluation Office, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi, China
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4
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Wang Z, Lei X. Identifying the sequence specificities of circRNA-binding proteins based on a capsule network architecture. BMC Bioinformatics 2021; 22:19. [PMID: 33413092 PMCID: PMC7792089 DOI: 10.1186/s12859-020-03942-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
Background Circular RNAs (circRNAs) are widely expressed in cells and tissues and are involved in biological processes and human diseases. Recent studies have demonstrated that circRNAs can interact with RNA-binding proteins (RBPs), which is considered an important aspect for investigating the function of circRNAs. Results In this study, we design a slight variant of the capsule network, called circRB, to identify the sequence specificities of circRNAs binding to RBPs. In this model, the sequence features of circRNAs are extracted by convolution operations, and then, two dynamic routing algorithms in a capsule network are employed to discriminate between different binding sites by analysing the convolution features of binding sites. The experimental results show that the circRB method outperforms the existing computational methods. Afterwards, the trained models are applied to detect the sequence motifs on the seven circRNA-RBP bound sequence datasets and matched to known human RNA motifs. Some motifs on circular RNAs overlap with those on linear RNAs. Finally, we also predict binding sites on the reported full-length sequences of circRNAs interacting with RBPs, attempting to assist current studies. We hope that our model will contribute to better understanding the mechanisms of the interactions between RBPs and circRNAs. Conclusion In view of the poor studies about the sequence specificities of circRNA-binding proteins, we designed a classification framework called circRB based on the capsule network. The results show that the circRB method is an effective method, and it achieves higher prediction accuracy than other methods.
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Affiliation(s)
- Zhengfeng Wang
- School of Computer Science, Shaanxi Normal University, Xi'an, 710119, China.,College of Information Science and Engineering, Guilin University of Technology, Guilin, 541004, China
| | - Xiujuan Lei
- School of Computer Science, Shaanxi Normal University, Xi'an, 710119, China.
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5
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Pan YQ, Xing L. The Current View on the Helicase Activity of RNA Helicase A and Its Role in Gene Expression. Curr Protein Pept Sci 2020; 22:29-40. [PMID: 33143622 DOI: 10.2174/1389203721666201103084122] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 08/18/2020] [Accepted: 09/09/2020] [Indexed: 11/22/2022]
Abstract
RNA helicase A (RHA) is a DExH-box helicase that plays regulatory roles in a variety of cellular processes, including transcription, translation, RNA splicing, editing, transport, and processing, microRNA genesis and maintenance of genomic stability. It is involved in virus replication, oncogenesis, and innate immune response. RHA can unwind nucleic acid duplex by nucleoside triphosphate hydrolysis. The insight into the molecular mechanism of helicase activity is fundamental to understanding the role of RHA in the cell. Herein, we reviewed the current advances on the helicase activity of RHA and its relevance to gene expression, particularly, to the genesis of circular RNA.
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Affiliation(s)
- Yuan-Qing Pan
- Institute of Biomedical Sciences, Shanxi University, 92 Wucheng Road, Taiyuan 030006, Shanxi province, China
| | - Li Xing
- Institute of Biomedical Sciences, Shanxi University, 92 Wucheng Road, Taiyuan 030006, Shanxi province, China
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6
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Zhang C, Han B, Xu T, Li D. The biological function and potential mechanism of long non-coding RNAs in cardiovascular disease. J Cell Mol Med 2020; 24:12900-12909. [PMID: 33052009 PMCID: PMC7701533 DOI: 10.1111/jcmm.15968] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 09/20/2020] [Accepted: 09/22/2020] [Indexed: 12/14/2022] Open
Abstract
Long non-coding RNAs (lncRNAs), as part of the family of non-protein-coding transcripts, are implicated in the occurrence and progression of several cardiovascular diseases (CVDs). With recent advances in lncRNA research, these molecules are purported to regulate gene expression at multiple levels, thereby producing beneficial or detrimental biological effects during CVD pathogenesis. At the transcriptional level, lncRNAs affect gene expression by interacting with DNA and proteins, for example, components of chromatin-modifying complexes, or transcription factors affecting chromatin status. These potential mechanisms suggest that lncRNAs guide proteins to specific gene loci (eg promoter regions), or forestall proteins to specific genomic sites via DNA binding. Additionally, some lncRNAs are required for correct chromatin conformation, which occurs via chromatin looping in enhancer-like models. At the post-transcriptional level, lncRNAs interact with RNA molecules, mainly microRNAs (miRNAs) and mRNAs, potentially regulating CVD pathophysiological processes. Moreover, lncRNAs appear to post-transcriptionally modulate gene expression by participating in mRNA splicing, stability, degradation and translation. Thus, the purpose of this review is to provide a comprehensive summary of lncRNAs implicated in CVD biological processes, with an emphasis on potential mechanisms of action.
