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Song X, Xu Y, Li M, Guan X, Liu H, Zhang J, Sun H, Ma C, Zhang L, Zhao X, Zheng X, Zhu D. SRSF4-Associated ca-circFOXP1 Regulates Hypoxia-Induced PASMC Proliferation by the Formation of R Loop With Host Gene. Arterioscler Thromb Vasc Biol 2025; 45:e118-e135. [PMID: 39973750 DOI: 10.1161/atvbaha.124.322026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 01/24/2025] [Accepted: 02/04/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND Pulmonary hypertension (PH) is a rare and fatal disease, the pathological changes of which include pulmonary arterial smooth muscle cell (PASMC) proliferation, which is the pathological basis of pulmonary vascular remodeling. Studies have demonstrated that chromatin-associated circRNA can regulate a variety of biological processes. However, the role of chromatin-associated circRNA in the proliferation of PH remains largely unexplored. In this study, we aimed to identify the function and mechanism of chromatin-associated circRNA in PASMC proliferation in PH. METHODS The role of chromatin-associated circFOXP1 (ca-circFOXP1) was investigated in hypoxic mouse PASMCs and SuHX (Sugen5416+hypoxia) model mice through the use of antisense oligonucleotide knockdown and adeno-associated virus-mediated knockdown. Through bioinformatic sequence alignment, chromatin isolation by RNA purification, Cell Counting Kit 8, 5-ethynyl-2-deoxyuridine, Western blot, and other experiments, the function and mechanism of ca-circFOXP1 were verified. RESULTS The expression of ca-circFOXP1 was found to be significantly increased in SuHX model mice and hypoxic mouse PASMCs. Moreover, ca-circFOXP1 was found to regulate the level of the host protein FOXP1 (forkhead box protein 1) through the R loop, thereby influencing the phosphorylation activity of SMAD2 (SMAD family member 2) and, consequently, the proliferation of mouse PASMCs. It is noteworthy that the m6A modification was found to promote the formation of the R loop between ca-circFOXP1 and the host gene FOXP1, thereby regulating the expression of the host protein. Furthermore, we have identified that the splicing factor SRSF4 (serine/arginine rich splicing factor 4) can upregulate the expression of ca-circFOXP1 by splicing exons 6 and 9 of FOXP1 pre-mRNA. CONCLUSIONS The results demonstrated that the splicing factor SRSF4 upregulated the expression of ca-circFOXP1, and m6A methylation promoted R-loop formation between ca-circFOXP1 and host genes, regulated the level of host protein FOXP1, and then affected the phosphorylation activity of SMAD2, mediating PASMC proliferation, leading to pulmonary vascular remodeling. These results provide a theoretical basis for further study of the pathological mechanisms of hypoxic PH and may provide certain insights.
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MESH Headings
- Animals
- Cell Proliferation
- Pulmonary Artery/metabolism
- Pulmonary Artery/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Disease Models, Animal
- Mice
- Serine-Arginine Splicing Factors/metabolism
- Serine-Arginine Splicing Factors/genetics
- RNA, Circular/metabolism
- RNA, Circular/genetics
- Forkhead Transcription Factors/metabolism
- Forkhead Transcription Factors/genetics
- Male
- Smad2 Protein/metabolism
- Cell Hypoxia
- Mice, Inbred C57BL
- Cells, Cultured
- Signal Transduction
- Humans
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/genetics
- Hypertension, Pulmonary/pathology
- Vascular Remodeling
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Affiliation(s)
- Xinyue Song
- College of Pharmacy (X.S., Y.X., M.L., X.G., H.L., H.S., C.M., L.Z., X. Zhao, D.Z.), Harbin Medical University, P.R. China
- Central Laboratory of Harbin Medical University (Daqing), P.R. China (X.S., Y.X., M.L., X.G., H.L., J.Z., H.S., D.Z.)
| | - Ya Xu
- College of Pharmacy (X.S., Y.X., M.L., X.G., H.L., H.S., C.M., L.Z., X. Zhao, D.Z.), Harbin Medical University, P.R. China
- Central Laboratory of Harbin Medical University (Daqing), P.R. China (X.S., Y.X., M.L., X.G., H.L., J.Z., H.S., D.Z.)
| | - Mengnan Li
- College of Pharmacy (X.S., Y.X., M.L., X.G., H.L., H.S., C.M., L.Z., X. Zhao, D.Z.), Harbin Medical University, P.R. China
- Central Laboratory of Harbin Medical University (Daqing), P.R. China (X.S., Y.X., M.L., X.G., H.L., J.Z., H.S., D.Z.)
| | - Xiaoyu Guan
- College of Pharmacy (X.S., Y.X., M.L., X.G., H.L., H.S., C.M., L.Z., X. Zhao, D.Z.), Harbin Medical University, P.R. China
- Central Laboratory of Harbin Medical University (Daqing), P.R. China (X.S., Y.X., M.L., X.G., H.L., J.Z., H.S., D.Z.)
| | - Huiyu Liu
- College of Pharmacy (X.S., Y.X., M.L., X.G., H.L., H.S., C.M., L.Z., X. Zhao, D.Z.), Harbin Medical University, P.R. China
- Central Laboratory of Harbin Medical University (Daqing), P.R. China (X.S., Y.X., M.L., X.G., H.L., J.Z., H.S., D.Z.)
| | - Jingya Zhang
- Central Laboratory of Harbin Medical University (Daqing), P.R. China (X.S., Y.X., M.L., X.G., H.L., J.Z., H.S., D.Z.)
| | - Hanliang Sun
- College of Pharmacy (X.S., Y.X., M.L., X.G., H.L., H.S., C.M., L.Z., X. Zhao, D.Z.), Harbin Medical University, P.R. China
- Central Laboratory of Harbin Medical University (Daqing), P.R. China (X.S., Y.X., M.L., X.G., H.L., J.Z., H.S., D.Z.)
| | - Cui Ma
- College of Pharmacy (X.S., Y.X., M.L., X.G., H.L., H.S., C.M., L.Z., X. Zhao, D.Z.), Harbin Medical University, P.R. China
- College of Medical Laboratory Science and Technology (C.M., L.Z., X. Zhao), Harbin Medical University (Daqing), P.R. China
| | - Lixin Zhang
- College of Pharmacy (X.S., Y.X., M.L., X.G., H.L., H.S., C.M., L.Z., X. Zhao, D.Z.), Harbin Medical University, P.R. China
- College of Medical Laboratory Science and Technology (C.M., L.Z., X. Zhao), Harbin Medical University (Daqing), P.R. China
| | - Xijuan Zhao
- College of Pharmacy (X.S., Y.X., M.L., X.G., H.L., H.S., C.M., L.Z., X. Zhao, D.Z.), Harbin Medical University, P.R. China
- College of Medical Laboratory Science and Technology (C.M., L.Z., X. Zhao), Harbin Medical University (Daqing), P.R. China
| | - Xiaodong Zheng
- Department of Genetic and Cell Biology (X. Zheng), Harbin Medical University (Daqing), P.R. China
| | - Daling Zhu
- College of Pharmacy (X.S., Y.X., M.L., X.G., H.L., H.S., C.M., L.Z., X. Zhao, D.Z.), Harbin Medical University, P.R. China
- Key Laboratory of Cardiovascular Medicine Research, Ministry of Education (D.Z.), Harbin Medical University, P.R. China
- Central Laboratory of Harbin Medical University (Daqing), P.R. China (X.S., Y.X., M.L., X.G., H.L., J.Z., H.S., D.Z.)
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Yadav V, Singh T, Sharma D, Garg VK, Chakraborty P, Ghatak S, Satapathy SR. Unraveling the Regulatory Role of HuR/microRNA Axis in Colorectal Cancer Tumorigenesis. Cancers (Basel) 2024; 16:3183. [PMID: 39335155 PMCID: PMC11430344 DOI: 10.3390/cancers16183183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/04/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Colorectal cancer (CRC) remains a significant global health burden with high incidence and mortality. MicroRNAs (miRNAs) are small non-protein coding transcripts, conserved throughout evolution, with an important role in CRC tumorigenesis, and are either upregulated or downregulated in various cancers. RNA-binding proteins (RBPs) are known as essential regulators of miRNA activity. Human antigen R (HuR) is a prominent RBP known to drive tumorigenesis with a pivotal role in CRC. In this review, we discuss the regulatory role of the HuR/miRNA axis in CRC. Interestingly, miRNAs can directly target HuR, altering its expression and activity. However, HuR can also stabilize or degrade miRNAs, forming complex feedback loops that either activate or block CRC-associated signaling pathways. Dysregulation of the HuR/miRNA axis contributes to CRC initiation and progression. Additionally, HuR-miRNA regulation by other small non-coding RNAs, circular RNA (circRNAs), or long-non-coding RNAs (lncRNAs) is also explored here. Understanding this HuR-miRNA interplay could reveal novel biomarkers with better diagnostic or prognostic accuracy.
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Affiliation(s)
- Vikas Yadav
- Department of Translational Medicine, Clinical Research Centre, Lund University, 221 00 Malmö, Sweden;
| | - Tejveer Singh
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, University of Delhi, New Delhi 110021, India; (T.S.); (D.S.)