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Affiliation(s)
- Chengmeng Zhang
- Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, China
| | - Bing Han
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou, China
| | - Tongda Xu
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Dongye Li
- Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, China
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7
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Yu J, Shen W, Xu J, Gong B, Gao B, Zhu J. circUSP42 Is Downregulated in Triple-Negative Breast Cancer and Associated With Poor Prognosis. Technol Cancer Res Treat 2020; 19:1533033820950827. [PMID: 32938310 PMCID: PMC7502800 DOI: 10.1177/1533033820950827] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
We previously showed that microRNA-182 (miR-182) might promote cell proliferation and migration in triple-negative breast cancer (TNBC). This study aimed to investigate circular RNAs (circRNAs) that interact with miR-182 and play important roles in TNBC. Thirty patients with TNBC were enrolled. One pair of tumor and adjacent tissue samples (control) were submitted for circRNA sequencing to establish the expression profile of circRNAs. Concomitantly, circRNAs aberrantly expressed between TNBC and control groups were identified, and these differentially expressed circRNAs (DEcircRNAs) were subjected to Gene Ontology and KEGG pathway enrichment analyses, as well as prediction of interactions with miRNAs. The expression levels of 5 circRNAs interacting with miR-182 were validated using qRT-PCR. Associations between the expression of circUSP42 and clinicopathological features and prognosis were evaluated. A total of 825 upregulated and 1127 downregulated DEcircRNAs were identified between tumor and control groups. Upregulated DEcircRNAs were significantly involved in proteoglycans in cancer, and endocytosis. Downregulated DEcircRNAs were involved in the pathway of resistance to EGFR tyrosine kinase inhibitors. Prediction of circRNA-miRNA interactions showed that hsa_circ_0002032, chr6:131973682-132047340+, hsa_circ_0005982, hsa_circ_0007823 (circUSP42), and hsa_circ_0001777 might act as miRNA sponges for miR-182. qRT-PCR showed consistent results with circRNA sequencing data (P < 0.05). Downregulation of circUSP42 was significantly associated with lymph node metastasis (P = 0.005) and advanced clinical stage (P = 0.032). Furthermore, Kaplan-Meier plots showed that low expression of circUSP42 was closely associated with poor outcome (log-rank test, P < 0.001). Our data suggested that dysregulation of circUSP42 might contribute to the development and progression of TNBC.
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Affiliation(s)
- Jinling Yu
- Department of General Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Breast Surgery, Shanghai Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, China
| | - Weida Shen
- Department of Breast Surgery, Shanghai Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, China
| | - Jinping Xu
- Department of Pathology, Shanghai Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, China
| | - Bo Gong
- Department of Laboratory, Shanghai Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, China
| | - Beimin Gao
- Department of Breast Surgery, Shanghai Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, China
| | - Jiangfan Zhu
- Department of General Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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8
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Wang G, Guo X, Cheng L, Chu P, Chen M, Chen Y, Chang C. An integrated analysis of the circRNA-miRNA-mRNA network reveals novel insights into potential mechanisms of cell proliferation during liver regeneration. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2020; 47:3873-3884. [PMID: 31566012 DOI: 10.1080/21691401.2019.1669623] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cell proliferation constitutes the fundamental process and driving force behind regrowth during liver regeneration (LR). However, it remains unclear how competing endogenous RNA (ceRNA) networks affect hepatocyte proliferation and liver regeneration. Therefore, this study was designed to explore an LR-specific ceRNA network, which regulates cell proliferation. Based on the microarray data of mRNAs, and high-throughput sequencing data of miRNAs and circRNAs from regenerating livers, this study initially applied known 1484 LR associated mRNAs to perform GO analysis, and then selected 169 LR associated mRNAs involved in cell proliferation and the cell cycle. Subsequently, 188 interactive miRNA-mRNA pairs and 5206 circRNA-miRNA pairs, respectively, were predicted using bioinformatics methods. Next, in view of the differential expressions of these ceRNAs during LR, 26 miRNA-mRNA pairs and 71 circRNA-miRNA pairs were applied to generate a circRNA-miRNA-mRNA regulatory network, and only 14 triple interactive groups were obtained based on the predicted inverse interactions among ceRNAs. Finally, circ_19698/miR-423-5p axis was demonstrated to promote cell proliferation by modulating the expression of MYC, CCNA2, and CCND1 in rat BRL-3A cells. This study suggests a potential regulatory mechanism of cell proliferation in regenerating livers, as well as a novel pathway for modulating ceRNA networks to promote liver regeneration.
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Affiliation(s)
- Gaiping Wang
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
| | - Xueqiang Guo
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
| | - Liya Cheng
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
| | - Peipei Chu
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
| | - Meng Chen
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
| | - Yanhui Chen
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
| | - Cuifang Chang
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
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9
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Liu J, Li Z, Teng W, Ye X. Identification of downregulated circRNAs from tissue and plasma of patients with gastric cancer and construction of a circRNA-miRNA-mRNA network. J Cell Biochem 2020; 121:4590-4600. [PMID: 32052496 DOI: 10.1002/jcb.29673] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 01/24/2020] [Indexed: 12/26/2022]
Abstract
The connection between circular RNAs (circRNAs) and gastric cancer has been reported widely in recent years. However, previous studies have focused mainly on circRNAs from gastric cancer tissue. The objectives of the present study were to detect dysregulated circRNAs from both tissue and plasma of patients with gastric cancer and to explore their potential roles in the pathogenesis of gastric cancer. Expression profiles of circRNAs were obtained from the Gene Expression Omnibus (GEO) and analyzed using the GEO2R tool to identify differential expressed circRNAs. The significance threshold was set as |log2 (fold change)| > 2 and adjusted P < .05. The microRNA (miRNA) binding sites of the differentially expressed circRNAs were predicted using the Circular RNA Interactome web tool. TargetScan and the miRNet database were used to predict the miRNA target genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed using Database for Annotation Visualization and Integrated Discovery. Hub genes were identified and a network was constructed with Cytoscape. The overall survival rates for the selected miRNAs and messenger RNAs were evaluated by Kaplan-Meier Plotter. A total of three downregulated circRNAs (hsa_circ_0001190, hsa_circ_0036287, and hsa_circ_0048607) were identified in this study. Six miRNAs and eight hub genes met the significance criteria and were selected for further analysis. A circRNA-miRNA-hub gene network was constructed based on three circRNAs, six miRNAs, and eight hub genes. Evaluation of overall survival rates for the hub genes showed that low expression levels of GADD45A, PPP1CB, PJA2, and KLF2 were associated with poor overall survival. This study identified potential novel plasma circRNA biomarkers and provides insights into the underlying mechanisms of gastric cancer pathogenesis.
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Affiliation(s)
- Jingfu Liu
- Department of Blood Transfusion, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Zhen Li
- Department of Blood Transfusion, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Wenhao Teng
- Department of Gastrointestinal Surgery, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Xianren Ye
- Department of Blood Transfusion, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China.,Fujian Provincial Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian, China
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10
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Large-Scale Profiling of RBP-circRNA Interactions from Public CLIP-Seq Datasets. Genes (Basel) 2020; 11:genes11010054. [PMID: 31947823 PMCID: PMC7016857 DOI: 10.3390/genes11010054] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 12/26/2019] [Accepted: 12/29/2019] [Indexed: 12/14/2022] Open
Abstract
Circular RNAs are a special type of RNA that has recently attracted a lot of research interest in studying its formation and function. RNA binding proteins (RBPs) that bind circRNAs are important in these processes, but have been relatively less studied. CLIP-Seq technology has been invented and applied to profile RBP-RNA interactions on the genome-wide scale. While mRNAs are usually the focus of CLIP-Seq experiments, RBP-circRNA interactions could also be identified through specialized analysis of CLIP-Seq datasets. However, many technical difficulties are involved in this process, such as the usually short read length of CLIP-Seq reads. In this study, we created a pipeline called Clirc specialized for profiling circRNAs in CLIP-Seq data and analyzing the characteristics of RBP-circRNA interactions. In conclusion, to our knowledge, this is one of the first studies to investigate circRNAs and their binding partners through repurposing CLIP-Seq datasets, and we hope our work will become a valuable resource for future studies into the biogenesis and function of circRNAs.
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11
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Sui W, Gan Q, Chang Y, Ou M, Chen J, Lin H, Xue W, Wu Y, He H, Tang D, Dai Y. Differential expression profile study and gene function analysis of maternal foetal-derived circRNA for screening for Down's syndrome. Exp Ther Med 2019; 19:1006-1016. [PMID: 32010263 PMCID: PMC6966235 DOI: 10.3892/etm.2019.8288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 10/08/2019] [Indexed: 12/12/2022] Open
Abstract
Recent studies have shown that circular RNAs (circRNAs) exhibit differential expression in certain diseases. However, to the best of our knowledge, maternal fetal-derived circRNAs and mRNAs associated with Down's syndrome (DS) have not yet been investigated. A total of 12 umbilical cord blood samples were collected from pregnant women, including six women carrying fetuses with DS (diagnosed by G-banding karyotype analysis), and six women carrying fetuses without DS. In addition, 12 peripheral blood samples were obtained from children, including six children with DS and six children without DS. Gene chip technology was used to screen for differentially expressed circRNAs and mRNAs in the cord blood samples, and were subsequently verified by reverse transcription-quantitative polymerase chain reaction in peripheral blood from the children to identify potential biomarkers. Furthermore, circRNA/microRNA (miRNA) interactions were predicted using Arraystar miRNA target prediction software. There was a significant difference in the expression of hsa_circRNA_103127, hsa_circRNA_103112 and hsa_circRNA_104907 between cord blood obtained from the women carrying fetuses with and without DS, and between peripheral blood obtained from children with and without DS (P<0.01). As hsa_circRNA_103112 exhibited significant differences in expression between cord blood obtained from the women carrying fetuses with and without DS and between peripheral blood obtained from children with and without DS, its corresponding gene, ubiquitin specific peptidase 25, may be involved in the pathogenesis of the condition. These results suggested that hsa_circRNA_103112 may be upregulated in individuals with DS, resulting in an expression imbalance of diploid genes through interactions among circRNA, miRNA and mRNA. Therefore, the level of hsa_circRNA_103112 in the peripheral blood of a pregnant woman may serve as potential biomarker of fetal DS during non-invasive prenatal screening.