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences (INMAS-DRDO), New Delhi 110054, India
| | - Deepika Sharma
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, University of Delhi, New Delhi 110021, India; (T.S.); (D.S.)
| | - Vivek Kumar Garg
- Department of Medical Lab Technology, Chandigarh University, Gharuan, Mohali 140413, Punjab, India;
| | - Payel Chakraborty
- Amity Institute of Biotechnology, Amity University Kolkata, Kolkata 700135, West Bengal, India; (P.C.); (S.G.)
| | - Souvik Ghatak
- Amity Institute of Biotechnology, Amity University Kolkata, Kolkata 700135, West Bengal, India; (P.C.); (S.G.)
| | - Shakti Ranjan Satapathy
- Department of Translational Medicine, Clinical Research Centre, Lund University, 221 00 Malmö, Sweden;
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Powell AA, Velleman SG, Strasburg GM, Abrahante Lloréns JE, Reed KM. Circular RNA expression in turkey skeletal muscle satellite cells is significantly altered by thermal challenge. Front Physiol 2024; 15:1476487. [PMID: 39359572 PMCID: PMC11445135 DOI: 10.3389/fphys.2024.1476487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 08/28/2024] [Indexed: 10/04/2024] Open
Abstract
Introduction Understanding the genetic mechanisms behind muscle growth and development is crucial for improving the efficiency of animal protein production. Recent poultry studies have identified genes related to muscle development and explored how environmental stressors, such as temperature extremes, affect protein production and meat quality. Non-coding RNAs, including circular RNAs (circRNAs), play crucial roles in modulating gene expression and regulating the translation of mRNAs into proteins. This study examined circRNA expression in turkey skeletal muscle stem cells under thermal stress. The objectives were to identify and quantify circRNAs, assess circRNA abundance following RNAse R depletion, identify differentially expressed circRNAs (DECs), and predict potential microRNA (miRNA) targets for DECs and their associated genes. Materials and methods Cultured cells from two genetic lines (Nicholas commercial turkey and The Ohio State Random Bred Control 2) under three thermal treatments: cold (33°C), control (38°C), and hot (43°C) were compared at both the proliferation and differentiation stages. CircRNA prediction and differential expression and splicing analyses were conducted using the CIRIquant pipeline for both the untreated and RNase R depletion treated libraries. Predicted interactions between DECs and miRNAs, as well as the potential impact of circRNA secondary structure on these interactions, were investigated. Results A total of 11,125 circRNAs were predicted within the treatment groups, between both untreated and RNase R treated libraries. Differential expression analyses indicated that circRNA expression was significantly altered by thermal treatments and the genetic background of the stem cells. A total of 140 DECs were identified across the treatment comparisons. In general, more DECs within temperature treatment comparisons were identified in the proliferation stage and more DECs within genetic line comparisons were identified in the differentiation stage. Discussion This study highlights the significant impact of environmental stressors on non-coding RNAs and their role in gene regulation. Elucidating the role of non-coding RNAs in gene regulation can help further our understanding of muscle development and poultry production, underscoring the broader implications of this research for enhancing animal protein production efficiency.
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Affiliation(s)
- Ashley A Powell
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN, United States
| | - Sandra G Velleman
- Department of Animal Sciences, The Ohio State University, Wooster, OH, United States
| | - Gale M Strasburg
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States
| | | | - Kent M Reed
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN, United States
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Siedlecki E, Remiszewski P, Stec R. The Role of circHIPK3 in Tumorigenesis and Its Potential as a Biomarker in Lung Cancer. Cells 2024; 13:1483. [PMID: 39273053 PMCID: PMC11393915 DOI: 10.3390/cells13171483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/27/2024] [Accepted: 08/31/2024] [Indexed: 09/15/2024] Open
Abstract
Lung cancer treatment and detection can be improved by the identification of new biomarkers. Novel approaches in investigating circular RNAs (circRNAs) as biomarkers have yielded promising results. A circRNA molecule circHIPK3 was found to be widely expressed in non-small-cell lung cancer (NSCLC) cells, where it plays a crucial role in lung cancer tumorigenesis. CircHIPK3 promotes lung cancer progression by sponging oncosuppressive miRNAs such as miR-124, miR-381-3p, miR-149, and miR-107, which results in increased cell proliferation, migration, and resistance to therapies. Inhibiting circHIPK3 has been demonstrated to suppress tumour growth and induce apoptosis, which suggests its potential use in the development of new lung cancer treatment strategies targeting circHIPK3-related pathways. As a biomarker, circHIPK3 shows promise for early detection and monitoring of lung cancer. CircHIPK3 increased expression levels in lung cancer cells, and its potential link to metastasis risk highlights its clinical relevance. Given the promising preliminary findings, more clinical trials are needed to validate circHIPK3 efficacy as a biomarker. Moreover, future research should determine if the mechanisms discovered in NSCLC apply to small cell lung cancer (SCLC) to investigate circHIPK3-targeted therapies for SCLC.
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Affiliation(s)
- Eryk Siedlecki
- Department of Oncology, Medical University of Warsaw, 02-097 Warsaw, Poland; (P.R.); (R.S.)
- Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Piotr Remiszewski
- Department of Oncology, Medical University of Warsaw, 02-097 Warsaw, Poland; (P.R.); (R.S.)
- Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Rafał Stec
- Department of Oncology, Medical University of Warsaw, 02-097 Warsaw, Poland; (P.R.); (R.S.)
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5
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Zhand S, Liao J, Castorina A, Yuen ML, Ebrahimi Warkiani M, Cheng YY. Small Extracellular Vesicle-Derived Circular RNA hsa_circ_0007386 as a Biomarker for the Diagnosis of Pleural Mesothelioma. Cells 2024; 13:1037. [PMID: 38920665 PMCID: PMC11201843 DOI: 10.3390/cells13121037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 05/30/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024] Open
Abstract
Pleural mesothelioma (PM) is a highly aggressive tumor that is caused by asbestos exposure and lacks effective therapeutic regimens. Current procedures for PM diagnosis are invasive and can take a long time to reach a definitive result. Small extracellular vesicles (sEVs) have been identified as important communicators between tumor cells and their microenvironment via their cargo including circular RNAs (circRNAs). CircRNAs are thermodynamically stable, highly conserved, and have been found to be dysregulated in cancer. This study aimed to identify potential biomarkers for PM diagnosis by investigating the expression of specific circRNA gene pattern (hsa_circ_0007386) in cells and sEVs using digital polymerase chain reaction (dPCR). For this reason, 5 PM, 14 non-PM, and one normal mesothelial cell line were cultured. The sEV was isolated from the cells using the gold standard ultracentrifuge method. The RNA was extracted from both cells and sEVs, cDNA was synthesized, and dPCR was run. Results showed that hsa_circ_0007386 was significantly overexpressed in PM cell lines and sEVs compared to non-PM and normal mesothelial cell lines (p < 0.0001). The upregulation of hsa_circ_0007386 in PM highlights its potential as a diagnostic biomarker. This study underscores the importance and potential of circRNAs and sEVs as cancer diagnostic tools.
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Affiliation(s)
- Sareh Zhand
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Jiayan Liao
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Alessandro Castorina
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Man-Lee Yuen
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Majid Ebrahimi Warkiani
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
- Institute of Molecular Medicine, Sechenov First Moscow State University, Moscow 119991, Russia
| | - Yuen-Yee Cheng
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
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Valenti MT, Zerlotin R, Cominacini M, Bolognin S, Grano M, Dalle Carbonare L. Exploring the Role of Circular RNA in Bone Biology: A Comprehensive Review. Cells 2024; 13:999. [PMID: 38920630 PMCID: PMC11201515 DOI: 10.3390/cells13120999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/05/2024] [Accepted: 06/07/2024] [Indexed: 06/27/2024] Open
Abstract
Circular RNAs (circRNAs) have emerged as pivotal regulators of gene expression with diverse roles in various biological processes. In recent years, research into circRNAs' involvement in bone biology has gained significant attention, unveiling their potential as novel regulators and biomarkers in bone-related disorders and diseases. CircRNAs, characterized by their closed-loop structure, exhibit stability and resistance to degradation, underscoring their functional significance. In bone tissue, circRNAs are involved in critical processes such as osteogenic differentiation, osteoclastogenesis, and bone remodeling through intricate molecular mechanisms including microRNA regulation. Dysregulated circRNAs are associated with various bone disorders, suggesting their potential as diagnostic and prognostic biomarkers. The therapeutic targeting of these circRNAs holds promise for addressing bone-related conditions, offering new perspectives for precision medicine. Thus, circRNAs constitute integral components of bone regulatory networks, impacting both physiological bone homeostasis and pathological conditions. This review provides a comprehensive overview of circRNAs in bone biology, emphasizing their regulatory mechanisms, functional implications, and therapeutic potential.
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Affiliation(s)
- Maria Teresa Valenti
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37100 Verona, Italy
| | - Roberta Zerlotin
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy; (R.Z.); (M.G.)
| | - Mattia Cominacini
- Department of Engineering for the Innovation Medicine, University of Verona, 37100 Verona, Italy; (M.C.); (L.D.C.)
| | - Silvia Bolognin
- MERLN Institute, Maastricht University, Universiteitssingel 40, 6229 ET Maastricht, The Netherlands;
| | - Maria Grano
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy; (R.Z.); (M.G.)
| | - Luca Dalle Carbonare
- Department of Engineering for the Innovation Medicine, University of Verona, 37100 Verona, Italy; (M.C.); (L.D.C.)