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Affiliation(s)
- Weiguo Sui
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,Kidney Diseases Research, Department of Nephrology, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Qing Gan
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,Kidney Diseases Research, Department of Nephrology, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Yan Chang
- Reproductive Center, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Minglin Ou
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,Kidney Diseases Research, Department of Nephrology, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Jiejing Chen
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,Kidney Diseases Research, Department of Nephrology, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Hua Lin
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,Kidney Diseases Research, Department of Nephrology, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Wen Xue
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,Kidney Diseases Research, Department of Nephrology, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Yan Wu
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
| | - Huiyan He
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
| | - Donge Tang
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
| | - Yong Dai
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,Kidney Diseases Research, Department of Nephrology, Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
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12
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Zhou JZ, Hu MR, Diao HL, Wang QW, Huang Q, Ge BJ. Comprehensive analysis of differentially expressed circRNAs revealed a ceRNA network in pancreatic ductaladenocarcinoma. Arch Med Sci 2019; 15:979-991. [PMID: 31360192 PMCID: PMC6657245 DOI: 10.5114/aoms.2019.85204] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 05/09/2018] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. However, the molecular mechanisms underlying PDAC are still not completely understood. Circular RNAs (circRNAs) are a unique class of RNA formed by special loop splicing. More and more researchers have paid attention to circRNAs. MATERIAL AND METHODS In this study, we constructed a circRNA-mediated competing endogenous RNA (ceRNA) network in PDAC. Gene ontology (GO) analysis was performed to explore circRNAs' potential roles in PDAC progression. We also constructed an up-stream transcriptional network of circRNAs' parental genes and found that many transcription factors (TFs), such as tumor protein p53 (TP53) and MYC, could regulate their expression. RESULTS This study, which aimed to identify differentially expressed circRNAs in PDAC, suggested that circRNAs may also act as biomarkers for PDAC. We analyzed two public datasets (GSE69362 and GSE79634) to identify differentially expressed circRNAs in PDAC. Finally, we found that DExH-Box Helicase 9 (DHX9) may be a potential regulator of circRNA formation in PDAC. Genomic loci of four down-regulated circRNAs - hsa_circ_000691, hsa_circ_0049392, hsa_circ_0005203, and hsa_circ_0001626 - contained DHX9 binding sites, suggesting that they may be directly regulated by DHX9. CONCLUSIONS Our study identified differentially expressed circRNAs in PDAC, suggesting that circRNAs may also act as biomarkers for PDAC. Additional investigations of function and up-stream regulation of differentially expressed circRNA in PDAC are still needed.
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Affiliation(s)
- Jin-Zhe Zhou
- Department of General Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Mu-Ren Hu
- Department of General Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hong-Liang Diao
- Department of General Surgery, Karamay Central Hospital, Karamay, Xinjiang, China
| | - Qi-Wei Wang
- Department of General Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qi Huang
- Department of General Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bu-Jun Ge
- Department of General Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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13
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Zhao RT, Zhou J, Dong XL, Bi CW, Jiang RC, Dong JF, Tian Y, Yuan HJ, Zhang JN. Circular Ribonucleic Acid Expression Alteration in Exosomes from the Brain Extracellular Space after Traumatic Brain Injury in Mice. J Neurotrauma 2018; 35:2056-2066. [PMID: 29409384 DOI: 10.1089/neu.2017.5502] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Rui-ting Zhao
- Department of Pharmacy, General Hospital, Tianjin Medical University, Tianjin, China
| | - Ju Zhou
- Department of Pharmacy, General Hospital, Tianjin Medical University, Tianjin, China
| | - Xin-long Dong
- Department of Neurosurgery, General Hospital, Tianjin Neurological Institute, Tianjin Medical University, Tianjin, China
| | - Chong-wen Bi
- Department of Pharmacy, General Hospital, Tianjin Medical University, Tianjin, China
| | - Rong-cai Jiang
- Department of Neurosurgery, General Hospital, Tianjin Neurological Institute, Tianjin Medical University, Tianjin, China
| | - Jing-fei Dong
- Bloodworks Research Institute, Bloodworks Northwest, Seattle, Washington
- Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
| | - Ye Tian
- Department of Neurosurgery, General Hospital, Tianjin Neurological Institute, Tianjin Medical University, Tianjin, China
| | - Heng-jie Yuan
- Department of Pharmacy, General Hospital, Tianjin Medical University, Tianjin, China
- Department of Neurosurgery, General Hospital, Tianjin Neurological Institute, Tianjin Medical University, Tianjin, China
| | - Jian-ning Zhang
- Department of Neurosurgery, General Hospital, Tianjin Neurological Institute, Tianjin Medical University, Tianjin, China
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14
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Circular RNAs and their associations with breast cancer subtypes. Oncotarget 2018; 7:80967-80979. [PMID: 27829232 PMCID: PMC5348369 DOI: 10.18632/oncotarget.13134] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 10/29/2016] [Indexed: 12/22/2022] Open
Abstract
Circular RNAs (circRNAs) are highly stable forms of non-coding RNAs with diverse biological functions. They are implicated in modulation of gene expression thus affecting various cellular and disease processes. Based on existing bioinformatics approaches, we developed a comprehensive workflow called Circ-Seq to identify and report expressed circRNAs. Circ-Seq also provides informative genomic annotation along circRNA fused junctions thus allowing prioritization of circRNA candidates. We applied Circ-Seq first to RNA-sequence data from breast cancer cell lines and validated one of the large circRNAs identified. Circ-Seq was then applied to a larger cohort of breast cancer samples (n = 885) provided by The Cancer Genome Atlas (TCGA), including tumors and normal-adjacent tissue samples. Notably, circRNA results reveal that normal-adjacent tissues in estrogen receptor positive (ER+) subtype have relatively higher numbers of circRNAs than tumor samples in TCGA. Similar phenomenon of high circRNA numbers were observed in normal breast-mammary tissues from the Genotype-Tissue Expression (GTEx) project. Finally, we observed that number of circRNAs in normal-adjacent samples of ER+ subtype is inversely correlated to the risk-of-relapse proliferation (ROR-P) score for proliferating genes, suggesting that circRNA frequency may be a marker for cell proliferation in breast cancer. The Circ-Seq workflow will function for both single and multi-threaded compute environments. We believe that Circ-Seq will be a valuable tool to identify circRNAs useful in the diagnosis and treatment of other cancers and complex diseases.
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15
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Tan WLW, Lim BTS, Anene-Nzelu CGO, Ackers-Johnson M, Dashi A, See K, Tiang Z, Lee DP, Chua WW, Luu TDA, Li PYQ, Richards AM, Foo RSY. A landscape of circular RNA expression in the human heart. Cardiovasc Res 2017; 113:298-309. [PMID: 28082450 DOI: 10.1093/cvr/cvw250] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Accepted: 12/06/2016] [Indexed: 12/17/2022] Open
Abstract
Aims Circular RNA (circRNA) is a newly validated class of single-stranded RNA, ubiquitously expressed in mammalian tissues and possessing key functions including acting as microRNA sponges and as transcriptional regulators by binding to RNA-binding proteins. While independent studies confirm the expression of circRNA in various tissue types, genome-wide circRNA expression in the heart has yet to be described in detail. Methods and results We performed deep RNA-sequencing on ribosomal-depleted RNA isolated from 12 human hearts, 25 mouse hearts and across a 28-day differentiation time-course of human embryonic stem cell-derived cardiomyocytes. Using purpose-designed bioinformatics tools, we uncovered a total of 15 318 and 3017 cardiac circRNA within human and mouse, respectively. Their abundance generally correlates with the abundance of their cognate linear RNA, but selected circRNAs exist at disproportionately higher abundance. Top highly expressed circRNA corresponded to key cardiac genes including Titin (TTN), RYR2, and DMD. The most abundant cardiac-expressed circRNA is a cytoplasmic localized single-exon circSLC8A1-1. The longest human transcript TTN alone generates up to 415 different exonic circRNA isoforms, the majority (83%) of which originates from the I-band domain. Finally, we confirmed the expression of selected cardiac circRNA by RT-PCR, Sanger sequencing and single molecule RNA-fluorescence in situ hybridization. Conclusions Our data provide a detailed circRNA expression landscape in hearts. There is a high-abundance of specific cardiac-expressed circRNA. These findings open up a new avenue for future investigation into this emerging class of RNA.
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Affiliation(s)
- Wilson L W Tan
- Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.,Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore
| | - Benson T S Lim
- Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.,Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore
| | - Chukwuemeka G O Anene-Nzelu
- Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.,Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore
| | - Matthew Ackers-Johnson
- Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.,Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore
| | - Albert Dashi
- Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.,Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore
| | - Kelvin See
- Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore
| | - Zenia Tiang
- Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.,Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore
| | - Dominic Paul Lee
- Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore
| | - Wee Woon Chua
- Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore
| | - Tuan D A Luu
- Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore
| | - Peter Y Q Li
- Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore
| | - Arthur Mark Richards
- Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore
| | - Roger S Y Foo
- Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.,Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore
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16
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Yang Q, Du WW, Wu N, Yang W, Awan FM, Fang L, Ma J, Li X, Zeng Y, Yang Z, Dong J, Khorshidi A, Yang BB. A circular RNA promotes tumorigenesis by inducing c-myc nuclear translocation. Cell Death Differ 2017; 24:1609-1620. [PMID: 28622299 PMCID: PMC5563992 DOI: 10.1038/cdd.2017.86] [Citation(s) in RCA: 251] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 04/10/2017] [Accepted: 04/26/2017] [Indexed: 12/31/2022] Open
Abstract
Circular RNAs (circRNAs) are a subclass of noncoding RNAs widely expressed in mammalian cells. We report here the tumorigenic capacity of a circRNA derived from angiomotin-like1 (circ-Amotl1). Circ-Amotl1 is highly expressed in patient tumor samples and cancer cell lines. Single-cell inoculations using circ-Amotl1-transfected tumor cells showed a 30-fold increase in proliferative capacity relative to control. Agarose colony-formation assays similarly revealed a 142-fold increase. Tumor-take rate in nude mouse xenografts using 6-day (219 cells) and 3-day (9 cells) colonies were 100%, suggesting tumor-forming potential of every cell. Subcutaneous single-cell injections led to the formation of palpable tumors in 41% of mice, with tumor sizes >1 cm3 in 1 month. We further found that this potent tumorigenicity was triggered through interactions between circ-Amotl1 and c-myc. A putative binding site was identified in silico and tested experimentally. Ectopic expression of circ-Amotl1 increased retention of nuclear c-myc, appearing to promote c-myc stability and upregulate c-myc targets. Expression of circ-Amotl1 also increased the affinity of c-myc binding to a number of promoters. Our study therefore reveals a novel function of circRNAs in tumorigenesis, and this subclass of noncoding RNAs may represent a potential target in cancer therapy.