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Guo Y, Huang C, Qiu L, Fu J, Xu C, Yang F. CircTHBS1 promotes trophoblast cell migration and invasion and inhibits trophoblast apoptosis by regulating miR-136-3p/IGF2R axis. FASEB J 2024; 38:e23598. [PMID: 38581244 DOI: 10.1096/fj.202302113rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 03/16/2024] [Accepted: 03/25/2024] [Indexed: 04/08/2024]
Abstract
The precise molecular mechanism behind fetal growth restriction (FGR) is still unclear, although there is a strong connection between placental dysfunction, inadequate trophoblast invasion, and its etiology and pathogenesis. As a new type of non-coding RNA, circRNA has been shown to play a crucial role in the development of FGR. This investigation identified the downregulation of hsa_circ_0034533 (circTHBS1) in FGR placentas through high-sequencing analysis and confirmed this finding in 25 clinical placenta samples using qRT-PCR. Subsequent in vitro functional assays demonstrated that silencing circTHBS1 inhibited trophoblast proliferation, migration, invasion, and epithelial mesenchymal transition (EMT) progression and promoted apoptosis. Furthermore, when circTHBS1 was overexpressed, cell function experiments showed the opposite result. Analysis using fluorescence in situ hybridization revealed that circTHBS1 was primarily found in the cytoplasmic region. Through bioinformatics analysis, we anticipated the involvement of miR-136-3p and IGF2R in downstream processes, which was subsequently validated through qRT-PCR and dual-luciferase assays. Moreover, the inhibition of miR-136-3p or the overexpression of IGF2R partially reinstated proliferation, migration, and invasion abilities following the silencing of circTHBS1. In summary, the circTHBS1/miR-136-3p/IGF2R axis plays a crucial role in the progression and development of FGR, offering potential avenues for the exploration of biological indicators and treatment targets.
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Affiliation(s)
- Yanyan Guo
- Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Chuyi Huang
- Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Liyan Qiu
- Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jiahui Fu
- Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Cailing Xu
- Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Fang Yang
- Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Cui Z, Zhou L, An X, Liu W, Li J, Zhang Y, Zhang W. The Combination of circEPSTI1 and MIF Offers Diagnostic Value for Endometrial Cancer. Int J Gen Med 2024; 17:1395-1403. [PMID: 38617055 PMCID: PMC11011707 DOI: 10.2147/ijgm.s441861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 03/04/2024] [Indexed: 04/16/2024] Open
Abstract
Background Circular RNAs (circRNAs) exhibit unique patterns of expression and high levels of stability in patient plasma samples such that they represent ideal non-invasive biomarkers that can be leveraged to detect a wide array of diseases including endometrial cancer (EC). This study was designed to identify circRNAs with potential diagnostic utility in serum samples from EC patients while also evaluating the utility of macrophage migration inhibitory factor (MIF) as a biomarker when screening for this form of cancer in the clinic. Methods Levels of circEPSTI1 and MIF were assessed in the plasma of EC patients and healthy subjects (n=186 each) through qPCR and ELISAs. The diagnostic utility of these biomarkers was assessed with receiver operating characteristic curve (ROC) analyses. Results Relative to healthy subjects, EC patient serum contained significantly elevated circEPSTI1 and MIF. An association was noted between circEPSTI1 expression in stages, histologic grade, and residual tumor. ROC curves confirmed that serum circEPSTI1 levels distinguished between controls and patients with EC with an Area of 0.835 and serum MIF levels distinguished between controls and patients with EC with an Area of 0.6646. When instead diagnosing patients based on the combination of MIF and circEPSTI1, the Area further rose to 0.8604. Conclusion Assessing the combination of circEPSTI1 and MIF may be a viable approach to reliably diagnosing EC.
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Affiliation(s)
- Zhili Cui
- Department of Gynecology, Affiliated Hospital of Hebei University of Engineering, Handan, Hebei, 056002, People’s Republic of China
| | - Liyuan Zhou
- Department of Gynecology, Affiliated Hospital of Hebei University of Engineering, Handan, Hebei, 056002, People’s Republic of China
| | - Xin An
- Department of Pathology, Handan First Hospital, Handan, Hebei, 056000, People’s Republic of China
| | - Wenli Liu
- Department of Gynecology, Affiliated Hospital of Hebei University of Engineering, Handan, Hebei, 056002, People’s Republic of China
| | - Jingxia Li
- Department of Gynecology, Affiliated Hospital of Hebei University of Engineering, Handan, Hebei, 056002, People’s Republic of China
| | - Yueping Zhang
- Shexian Maternal and Child Health Hospital, Shexian, Hebei, 056004, People’s Republic of China
| | - Wei Zhang
- Department of Gynecology, Handan Traditional Chinese Medicine Hospital, Handan, Hebei, 056001, People’s Republic of China
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9
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Liu K, Chen H, Li Y, Wang B, Li Q, Zhang L, Liu X, Wang C, Ertas YN, Shi H. Autophagy flux in bladder cancer: Cell death crosstalk, drug and nanotherapeutics. Cancer Lett 2024; 591:216867. [PMID: 38593919 DOI: 10.1016/j.canlet.2024.216867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/20/2024] [Accepted: 04/03/2024] [Indexed: 04/11/2024]
Abstract
Autophagy, a self-digestion mechanism, has emerged as a promising target in the realm of cancer therapy, particularly in bladder cancer (BCa), a urological malignancy characterized by dysregulated biological processes contributing to its progression. This highly conserved catabolic mechanism exhibits aberrant activation in pathological events, prominently featured in human cancers. The nuanced role of autophagy in cancer has been unveiled as a double-edged sword, capable of functioning as both a pro-survival and pro-death mechanism in a context-dependent manner. In BCa, dysregulation of autophagy intertwines with cell death mechanisms, wherein pro-survival autophagy impedes apoptosis and ferroptosis, while pro-death autophagy diminishes tumor cell survival. The impact of autophagy on BCa progression is multifaceted, influencing metastasis rates and engaging with the epithelial-mesenchymal transition (EMT) mechanism. Pharmacological modulation of autophagy emerges as a viable strategy to impede BCa progression and augment cell death. Notably, the introduction of nanoparticles for targeted autophagy regulation holds promise as an innovative approach in BCa suppression. This review underscores the intricate interplay of autophagy with cell death pathways and its therapeutic implications in the nuanced landscape of bladder cancer.
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Affiliation(s)
- Kuan Liu
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Huijing Chen
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Yanhong Li
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Bei Wang
- Department of Gynecology, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Qian Li
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Lu Zhang
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Xiaohui Liu
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China.
| | - Ce Wang
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China.
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri, 38039, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, 38039, Turkey; UNAM-National Nanotechnology Research Center, Bilkent University, Ankara, 06800, Turkey.
| | - Hongyun Shi
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China.
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10
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Shrestha SM, Fang X, Ye H, Ren L, Ji Q, Shi R. A novel upregulated hsa_circ_0032746 regulates the oncogenesis of esophageal squamous cell carcinoma by regulating miR-4270/MCM3 axis. Hum Genomics 2024; 18:3. [PMID: 38200573 PMCID: PMC10777493 DOI: 10.1186/s40246-023-00564-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 12/06/2023] [Indexed: 01/12/2024] Open
Abstract
INTRODUCTION Circular RNAs (CircRNA) have emerged as an interest of research in recent years due to its regulatory role in various kinds of cancers of human body. Esophageal squamous cell carcinoma (ESCC) is one of the major disease subtype in Asian countries, including China. CircRNAs are formed by back-splicing covalently joined 3'- and 5'- ends rather than canonical splicing and are found to have binding affinity with miRNAs that conjointly contribute to oncogenesis. MATERIALS AND METHODS 4 pairs of normal, cancer adjacent tissues and cancer tissues were analyzed by high-throughput RNA sequencing and 84 differentially upregulated circRNAs were detected in cancer tissues. hsa_circ_0032746 was silenced by siRNA and lentivirus and then further proliferation, migration and invasion were performed by CCK-8 and transwell assays. Bioinformatic analysis predicted binding affinity of circRNA/miRNA/mRNA axis. RESULTS After qPCR validation, we selected a novel upregulated hsa_circ_0032746 to explore its biogenetic functions which showed high expression in cancer tissues but not in cancer adjacent tissues. The clinicopathological relation of hsa_circ_0032746 showed positive correlation with the tumor location (P = 0.026) and gender (P = 0.05). We also predicted that hsa_circ_0032746 could sponge with microRNA. Bioinformatic analysis predicted 11 microRNA response element (MRE) sequences of hsa_circ_0032746 and dual luciferase reporter assay confirmed binding affinity with miR4270 evidencing further study of circRNA/miRNA role. The knockdown of hsa_circ_0032746 by siRNA and lentivirus demonstrated that proliferation, invasion and migration of ESCC were inhibited in vitro and vivo experiments. Bioinformatic analysis further predicted MCM3 as a target of miR-4270 and was found upregulated in ESCC upon validation. miR4270 mimic decreased the level of hsa_circ_0032746 and MCM3 while further rescue experiments demonstrated that hsa_circ_0032746 was dependent on miR4270/MCM3 axis on the development process of ESCC. CONCLUSION We revealed for the first time that circ_0032746/mir4270/MCM3 contributes in proliferation, migration and invasion of ESCC and could have potential prognostic and therapeutic significance.
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Affiliation(s)
- Sachin Mulmi Shrestha
- Department of Gastroenterology, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Xin Fang
- Department of Gastroenterology, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Hui Ye
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu Province, China
| | - Lihua Ren
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu Province, China
| | - Qinghua Ji
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu Province, China
| | - Ruihua Shi
- Department of Gastroenterology, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China.
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu Province, China.
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11
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Schemiko Almeida K, Rossi SA, Alves LR. RNA-containing extracellular vesicles in infection. RNA Biol 2024; 21:37-51. [PMID: 39589334 PMCID: PMC11601058 DOI: 10.1080/15476286.2024.2431781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 11/07/2024] [Accepted: 11/15/2024] [Indexed: 11/27/2024] Open
Abstract
Extracellular vesicles (EVs) are membrane-bound particles released by cells that play vital roles in intercellular communication by transporting diverse biologically active molecules, including RNA molecules, including mRNA, miRNA, lncRNA, and other regulatory RNAs. These RNA types are protected within the lipid bilayer of EVs, ensuring their stability and enabling long-distance cellular interactions. Notably, EVs play roles in infection, where pathogens and host cells use EV-mediated RNA transfer to influence immune responses and disease outcomes. For example, bacterial EVs play a crucial role in infection by modulating host immune responses and facilitating pathogen invasion. This review explores the complex interactions between EV-associated RNA and host-pathogen dynamics in bacteria, parasites, and fungi, aiming to uncover molecular mechanisms in infectious diseases and potential therapeutic targets.