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Affiliation(s)
- Qi Yang
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - William W Du
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Nan Wu
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Weining Yang
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Faryal Mehwish Awan
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Ling Fang
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- China–Japan Union Hospital of Jilin University, Jilin, China
| | - Jian Ma
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Xiangmin Li
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Yan Zeng
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Zhenguo Yang
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Jun Dong
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Azam Khorshidi
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Burton B Yang
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
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17
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Mi T, Luo C, Hu Y, Qu C, Wang X, Guo S, Du Y. Spectrum construction of differentially expressed circular RNAs in patients with leukoaraiosis and function analysis of differentially expressed genes. Mol Med Rep 2017; 16:2563-2569. [PMID: 28677780 PMCID: PMC5548020 DOI: 10.3892/mmr.2017.6871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Accepted: 03/03/2017] [Indexed: 01/26/2023] Open
Abstract
Circular RNAs (circRNAs) are class of endogenous RNAs that have a role in the regulation of gene expression. The present study aimed to investigate the diagnostic value and role of circRNA in the pathogenesis of leukoaraiosis (LA). The present study performed Arraystar Human circRNA Array analysis of 6 samples from LA cases and 6 samples from control cases. Differentially expressed (DE) circRNAs between two samples were identified through fold-change (>1.5-fold) screening. Afterwards, based on DE circRNAs, the gene ontology (GO) analysis of upregulated DE genes identified from DE circRNAs demonstrated that DE genes were primarily associated with cellular metabolic processes, membrane-bound organelles and binding. However, none were enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Downregulated DE genes were enriched in cellular localization, cytoplasm and kinase binding. For the KEGG pathways, the downregulated DE genes were primarily associated with the insulin signaling pathway. The results of the present study indicated that the DE genes from differently expressed circRNAs may have an important role in the pathogenesis of LA and may be a novel targfet for further research.
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Affiliation(s)
- Te Mi
- Department of ICU, Jining No. 1 People's Hospital, Jining, Shandong 272000, P.R. China
| | - Changjiang Luo
- Department of Neurology, Provincial Hospital Affiliated to Shandong University (South Branch), Jinan, Shandong 250002, P.R. China
| | - Yawei Hu
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University Jining, Shandong 272029, P.R. China
| | - Chuanqiang Qu
- Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xiang Wang
- Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Shougang Guo
- Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Yifeng Du
- Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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18
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Greene J, Baird AM, Brady L, Lim M, Gray SG, McDermott R, Finn SP. Circular RNAs: Biogenesis, Function and Role in Human Diseases. Front Mol Biosci 2017. [PMID: 28634583 PMCID: PMC5459888 DOI: 10.3389/fmolb.2017.00038] [Citation(s) in RCA: 426] [Impact Index Per Article: 53.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Circular RNAs (circRNAs) are currently classed as non-coding RNA (ncRNA) that, unlike linear RNAs, form covalently closed continuous loops and act as gene regulators in mammals. They were originally thought to represent errors in splicing and considered to be of low abundance, however, there is now an increased appreciation of their important function in gene regulation. circRNAs are differentially generated by backsplicing of exons or from lariat introns. Unlike linear RNA, the 3' and 5' ends normally present in an RNA molecule have been joined together by covalent bonds leading to circularization. Interestingly, they have been found to be abundant, evolutionally conserved and relatively stable in the cytoplasm. These features confer numerous potential functions to circRNAs, such as acting as miRNA sponges, or binding to RNA-associated proteins to form RNA-protein complexes that regulate gene transcription. It has been proposed that circRNA regulate gene expression at the transcriptional or post-transcriptional level by interacting with miRNAs and that circRNAs may have a role in regulating miRNA function in cancer initiation and progression. circRNAs appear to be more often downregulated in tumor tissue compared to normal tissue and this may be due to (i) errors in the back-splice machinery in malignant tissues, (ii) degradation of circRNAs by deregulated miRNAs in tumor tissue, or (iii) increasing cell proliferation leading to a reduction of circRNAs. circRNAs have been identified in exosomes and more recently, chromosomal translocations in cancer have been shown to generate aberrant fusion-circRNAs associated with resistance to drug treatments. In addition, though originally thought to be non-coding, there is now increasing evidence to suggest that select circRNAs can be translated into functional proteins. Although much remains to be elucidated about circRNA biology and mechanisms of gene regulation, these ncRNAs are quickly emerging as potential disease biomarkers and therapeutic targets in cancer.