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Affiliation(s)
- Kayo Schemiko Almeida
- Gene Expression Regulation Laboratory, Carlos Chagas Institute, FIOCRUZ, Curitiba, PR, Brazil
| | - Suélen Andreia Rossi
- Gene Expression Regulation Laboratory, Carlos Chagas Institute, FIOCRUZ, Curitiba, PR, Brazil
| | - Lysangela Ronalte Alves
- Gene Expression Regulation Laboratory, Carlos Chagas Institute, FIOCRUZ, Curitiba, PR, Brazil
- National Institute of Science and Technology in Human Pathogenic Fungi, São Paulo, Brazil
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12
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Chang J, Shin MK, Park J, Hwang HJ, Locker N, Ahn J, Kim D, Baek D, Park Y, Lee Y, Boo SH, Kim HI, Kim YK. An interaction between eIF4A3 and eIF3g drives the internal initiation of translation. Nucleic Acids Res 2023; 51:10950-10969. [PMID: 37811880 PMCID: PMC10639049 DOI: 10.1093/nar/gkad763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 08/30/2023] [Accepted: 09/08/2023] [Indexed: 10/10/2023] Open
Abstract
An RNA structure or modified RNA sequences can provide a platform for ribosome loading and internal translation initiation. The functional significance of internal translation has recently been highlighted by the discovery that a subset of circular RNAs (circRNAs) is internally translated. However, the molecular mechanisms underlying the internal initiation of translation in circRNAs remain unclear. Here, we identify eIF3g (a subunit of eIF3 complex) as a binding partner of eIF4A3, a core component of the exon-junction complex (EJC) that is deposited onto spliced mRNAs and plays multiple roles in the regulation of gene expression. The direct interaction between eIF4A3-eIF3g serves as a molecular linker between the eIF4A3 and eIF3 complex, thereby facilitating internal ribosomal entry. Protein synthesis from in vitro-synthesized circRNA demonstrates eIF4A3-driven internal translation, which relies on the eIF4A3-eIF3g interaction. Furthermore, our transcriptome-wide analysis shows that efficient polysomal association of endogenous circRNAs requires eIF4A3. Notably, a subset of endogenous circRNAs can express a full-length intact protein, such as β-catenin, in an eIF4A3-dependent manner. Collectively, our results expand the understanding of the protein-coding potential of the human transcriptome, including circRNAs.
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Affiliation(s)
- Jeeyoon Chang
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
| | - Min-Kyung Shin
- Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea
| | - Joori Park
- Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea
| | - Hyun Jung Hwang
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
| | - Nicolas Locker
- Department of Microbial and Cellular Sciences, University of Surrey, Guildford GU2 7HX, UK
| | - Junhak Ahn
- School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Doyeon Kim
- School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Daehyun Baek
- School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Yeonkyoung Park
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
| | - Yujin Lee
- Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea
| | - Sung Ho Boo
- Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea
| | - Hyeong-In Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
| | - Yoon Ki Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
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13
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Luo X, Liu J, Wang X, Yuan J, Zhang Y. Circ-DTL sponges miR-758-3p to accelerate cervical cancer malignant progression by regulating DCUN1D1 expression. J Biochem Mol Toxicol 2023; 37:e23462. [PMID: 37522575 DOI: 10.1002/jbt.23462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 05/26/2023] [Accepted: 07/04/2023] [Indexed: 08/01/2023]
Abstract
Circular RNAs (circRNAs) play important roles in regulating various cancer progression. However, the function and clinical significance of circ-denticleless E3 ubiquitin proteinligase homolog (DTL) in cervical cancer (CC) have not been studied. The present work explored the function and mechanism of circ-DTL in CC development. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to examine the expression of circ-DTL, miR-758-3p, and DCUN1D1. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used to detect cell proliferation. Cell cycle and cell apoptosis were investigated by flow cytometry. Wound-healing assay and transwell assay were conducted to assess cell migration and cell invasion. Western blot assay was carried out to determine protein expression. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to identify the relationship between miR-758-3p and circ-DTL or DCUN1D1. Xenograft mouse model assay was conducted to explore the role of circ-DTL in CC progression in vivo. Circ-DTL and DCUN1D1 expression were upregulated in CC tissues and CC cells, but miR-758-3p expression was downregulated. Knockdown of circ-DTL inhibited CC cell growth, migration, and invasion and promoted cell cycle arrest and cell apoptosis. Circ-DTL could sponge miR-758-3p to modulate CC cell progression. Moreover, miR-758-3p inhibited CC malignant development by suppressing DCUN1D1 expression. In addition, circ-DTL knockdown repressed CC cell tumor properties in vivo. Circ-DTL acted as a tumor promoter in CC development by regulating the miR-758-3p/DCUN1D1 pathway.
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Affiliation(s)
- Xiaoning Luo
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jiewen Liu
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xiangcai Wang
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jun Yuan
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Yu Zhang
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, Jiangxi, China
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Tian W, Liu Y, Zhang W, Nie R, Ling Y, Zhang B, Zhang H, Wu C. CircDOCK7 facilitates the proliferation and adipogenic differentiation of chicken abdominal preadipocytes through the gga-miR-301b-3p/ACSL1 axis. J Anim Sci Biotechnol 2023; 14:91. [PMID: 37408086 DOI: 10.1186/s40104-023-00891-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 05/07/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND Abdominal fat deposition depends on both the proliferation of preadipocytes and their maturation into adipocytes, which is a well-orchestrated multistep process involving many regulatory molecules. Circular RNAs (circRNAs) have emergingly been implicated in mammalian adipogenesis. However, circRNA-mediated regulation in chicken adipogenesis remains unclear. Our previous circRNA sequencing data identified a differentially expressed novel circRNA, 8:27,886,180|27,889,657, during the adipogenic differentiation of chicken abdominal preadipocytes. This study aimed to investigate the regulatory role of circDOCK7 in the proliferation and adipogenic differentiation of chicken abdominal preadipocytes, and explore its molecular mechanisms of competing endogenous RNA underlying chicken adipogenesis. RESULTS Our results showed that 8:27,886,180|27,889,657 is an exonic circRNA derived from the head-to-tail splicing of exons 19-22 of the dedicator of cytokinesis 7 (DOCK7) gene, abbreviated as circDOCK7. CircDOCK7 is mainly distributed in the cytoplasm of chicken abdominal preadipocytes and is stable because of its RNase R resistance and longer half-life. CircDOCK7 is significantly upregulated in the abdominal fat tissues of fat chickens compared to lean chickens, and its expression gradually increases during the proliferation and adipogenic differentiation of chicken abdominal preadipocytes. Functionally, the gain- and loss-of-function experiments showed that circDOCK7 promoted proliferation, G0/G1- to S-phase progression, and glucose uptake capacity of chicken abdominal preadipocytes, in parallel with adipogenic differentiation characterized by remarkably increased intracellular lipid droplet accumulation and triglyceride and acetyl coenzyme A content in differentiated chicken abdominal preadipocytes. Mechanistically, a pull-down assay and a dual-luciferase reporter assay confirmed that circDOCK7 interacted with gga-miR-301b-3p, which was identified as an inhibitor of chicken abdominal adipogenesis. Moreover, the ACSL1 gene was demonstrated to be a direct target of gga-miR-301b-3p. Chicken ACSL1 protein is localized in the endoplasmic reticulum and mitochondria of chicken abdominal preadipocytes and acts as an adipogenesis accelerator. Rescue experiments showed that circDOCK7 could counteract the inhibitory effects of gga-miR-301b-3p on ACSL1 mRNA abundance as well as the proliferation and adipogenic differentiation of chicken abdominal preadipocytes. CONCLUSIONS CircDOCK7 serves as a miRNA sponge that directly sequesters gga-miR-301b-3p away from the ACSL1 gene, thus augmenting adipogenesis in chickens. These findings may elucidate a new regulatory mechanism underlying abdominal fat deposition in chickens.
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Affiliation(s)
- Weihua Tian
- National Engineering Laboratory for Animal Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Ye Liu
- National Engineering Laboratory for Animal Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Wenhui Zhang
- National Engineering Laboratory for Animal Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Ruixue Nie
- National Engineering Laboratory for Animal Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Yao Ling
- National Engineering Laboratory for Animal Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Bo Zhang
- National Engineering Laboratory for Animal Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Hao Zhang
- National Engineering Laboratory for Animal Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
| | - Changxin Wu
- National Engineering Laboratory for Animal Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
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15
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Sun J, Li L, Chen X, Yang C, Wang L. The circRNA-0001361/miR-491/FGFR4 axis is associated with axillary response evaluated by ultrasound following NAC in subjects with breast cancer. Biochem Biophys Rep 2023; 34:101481. [PMID: 37250983 PMCID: PMC10209698 DOI: 10.1016/j.bbrep.2023.101481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/21/2023] [Accepted: 04/27/2023] [Indexed: 05/31/2023] Open
Abstract
Background miR-491-5p has been reported to regulate the expression of FGFR4 and promote gastric cancer metastasis. Hsa_circ_0001361 was demonstrated to play an oncogenic role in bladder cancer invasion and metastasis by sponging the expression of miR-491-5p. This work aimed to study the molecular mechanism of the effect of hsa_circ_0001361 on axillary response in the treatment of breast cancer. Methods Ultrasound examinations was performed to evaluate the response of breast cancer patients receiving NAC treatment. Quantitative real-time PCR, IHC assay, luciferase assay and Western blot were performed to analyze the molecular interaction between miR-491, circRNA_0001631 and FGFR4. Results Patients with low circRNA_0001631 expression had a better outcome after NAC treatment. The expression of miR-491 was remarkably higher in the tissue sample and serum collected from patients with lower circRNA_0001631 expression. On the contrary, the FGFR4 expression was notably suppressed in the tissue sample and serum collected from patients with lower circRNA_0001631 expression when compared with patients with high circRNA_0001631 expression. The luciferase activities of circRNA_0001631 and FGFR4 were effectively suppressed by miR-491 in MCF-7 and MDA-MB-231 cells. Moreover, inhibition of circRNA_0001631 expression using circRNA_0001361 shRNA effectively suppressed the expression of FGFR4 protein in MCF-7 and MDA-MB-231 cells. Up-regulation of circRNA_0001631 expression remarkably enhanced the expression of FGFR4 protein in MCF-7 and MDA-MB-231 cells. Conclusion Our study suggested that the up-regulation of hsa_circRNA-0001361 could up-regulate the expression of FGFR4 via sponging the expression of miR-491-5p, resulting in the alleviated axillary response after neoadjuvant chemotherapy (NAC) in breast cancer.
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Affiliation(s)
| | | | | | - Chunfeng Yang
- Department of Ultrasound, Yantai Yuhuangding Hospital, Yantai, 264099, China
| | - Li Wang
- Department of Ultrasound, Yantai Yuhuangding Hospital, Yantai, 264099, China
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16
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Watts ME, Oksanen M, Lejerkrans S, Mastropasqua F, Gorospe M, Tammimies K. Circular RNAs arising from synaptic host genes during human neuronal differentiation are modulated by SFPQ RNA-binding protein. BMC Biol 2023; 21:127. [PMID: 37237280 DOI: 10.1186/s12915-023-01627-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND Circular RNA (circRNA) molecules, generated through non-canonical back-splicing of exon-exon junctions, have recently been implicated in diverse biological functions including transcriptional regulation and modulation of protein interactions. CircRNAs are emerging as a key component of the complex neural transcriptome implicated in brain development. However, the specific expression patterns and functions of circRNAs in human neuronal differentiation have not been explored. RESULTS Using total RNA sequencing analysis, we identified expressed circRNAs during the differentiation of human neuroepithelial stem (NES) cells into developing neurons and discovered that many circRNAs originated from host genes associated with synaptic function. Interestingly, when assessing population data, exons giving rise to circRNAs in our dataset had a higher frequency of genetic variants. Additionally, screening for RNA-binding protein sites identified enrichment of Splicing Factor Proline and Glutamine Rich (SFPQ) motifs in increased circRNAs, several of which were reduced by SFPQ knockdown and enriched in SFPQ ribonucleoprotein complexes. CONCLUSIONS Our study provides an in-depth characterisation of circRNAs in a human neuronal differentiation model and highlights SFPQ as both a regulator and binding partner of circRNAs elevated during neuronal maturation.
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Affiliation(s)
- Michelle E Watts
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden
| | - Marika Oksanen
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, NIH, Baltimore, MD, USA
| | - Sanna Lejerkrans
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden
| | - Francesca Mastropasqua
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, NIH, Baltimore, MD, USA
| | - Kristiina Tammimies
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden.
- Karolinska Institutet, BioClinicum J9:30, Visionsgatan 4, 171 56, Solna, Sweden.
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17
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Wei J, Li M, Xue C, Chen S, Zheng L, Deng H, Tang F, Li G, Xiong W, Zeng Z, Zhou M. Understanding the roles and regulation patterns of circRNA on its host gene in tumorigenesis and tumor progression. J Exp Clin Cancer Res 2023; 42:86. [PMID: 37060016 PMCID: PMC10105446 DOI: 10.1186/s13046-023-02657-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/29/2023] [Indexed: 04/16/2023] Open
Abstract
Circular RNAs (circRNAs) are a novel type of endogenous non-coding RNAs, which are covalently closed loop structures formed by precursor mRNAs (pre-mRNAs) through back-splicing. CircRNAs are abnormally expressed in many tumors, and play critical roles in a variety of tumors as oncogenes or tumor suppressor genes by sponging miRNAs, regulating alternative splicing and transcription, cis-regulating host genes, interacting with RNA binding proteins (RBPs) or encoding polypeptides. Among them, the regulation of circRNAs on their corresponding host genes is a critical way for circRNAs to exit their functions. Accumulating evidence suggests that circRNAs are able to regulate the expression of host genes at the transcriptional level, post-transcriptional level, translational level, post-translational level, or by encoding polypeptides. Therefore, this paper mainly summarized the roles and association of circRNAs and their corresponding host genes in tumorigenesis and tumor progression, generalized the circRNAs that function synergistically or antagonistically with their host genes, and elaborated the mechanisms of mutual regulation between circRNAs and their host genes. More importantly, this review provides specific references for revealing the potential application of circRNAs combined with their host genes in tumor diagnosis, treatment and prognosis.
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Affiliation(s)
- Jianxia Wei
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Cancer Research Institute, Central South University, Changsha, 410078, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, China
| | - Mengna Li
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Cancer Research Institute, Central South University, Changsha, 410078, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, China
| | - Changning Xue
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Cancer Research Institute, Central South University, Changsha, 410078, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, China
| | - Shipeng Chen
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Cancer Research Institute, Central South University, Changsha, 410078, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, China
| | - Lemei Zheng
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Cancer Research Institute, Central South University, Changsha, 410078, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, China
| | - Hongyu Deng
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Cancer Research Institute, Central South University, Changsha, 410078, China
| | - Faqing Tang
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Cancer Research Institute, Central South University, Changsha, 410078, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Cancer Research Institute, Central South University, Changsha, 410078, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Cancer Research Institute, Central South University, Changsha, 410078, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, China
| | - Ming Zhou
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China.
- Cancer Research Institute, Central South University, Changsha, 410078, China.
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, China.
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Huang X, Yu Q. Bioinformatic analysis confirms differences in circular RNA expression profiles of cumulus cells between patients with ovarian and peritoneal endometriosis-associated infertility. Front Endocrinol (Lausanne) 2023; 14:1137235. [PMID: 37008951 PMCID: PMC10050890 DOI: 10.3389/fendo.2023.1137235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 03/06/2023] [Indexed: 03/17/2023] Open
Abstract
Endometriosis has a detrimental effect on oocyte quality, and ovarian endometriosis (OEM) and peritoneal endometriosis (PEM) may have different effects on female fertility. Therefore, we conducted a study to explore the circular RNA (circRNA) expression profiles of cumulus cells (CCs) in patients with OEM (n = 3), PEM (n = 3), and tubal factor infertility (TFI, n = 3) using high-throughput sequencing techniques and attempted to identify common and unique circRNAs in the OEM and PEM groups. The CIRCexplorer2 program was used to identify circRNAs. Seven candidate circRNAs were validated in 30 samples using quantitative real-time polymerase chain reaction (qRT-PCR). Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to annotate the function of circRNA-targeted genes, which were verified by sequencing results and constructed circRNA-miRNA-mRNA networks. A total of 11833 circRNAs were identified in nine samples. The numbers of differentially expressed circRNAs between the OEM and TFI groups, PEM and TFI groups, and OEM and PEM groups were 130, 71, and 191, respectively. After taking intersections, 11 circRNAs were considered common circRNAs in the OEM and PEM groups; 39 circRNAs in the OEM group and 17 circRNAs in the PEM group were identified as unique key circRNAs. During qRT-PCR validation, hsa_circ_0003638 was significantly upregulated in the PEM group compared to that in the OEM and TFI groups. Functional analysis of circRNA-targeted genes revealed that apoptosis, PI3K-AKT, and p53 signaling pathways were enriched in the PEM-TFI comparison groups, whereas the functions of target genes involved in the JAK-STAT and TGF-β signaling pathways were enriched in the PEM-OEM comparison groups. Our findings confirmed differences in circRNA expression profiles of CCs between patients with OEM and PEM infertility and provide new insights into the different effects of various endometriosis phenotypes on oocytes.
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Affiliation(s)
| | - Qi Yu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
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Tong Y, Zhang S, Riddle S, Song R, Yue D. Circular RNAs in the Origin of Developmental Lung Disease: Promising Diagnostic and Therapeutic Biomarkers. Biomolecules 2023; 13:biom13030533. [PMID: 36979468 PMCID: PMC10046088 DOI: 10.3390/biom13030533] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/11/2023] [Accepted: 03/12/2023] [Indexed: 03/17/2023] Open
Abstract
Circular RNA (circRNA) is a newly discovered noncoding RNA that regulates gene transcription, binds to RNA-related proteins, and encodes protein microRNAs (miRNAs). The development of molecular biomarkers such as circRNAs holds great promise in the diagnosis and prognosis of clinical disorders. Importantly, circRNA-mediated maternal-fetus risk factors including environmental (high altitude), maternal (preeclampsia, smoking, and chorioamnionitis), placental, and fetal (preterm birth and low birth weight) factors are the early origins and likely to contribute to the occurrence and progression of developmental and pediatric cardiopulmonary disorders. Although studies of circRNAs in normal cardiopulmonary development and developmental diseases have just begun, some studies have revealed their expression patterns. Here, we provide an overview of circRNAs’ biogenesis and biological functions. Furthermore, this review aims to emphasize the importance of circRNAs in maternal-fetus risk factors. Likewise, the potential biomarker and therapeutic target of circRNAs in developmental and pediatric lung diseases are explored.