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Affiliation(s)
- John Greene
- Department of Histopathology and Morbid Anatomy, School of Medicine, Trinity College DublinDublin, Ireland.,Department of Medical Oncology, Tallaght HospitalDublin, Ireland
| | - Anne-Marie Baird
- Department of Histopathology and Morbid Anatomy, School of Medicine, Trinity College DublinDublin, Ireland.,Thoracic Oncology Research Group, Trinity Translational Medical Institute, St. James's HospitalDublin, Ireland.,Department of Clinical Medicine, Trinity College DublinDublin, Ireland.,Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation, Queensland University of TechnologyBrisbane, QLD, Australia
| | - Lauren Brady
- Department of Histopathology and Morbid Anatomy, School of Medicine, Trinity College DublinDublin, Ireland
| | - Marvin Lim
- Department of Medical Oncology, St. Vincent's University HospitalDublin, Ireland
| | - Steven G Gray
- Thoracic Oncology Research Group, Trinity Translational Medical Institute, St. James's HospitalDublin, Ireland.,Department of Clinical Medicine, Trinity College DublinDublin, Ireland.,HOPE Directorate, St. James's HospitalDublin, Ireland.,Labmed Directorate, St. James's HospitalDublin, Ireland
| | - Raymond McDermott
- Department of Medical Oncology, Tallaght HospitalDublin, Ireland.,Department of Medical Oncology, St. Vincent's University HospitalDublin, Ireland
| | - Stephen P Finn
- Department of Histopathology and Morbid Anatomy, School of Medicine, Trinity College DublinDublin, Ireland.,Thoracic Oncology Research Group, Trinity Translational Medical Institute, St. James's HospitalDublin, Ireland.,Department of Clinical Medicine, Trinity College DublinDublin, Ireland.,Department of Histopathology, St. James's HospitalDublin, Ireland
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19
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Sui W, Shi Z, Xue W, Ou M, Zhu Y, Chen J, Lin H, Liu F, Dai Y. Circular RNA and gene expression profiles in gastric cancer based on microarray chip technology. Oncol Rep 2017; 37:1804-1814. [DOI: 10.3892/or.2017.5415] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 01/09/2017] [Indexed: 12/12/2022] Open
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20
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Samir M, Vaas LAI, Pessler F. MicroRNAs in the Host Response to Viral Infections of Veterinary Importance. Front Vet Sci 2016; 3:86. [PMID: 27800484 PMCID: PMC5065965 DOI: 10.3389/fvets.2016.00086] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 09/12/2016] [Indexed: 12/13/2022] Open
Abstract
The discovery of small regulatory non-coding RNAs has been an exciting advance in the field of genomics. MicroRNAs (miRNAs) are endogenous RNA molecules, approximately 22 nucleotides in length, that regulate gene expression, mostly at the posttranscriptional level. MiRNA profiling technologies have made it possible to identify and quantify novel miRNAs and to study their regulation and potential roles in disease pathogenesis. Although miRNAs have been extensively investigated in viral infections of humans, their implications in viral diseases affecting animals of veterinary importance are much less understood. The number of annotated miRNAs in different animal species is growing continuously, and novel roles in regulating host–pathogen interactions are being discovered, for instance, miRNA-mediated augmentation of viral transcription and replication. In this review, we present an overview of synthesis and function of miRNAs and an update on the current state of research on host-encoded miRNAs in the genesis of viral infectious diseases in their natural animal host as well as in selected in vivo and in vitro laboratory models.
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Affiliation(s)
- Mohamed Samir
- TWINCORE, Center for Experimental and Clinical Infection Research, Hannover, Germany; Department of Zoonoses, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Lea A I Vaas
- TWINCORE, Center for Experimental and Clinical Infection Research , Hannover , Germany
| | - Frank Pessler
- TWINCORE, Center for Experimental and Clinical Infection Research, Hannover, Germany; Helmholtz Center for Infection Research, Braunschweig, Germany
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21
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Abu N, Jamal R. Circular RNAs as Promising Biomarkers: A Mini-Review. Front Physiol 2016; 7:355. [PMID: 27588005 PMCID: PMC4988965 DOI: 10.3389/fphys.2016.00355] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 08/04/2016] [Indexed: 01/01/2023] Open
Abstract
The interest in circular RNAs has resurfaced in the past few years. What was considered as "junk" for nearly two decades is now one of the most interesting molecules. Circular RNAs are non-coding RNAs that are formed by back-splicing events and have covalently closed loops with no poly-adenylated tails. The regulation of circular RNAs is distinctive and they are selectively abundant in different types of tissues. Based on the current knowledge of circular RNAs, these molecules have the potential to be the "next big thing" especially as biomarkers for different diseases. This mini-review attempts to concisely look at the biology of circular RNAs, the putative functional activities, the prevalence of circular RNAs, and the possible role of circular RNA as biomarkers for diagnosis or measuring drug response.