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Affiliation(s)
- Yajie Tong
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Shuqing Zhang
- School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Suzette Riddle
- Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Rui Song
- Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Correspondence: (R.S.); (D.Y.); Tel.: +01-909-558-4325 (R.S.); +86-24-9661551125 (D.Y.)
| | - Dongmei Yue
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
- Correspondence: (R.S.); (D.Y.); Tel.: +01-909-558-4325 (R.S.); +86-24-9661551125 (D.Y.)
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CircZNF367 suppresses osteogenic differentiation of human bone marrow mesenchymal stromal/stem cells via reducing HuR-mediated mRNA stability of LRP5. Hum Cell 2023; 36:146-162. [PMID: 36169884 DOI: 10.1007/s13577-022-00798-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 09/19/2022] [Indexed: 01/07/2023]
Abstract
Osteoporosis is a highly prevalent disease characterized by bone mass loss and structural deterioration. There are evidences that altered differentiation of human bone marrow mesenchymal stromal/stem cells (hBMSCs) is a major cause for osteoporosis. Recent studies suggest that circular RNAs (circRNAs) are dysregulated in osteoporosis patients and involved in the pathogenesis of osteoporosis. In the present study, we are aimed to analyze the circRNA expression profiles in osteoporosis patients and identify potential circRNAs that involved in the differentiation of hBMSCs during osteoporosis. Transcriptome RNA-sequencing was conducted to search for differentially expressed circRNAs. Transwell assay, ARS and ALP staining, and ectopic bone formation model were performed to evaluate osteogenic differentiation of hBMSCs. RNA pull-down assay, RNA immunoprecipitation, western blot, and in vitro binding assay were conducted to evaluate the interaction of circRNAs and RNA-binding protein HuR. We found that hsa_circ_0008842 (designated as circZNF367) was upregulated in osteoporosis patients and decreased in hBMSCs during osteogenic differentiation. CircZNF367 overexpression suppressed migration, invasion and osteogenic differentiation of hBMSCs in vitro and in vivo. In comparison, knockdown of circZNF367 promoted migration, invasion and osteogenic differentiation of hBMSCs. CircZNF367 could interact with the RNA-binding protein HuR, thus reduced the mRNA stability of LRP5. Furthermore, HuR overexpression or LRP5 restoration abrogated the effects of circZNF367 overexpression on osteogenic differentiation of hBMSCs. Our results indicated that circZNF367 played a role in osteogenic differentiation of hBMSCs via reducing HuR-mediated mRNA stability of LRP5.
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Hussen BM, Abdullah SR, Hama Faraj GS, Rasul MF, Salihi A, Ghafouri-Fard S, Taheri M, Mokhtari M. Exosomal circular RNA: a signature for lung cancer progression. Cancer Cell Int 2022; 22:378. [PMID: 36457039 PMCID: PMC9714134 DOI: 10.1186/s12935-022-02793-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 11/15/2022] [Indexed: 12/03/2022] Open
Abstract
Membrane vesicles having a diameter of 30-150 nm are known as exosomes. Several cancer types secrete exosomes, which may contain proteins, circular RNAs (circRNAs), microRNAs, or DNA. CircRNAs are endogenous RNAs that do not code for proteins and can create continuous and covalently closed loops. In cancer pathogenesis, especially metastasis, exosomal circRNAs (exo-circRNAs) have a crucial role mainly due to the frequently aberrant expression levels within tumors. However, neither the activities nor the regulatory mechanisms of exo-circRNAs in advancing lung cancer (LC) are obvious. A better understanding of the regulation and network connections of exo-circRNAs will lead to better treatment for LCs. The main objective of the current review is to highlight the functions and mechanisms of exo-circRNAs in LC and assess the relationships between exo-circRNA dysregulation and LC progression. In addition, underline the possible therapeutic targets based on exo-circRNA modulating.
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Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq
- Medical Laboratory Science, Lebanese French University, Erbil, Kurdistan Region, Iraq
| | - Snur Rasool Abdullah
- Medical Laboratory Science, Lebanese French University, Erbil, Kurdistan Region, Iraq
| | - Goran Sedeeq Hama Faraj
- Department of Medical Laboratory Science, Komar University of Science and Technology, Sulaymaniyah, Iraq
| | - Mohammed Fatih Rasul
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Abbas Salihi
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region, Iraq
- Department of Biomedical Sciences, Cihan University-Erbil, Kurdistan Region, Erbil, 44001, Iraq
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Institute of Human Genetics, Jena University Hospital, Jena, Germany.
| | - Majid Mokhtari
- Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Wu Z, Yu X, Zhang S, He Y, Guo W. Mechanism underlying circRNA dysregulation in the TME of digestive system cancer. Front Immunol 2022; 13:951561. [PMID: 36238299 PMCID: PMC9550895 DOI: 10.3389/fimmu.2022.951561] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 09/12/2022] [Indexed: 11/18/2022] Open
Abstract
Circular RNAs (circRNAs) are a new series of noncoding RNAs (ncRNAs) that have been reported to be expressed in eukaryotic cells and have a variety of biological functions in the regulation of cancer pathogenesis and progression. The TME, as a microscopic ecological environment, consists of a variety of cells, including tumor cells, immune cells and other normal cells, ECM and a large number of signaling molecules. The crosstalk between circRNAs and the TME plays a complicated role in affecting the malignant behaviors of digestive system cancers. Herein, we summarize the mechanisms underlying aberrant circRNA expression in the TME of the digestive system cancers, including immune surveillance, angiogenesis, EMT, and ECM remodelling. The regulation of the TME by circRNA is expected to be a new therapeutic method.
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Affiliation(s)
- Zeyu Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiao Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuting He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Wenzhi Guo, ; Yuting He,
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Wenzhi Guo, ; Yuting He,
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Zhang Y, Zhu M, Zhang X, Dai K, Liang Z, Pan J, Zhang Z, Cao M, Xue R, Cao G, Hu X, Gong C. Micropeptide vsp21 translated by Reovirus circular RNA 000048 attenuates viral replication. Int J Biol Macromol 2022; 209:1179-1187. [PMID: 35461859 DOI: 10.1016/j.ijbiomac.2022.04.136] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 04/17/2022] [Accepted: 04/18/2022] [Indexed: 12/13/2022]
Abstract
To date, some DNA viruses and single-stranded RNA viruses have been found to generate circRNAs. However, the reports on circRNAs produced by double-stranded RNA viruses are very limited. In this study, Bombyx mori cypovirus (BmCPV), a typical double-stranded RNA virus belonging to the Reoviridae, was demonstrated to generate viral circRNAs (vcircRNAs) and a vcircRNA_000048 whose sequence corresponds with the region 164-1245 nt on the BmCPV genomic dsRNA S5 segment (GQ294468.1) was validated by PCR, Sanger sequencing, reverse transcription-rolling circle amplification, and Northern blotting. Furthermore, we verified that vcircRNA_000048 translates a micropeptide vsp21 with 21 amino acid residues in an IRES-dependent manner, and vsp21 attenuates the viral replication. These findings provided a novel clue to understanding the regulation of viral multiplication and interaction of reovirus with the host.
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Affiliation(s)
- Yunshan Zhang
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Min Zhu
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Xing Zhang
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Kun Dai
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Zi Liang
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Jun Pan
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Ziyao Zhang
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Manman Cao
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Renyu Xue
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Guangli Cao
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Xiaolong Hu
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China; Institute of Agricultural Biotechnology and Ecological Research, Soochow University, Suzhou 215123, China.
| | - Chengliang Gong
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China; Institute of Agricultural Biotechnology and Ecological Research, Soochow University, Suzhou 215123, China.
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24
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Yang YP, Chang YL, Lai YH, Tsai PH, Hsiao YJ, Nguyen LH, Lim XZ, Weng CC, Ko YL, Yang CH, Hwang DK, Chen SJ, Chiou SH, Chiou GY, Wang AG, Chien Y. Retinal Circular RNA hsa_circ_0087207 Expression Promotes Apoptotic Cell Death in Induced Pluripotent Stem Cell-Derived Leber’s Hereditary Optic Neuropathy-like Models. Biomedicines 2022; 10:biomedicines10040788. [PMID: 35453537 PMCID: PMC9027941 DOI: 10.3390/biomedicines10040788] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 02/01/2023] Open
Abstract
Backgrounds: Leber’s hereditary optic neuropathy (LHON) is known as an inherited retinal disorder characterized by the bilateral central vision loss and degeneration of retinal ganglion cells (RGCs). Unaffected LHON carriers are generally asymptomatic, suggesting that certain factors may contribute to the disease manifestations between carriers and patients who carry the same mutated genotypes. Methods: We first aimed to establish the iPSC-differentiated RGCs from the normal healthy subject, the carrier, and the LHON patient and then compared the differential expression profile of circular RNAs (CircRNAs) among RGCs from these donors in vitro. We further overexpressed or knocked down the most upregulated circRNA to examine whether this circRNA contributes to the distinct phenotypic manifestations between the carrier- and patient-derived RGCs. Results: iPSCs were generated from the peripheral blood cells from the healthy subject, the carrier, and the LHON patient and successfully differentiated into RGCs. These RGCs carried equivalent intracellular reactive oxygen species, but only LHON-patient iPSC-derived RGCs exhibited remarkable apoptosis. Next-generation sequencing and quantitative real-time PCR revealed the circRNA hsa_circ_0087207 as the most upregulated circRNA in LHON-patient iPSC-derived RGCs. Overexpression of hsa_circ_0087207 increased the apoptosis in carrier iPSC-derived RGCs, while knockdown of hsa_circ_0087207 attenuated the apoptosis in LHON-patient iPSC-derived RGCs. Predicted by bioinformatics approaches, hsa_circ_0087207 acts as the sponge of miR-665 to induce the expression of a variety of apoptosis-related genes in LHON patient iPSC-derived RGCs. Conclusions: Our data indicated that hsa_circ_0087207 upregulation distinguishes the disease phenotype manifestations between iPSC-derived RGCs generated from the LHON patient and carrier. Targeting the hsa_circ_0087207/miR-665 axis might hold therapeutic promises for the treatment of LHON.
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Affiliation(s)
- Yi-Ping Yang
- Department of Medical Research, Taipei Veteran General Hospital, Taipei 11217, Taiwan; (Y.-P.Y.); (Y.-H.L.); (P.-H.T.); (Y.-J.H.); (L.H.N.); (X.-Z.L.); (Y.-L.K.); (S.-H.C.)
- Institute of Food Safety and Health Risk Assessment, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (D.-K.H.); (S.-J.C.); (A.-G.W.)
| | - Yuh-Lih Chang
- Department of Pharmacy, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
- Department of Pharmacy, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan
| | - Yun-Hsien Lai
- Department of Medical Research, Taipei Veteran General Hospital, Taipei 11217, Taiwan; (Y.-P.Y.); (Y.-H.L.); (P.-H.T.); (Y.-J.H.); (L.H.N.); (X.-Z.L.); (Y.-L.K.); (S.-H.C.)
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan
| | - Ping-Hsing Tsai
- Department of Medical Research, Taipei Veteran General Hospital, Taipei 11217, Taiwan; (Y.-P.Y.); (Y.-H.L.); (P.-H.T.); (Y.-J.H.); (L.H.N.); (X.-Z.L.); (Y.-L.K.); (S.-H.C.)
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan
| | - Yu-Jer Hsiao
- Department of Medical Research, Taipei Veteran General Hospital, Taipei 11217, Taiwan; (Y.-P.Y.); (Y.-H.L.); (P.-H.T.); (Y.-J.H.); (L.H.N.); (X.-Z.L.); (Y.-L.K.); (S.-H.C.)
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (D.-K.H.); (S.-J.C.); (A.-G.W.)
| | - Long Hoang Nguyen
- Department of Medical Research, Taipei Veteran General Hospital, Taipei 11217, Taiwan; (Y.-P.Y.); (Y.-H.L.); (P.-H.T.); (Y.-J.H.); (L.H.N.); (X.-Z.L.); (Y.-L.K.); (S.-H.C.)
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan
- Department of Basic Medical Sciences, Hanoi University of Pharmacy, Hanoi 100000, Vietnam
| | - Xue-Zhen Lim
- Department of Medical Research, Taipei Veteran General Hospital, Taipei 11217, Taiwan; (Y.-P.Y.); (Y.-H.L.); (P.-H.T.); (Y.-J.H.); (L.H.N.); (X.-Z.L.); (Y.-L.K.); (S.-H.C.)
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan
| | - Chang-Chi Weng
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
| | - Yu-Ling Ko
- Department of Medical Research, Taipei Veteran General Hospital, Taipei 11217, Taiwan; (Y.-P.Y.); (Y.-H.L.); (P.-H.T.); (Y.-J.H.); (L.H.N.); (X.-Z.L.); (Y.-L.K.); (S.-H.C.)
| | - Chang-Hao Yang
- Department of Ophthalmology, National Taiwan University Hospital, Taipei 10002, Taiwan;
- Department of Ophthalmology, College of Medicine, National Taiwan University, Taipei 11217, Taiwan
| | - De-Kuang Hwang
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (D.-K.H.); (S.-J.C.); (A.-G.W.)
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
| | - Shih-Jen Chen
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (D.-K.H.); (S.-J.C.); (A.-G.W.)
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
| | - Shih-Hwa Chiou
- Department of Medical Research, Taipei Veteran General Hospital, Taipei 11217, Taiwan; (Y.-P.Y.); (Y.-H.L.); (P.-H.T.); (Y.-J.H.); (L.H.N.); (X.-Z.L.); (Y.-L.K.); (S.-H.C.)
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (D.-K.H.); (S.-J.C.); (A.-G.W.)
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
- Genomic Research Center, Academia Sinica, Taipei 11217, Taiwan
| | - Guang-Yuh Chiou
- Department of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan
- Correspondence: (G.-Y.C.); (Y.C.)
| | - An-Guor Wang
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (D.-K.H.); (S.-J.C.); (A.-G.W.)
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
| | - Yueh Chien
- Department of Medical Research, Taipei Veteran General Hospital, Taipei 11217, Taiwan; (Y.-P.Y.); (Y.-H.L.); (P.-H.T.); (Y.-J.H.); (L.H.N.); (X.-Z.L.); (Y.-L.K.); (S.-H.C.)
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (D.-K.H.); (S.-J.C.); (A.-G.W.)
- Correspondence: (G.-Y.C.); (Y.C.)
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Zucko D, Hayir A, Grinde K, Boris-Lawrie K. Circular RNA Profiles in Viremia and ART Suppression Predict Competing circRNA–miRNA–mRNA Networks Exclusive to HIV-1 Viremic Patients. Viruses 2022; 14:v14040683. [PMID: 35458413 PMCID: PMC9027527 DOI: 10.3390/v14040683] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/17/2022] [Accepted: 03/19/2022] [Indexed: 02/01/2023] Open
Abstract
Since the onset of the HIV-1/AIDS epidemic in 1981, 75 million people have been infected with the virus, and the disease remains a public health crisis worldwide. Circular RNAs (circRNAs) are derived from excised exons and introns during backsplicing, a form of alternative splicing. The relevance of unconventional, non-capped, and non-poly(A) transcripts to transcriptomics studies remains to be routinely investigated. Knowledge gaps to be filled are the interface between host-encoded circRNAs and viral replication in chronically progressed patients and upon treatment with antiviral drugs. We implemented a bioinformatic pipeline and repurpose publicly archived RNA sequence reads from the blood of 19 HIV-1-positive patients that previously compared transcriptomes during viremia and viremia suppression by antiretroviral therapy (ART). The in silico analysis identified viremic patients’ circRNA that became undetectable after ART. The circRNAs originated from a subset of host genes enriched in the HDAC biological pathway. These circRNAs and parental mRNAs held in common a small collection of miRNA response elements (MREs), some of which were present in HIV-1 mRNAs. The function of the MRE-containing target mRNA enriched the RNA polymerase II GO pathway. To visualize the interplay between individual circRNA–miRNA–target mRNA, important for HIV-1 and potentially other diseases, an Interactive Circos tool was developed to efficiently parse the intricately competing endogenous network of circRNA–miRNA–mRNA interactions originating from seven circRNA singled out in viremic versus non-viremic patients. The combined downregulation of the identified circRNAs warrants investigation as a novel antiviral targeting strategy.
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Affiliation(s)
- Dora Zucko
- Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN 55108, USA; (D.Z.); (A.H.)
| | - Abdullgadir Hayir
- Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN 55108, USA; (D.Z.); (A.H.)
- Department of Mathematics, Statistics and Computer Science, Macalester College, Saint Paul, MN 55105, USA;
| | - Kelsey Grinde
- Department of Mathematics, Statistics and Computer Science, Macalester College, Saint Paul, MN 55105, USA;
| | - Kathleen Boris-Lawrie
- Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN 55108, USA; (D.Z.); (A.H.)
- Correspondence:
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Lyu M, Li X, Shen Y, Lu J, Zhang L, Zhong S, Wang J. CircATRNL1 and circZNF608 Inhibit Ovarian Cancer by Sequestering miR-152-5p and Encoding Protein. Front Genet 2022; 13:784089. [PMID: 35281849 PMCID: PMC8905624 DOI: 10.3389/fgene.2022.784089] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 01/31/2022] [Indexed: 12/27/2022] Open
Abstract
Background: CircRNAs have been found to be involved in the pathogenesis of various diseases. We aimed to explore the roles of circRNAs in ovarian cancer. Methods: The expression levels of circRNAs in ovarian cancer and normal ovarian tissues were analyzed using RNA sequencing. Fluorescent in situ hybridization (FISH), proliferation assays and transwell assays were used to assess the effects of circRNAs on ovarian cancer. Results: CircATRNL1 and circZNF608 were downregulated in 20 ovarian cancer tissues compared to normal tissues. CircATRNL1 and circZNF608 are mainly located in the cytoplasm of ovarian cancer cells, and circATRNL1 is a highly conserved circRNA. The overexpression of circATRNL1 and circZNF608 inhibits the proliferation and invasion of ovarian cancer cells. We predicted miRNA–circRNA interactions for circZNF608 and circATRNL1 and obtained 63 interactions. However, a luciferase reporter assay showed that only miR-152-5p was sequestered by circZNF608. Bioinformatics analysis and experiments indicated that circATRNL1 contains an internal ribosome entry site and an open reading frame encoding a 131 aa protein. Conclusion: In conclusion, circATRNL1 and circZNF608 are two downregulated circRNAs in ovarian cancer and work as tumor suppressors. CircZNF608 may exert antitumor activity in ovarian cancer by binding miR-152-5p, and circATRNL1 may encode a 131 aa protein.