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Affiliation(s)
- Nadiah Abu
- UKM Medical Molecular Biology Institute, University Kebangsaan Malaysia (UKM) Medical Centre Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute, University Kebangsaan Malaysia (UKM) Medical Centre Kuala Lumpur, Malaysia
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22
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Littlejohn M, Locarnini S, Yuen L. Origins and Evolution of Hepatitis B Virus and Hepatitis D Virus. Cold Spring Harb Perspect Med 2016; 6:a021360. [PMID: 26729756 DOI: 10.1101/cshperspect.a021360] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Members of the family Hepadnaviridae fall into two subgroups: mammalian and avian. The detection of endogenous avian hepadnavirus DNA integrated into the genomes of zebra finches has revealed a deep evolutionary origin of hepadnaviruses that was not previously recognized, dating back at least 40 million and possibly >80 million years ago. The nonprimate mammalian members of the Hepadnaviridae include the woodchuck hepatitis virus (WHV), the ground squirrel hepatitis virus, and arctic squirrel hepatitis virus, as well as a number of members of the recently described bat hepatitis virus. The identification of hepatitis B viruses (HBVs) in higher primates, such as chimpanzee, gorilla, orangutan, and gibbons that cluster with the human HBV, as well as a number of recombinant forms between humans and primates, further implies a more complex origin of this virus. We discuss the current theories of the origin and evolution of HBV and propose a model that includes cross-species transmissions and subsequent recombination events on a genetic backbone of genotype C HBV infection. The hepatitis delta virus (HDV) is a defective RNA virus requiring the presence of the HBV for the completion of its life cycle. The origins of this virus remain unknown, although some recent studies have suggested an ancient African radiation. The age of the association between HDV and HBV is also unknown.
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Affiliation(s)
- Margaret Littlejohn
- Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Doherty Institute, Melbourne 3000, Australia
| | - Stephen Locarnini
- Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Doherty Institute, Melbourne 3000, Australia
| | - Lilly Yuen
- Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Doherty Institute, Melbourne 3000, Australia
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23
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Abstract
Transcriptional and epigenetic regulation is critical for proper heart development, cardiac homeostasis, and pathogenesis. Long noncoding RNAs have emerged as key components of the transcriptional regulatory pathways that govern cardiac development as well as stress response, signaling, and remodeling in cardiac pathologies. Within the past few years, studies have identified many long noncoding RNAs in the context of cardiovascular biology and have begun to reveal the key functions of these transcripts. In this review, we discuss the growing roles of long noncoding RNAs in different aspects of cardiovascular development as well as pathological responses during injury or disease. In addition, we discuss diverse mechanisms by which long noncoding RNAs orchestrate cardiac transcriptional programs. Finally, we explore the exciting potential of this novel class of transcripts as biomarkers and novel therapeutic targets for cardiovascular diseases.
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Affiliation(s)
- Gizem Rizki
- From the Department of Biology, Massachusetts Institute of Technology, Cambridge
| | - Laurie A Boyer
- From the Department of Biology, Massachusetts Institute of Technology, Cambridge.
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Pan K, Lee JTH, Huang Z, Wong CM. Coupling and coordination in gene expression processes with pre-mRNA splicing. Int J Mol Sci 2015; 16:5682-96. [PMID: 25768347 PMCID: PMC4394499 DOI: 10.3390/ijms16035682] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 02/28/2015] [Accepted: 03/04/2015] [Indexed: 12/13/2022] Open
Abstract
RNA processing is a tightly regulated and highly complex pathway which includes transcription, splicing, editing, transportation, translation and degradation. It has been well-documented that splicing of RNA polymerase II medicated nascent transcripts occurs co-transcriptionally and is functionally coupled to other RNA processing. Recently, increasing experimental evidence indicated that pre-mRNA splicing influences RNA degradation and vice versa. In this review, we summarized the recent findings demonstrating the coupling of these two processes. In addition, we highlighted the importance of splicing in the production of intronic miRNA and circular RNAs, and hence the discovery of the novel mechanisms in the regulation of gene expression.
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Taylor JM. Host RNA circles and the origin of hepatitis delta virus. World J Gastroenterol 2014; 20:2971-2978. [PMID: 24659888 PMCID: PMC3961984 DOI: 10.3748/wjg.v20.i11.2971] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 12/20/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Recent reports show that many cellular RNAs are processed to form circular species that are relatively abundant and resistant to host nucleases. In some cases, such circles actually bind host microRNAs. Such depletion of available microRNAs appears to have biological roles; for instance, in homeostasis and disease. These findings regarding host RNA circles support a speculative reappraisal of the origin and mode of replication of hepatitis delta virus, hepatitis delta virus (HDV), an agent with a small circular RNA genome; specifically, it is proposed that in hepatocytes infected with hepatitis B virus (HBV), some viral RNA species are processed to circular forms, which by a series of chance events lead to an RNA that can be both replicated by host enzymes and assembled, using HBV envelope proteins, to form particles some of which are infectious. Such a model also may provide some new insights into the potential pathogenic potential of HDV infections. In return, new insights into HDV might provide information leading to a better understanding of the roles of the host RNA circles.
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