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Affiliation(s)
- Mengmeng Lyu
- Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China
| | - Xiujuan Li
- Department of General Surgery, The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China
| | - Yang Shen
- Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China
| | - Jin Lu
- Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China
| | - Lihua Zhang
- Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China
| | - Shanliang Zhong
- Center of Clinical Laboratory Science, The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China
| | - Jinhua Wang
- Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China
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Guo Y, Yu X, Su N, Shi N, Zhang S, Zhang L, Yang L, Zhao L, Guan Z, Zhang M, Duan M. Identification and characterization of circular RNAs in the A549 cells following Influenza A virus infection. Vet Microbiol 2022; 267:109390. [DOI: 10.1016/j.vetmic.2022.109390] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 02/22/2022] [Accepted: 02/27/2022] [Indexed: 01/01/2023]
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Dehghanian F, Azhir Z, Khalilian S, Grüning B. Non-coding RNAs underlying the pathophysiological links between type 2 diabetes and pancreatic cancer: A systematic review. J Diabetes Investig 2022; 13:405-428. [PMID: 34859606 PMCID: PMC8902405 DOI: 10.1111/jdi.13727] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/11/2021] [Accepted: 11/30/2021] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes is known as a risk factor for pancreatic cancer (PC). Various genetic and environmental factors cause both these global chronic diseases. The mechanisms that define their relationships are complex and poorly understood. Recent studies have implicated that metabolic abnormalities, including hyperglycemia and hyperinsulinemia, could lead to cell damage responses, cell transformation, and increased cancer risk. Hence, these kinds of abnormalities following molecular events could be essential to develop our understanding of this complicated link. Among different molecular events, focusing on shared signaling pathways including metabolic (PI3K/Akt/mTOR) and mitogenic (MAPK) pathways in addition to regulatory mechanisms of gene expression such as those involved in non-coding RNAs (miRNAs, circRNAs, and lncRNAs) could be considered as powerful tools to describe this association. A better understanding of the molecular mechanisms involved in the development of type 2 diabetes and pancreatic cancer would help us to find a new research area for developing therapeutic and preventive strategies. For this purpose, in this review, we focused on the shared molecular events resulting in type 2 diabetes and pancreatic cancer. First, a comprehensive literature review was performed to determine similar molecular pathways and non-coding RNAs; then, the final results were discussed in more detail.
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Affiliation(s)
- Fariba Dehghanian
- Department of Cell and Molecular Biology and MicrobiologyFaculty of Biological Science and TechnologyUniversity of IsfahanIsfahanIran
| | - Zahra Azhir
- Department of Cell and Molecular Biology and MicrobiologyFaculty of Biological Science and TechnologyUniversity of IsfahanIsfahanIran
| | - Sheyda Khalilian
- Department of Cell and Molecular Biology and MicrobiologyFaculty of Biological Science and TechnologyUniversity of IsfahanIsfahanIran
| | - Björn Grüning
- Department of Computer ScienceBioinformatics GroupUniversity of FreiburgFreiburgGermany
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Zheng L, Liang H, Zhang Q, Shen Z, Sun Y, Zhao X, Gong J, Hou Z, Jiang K, Wang Q, Jin Y, Yin Y. circPTEN1, a circular RNA generated from PTEN, suppresses cancer progression through inhibition of TGF-β/Smad signaling. Mol Cancer 2022; 21:41. [PMID: 35135542 PMCID: PMC8822707 DOI: 10.1186/s12943-022-01495-y] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 01/03/2022] [Indexed: 02/07/2023] Open
Abstract
Background PTEN is one of the most frequently mutated genes in human cancer. Although the roles of canonical PTEN protein and PTEN isoforms have been extensively explored, the current understanding of PTEN family members cannot fully illustrate the diversity of their roles in biological processes and tumor development. Notably, the function of noncoding RNAs arising from PTEN has been less elucidated.
Methods We searched circBase and circInteractome to analyze the potential of PTEN for generating circRNAs. Then, Sanger sequencing, RNase R and Actinomycin D assays were used to verify the ring structure of circPTEN1. In situ hybridization and qRT-PCR were used to determine the level of circPTEN1 in peritumor and tumor tissues of colorectal cancer (CRC). Furthermore, functional experiments, including Transwell assay, 3D multicellular tumor spheroid invasion assay and metastasis models, were performed using circPTEN1 knockdown and overexpression cell lines in vitro and in vivo to investigate the effects of circPTEN1 on tumor metastasis in CRC. Mechanistically, luciferase reporter assay, fluorescence in situ hybridization, electrophoretic mobility shift assay, RNA immunoprecipitation, RNA pull-down and mass spectrometry were executed. Results We identified a circular RNA generated from the PTEN gene, designated circPTEN1, that is frequently downregulated in colorectal cancer, and decreased expression of circPTEN1 predicts poor survival. Low expression of circPTEN1 promotes metastasis in PDX models in vivo and accelerates cancer cell invasion in vitro, whereas overexpression of circPTEN1 reveals opposite roles. Mechanically, we found that circPTEN1 is capable of binding the MH2 domain of Smad4 to disrupt its physical interaction with Smad2/3, which reduces the formation and subsequent nucleus translocation of Smad complexes and consequently suppresses the expression of its downstream genes associated with epithelial-mesenchymal transition upon TGF-β stimulation. Furthermore, we found that eIF4A3 suppresses the cyclization of circPTEN1 by directly binding to the circPTEN1 flanking region. Conclusions Our study uncovered a novel PTEN gene-generated circRNA with a tumor suppression function, and further revealed the mechanism of circPTEN1 in CRC metastasis mediated by TGF-β. The identification of circPTEN1 provides a new direction for PTEN investigation, and elucidation of circPTEN1/TGF-β/Smad signaling may pave the way for the development of a potential therapeutic strategy for the suppression of cancer progression. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-022-01495-y.
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Affiliation(s)
- Lin Zheng
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Hui Liang
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, 100191, China.
| | - Qiaoling Zhang
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Zichu Shen
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Yixin Sun
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Xuyang Zhao
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Jingjing Gong
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Zhiyuan Hou
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Kewei Jiang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, 100044, China
| | - Quan Wang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, 100044, China
| | - Yan Jin
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Yuxin Yin
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, 100191, China. .,Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen, 518036, China.
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Xu S, Song Y, Shao Y, Zhou H. Hsa_circ_0060927 Is a Novel Tumor Biomarker by Sponging miR-195-5p in the Malignant Transformation of OLK to OSCC. Front Oncol 2022; 11:747086. [PMID: 35087744 PMCID: PMC8786726 DOI: 10.3389/fonc.2021.747086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 12/14/2021] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE To investigate the clinical significance of differentially expressed circRNAs and candidate circRNAs in the transformation of oral leukoplakia (OLK) to oral squamous cell carcinoma (OSCC). METHODS We performed high-throughput circRNA sequencing in six cases of normal oral mucosal (NOM) tissues, six cases of OLK tissues, and six cases of OSCC tissues. Ten circRNAs with significant differential expression were verified by qRT-PCR. Enzyme tolerance assay and Sanger sequencing were performed on the screened target circRNA hsa_circ_0060927, and a qRT-PCR assay of hsa_circ_0060927 was performed in three tissues (24 cases in each group); this was followed by an ROC analysis. The ceRNA network was predicted using TargetScan and miRanda. MiR-195-5p and TRIM14 were selected as the downstream research objects of hsa_circ_0060927. The sponge mechanism of hsa_circ_0060927 was detected by AGO2 RIP. The interaction between hsa_circ_0060927 and miR-195-5p was verified by RNA pull-down assay and dual luciferase reporter gene assay. The expressions of hsa_circ_0060927, miR-195-5p, and TRIM14 were verified by normal oral epithelial primary cells and cell lines of LEUK1, SCC9, and SCC25. The hsa_circ_0060927 overexpressed plasmid and miR-195-5p mimics were constructed to transfection LEUK1 to detect the changes in cell proliferation, apoptosis, and migration. RESULTS The results of qRT-PCR validation were consistent with the sequencing results. Hsa_circ_0060927 is a true circRNA with trans-splicing sites. The expression of hsa_circ_0060927 increased in NOM, OLK, and OSCC. Overexpression of hsa_circ_0060927 enhanced the ability of cell proliferation and migration, and decreased cell apoptosis capacity. The prediction of ceRNA network suggested that hsa_circ_0060927 could regulate the target gene TRIM14 through sponging miR-195-5p. AGO2 RIP indicated that hsa_circ_0060927 had a sponge mechanism. RNA pull-down and dual luciferase reporter gene assay suggested that hsa_circ_0060927 interacted with miR-195-5p. Hsa_circ_0060927 was positively correlated with the expression of TRIM14, and could relieve the inhibition of miR-195-5p on TRIM14 to regulate cell proliferation, apoptosis, and migration of LEUK1 cells. CONCLUSION Hsa_circ_0060927 acted as a potential key ceRNA to sponge downstream miR-195-5p and promote OLK carcinogenesis by upregulating TRIM14. Hsa_circ_0060927 was expected to be a molecular marker for the prevention and treatment of OLK carcinogenesis through the hsa_circ_0060927/miR-195-5p/TRIM14 axis.
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Affiliation(s)
- Siming Xu
- Department of Oral Mucosal Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Oral Diseases, Shanghai, China.,Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Yuhan Song
- Department of Oral Mucosal Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Oral Diseases, Shanghai, China.,Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Yanxiong Shao
- Department of Oral Mucosal Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Oral Diseases, Shanghai, China.,Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Haiwen Zhou
- Department of Oral Mucosal Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Oral Diseases, Shanghai, China.,Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
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circ_ZFR Is Linked to Paclitaxel Resistance in Cervical Cancer via miR-944 Sponging and IL-10 Upregulation. Anal Cell Pathol (Amst) 2022; 2022:4807287. [PMID: 35127342 PMCID: PMC8813297 DOI: 10.1155/2022/4807287] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 12/29/2021] [Indexed: 01/22/2023] Open
Abstract
Objective Cervical cancer (CC) has an elevated rate of invasion and death despite surgical treatment, radiotherapy, and chemotherapy. Several studies revealed that circRNAs have a key contribution to the resistance of drugs against different types of carcinomas. The goal of the existing study was to figure out what role circ_ZFR plays in paclitaxel (PTX) resistance in cervical cancer (CC) patients. Materials and Methods Herein, two types of CC cells (SiHa/PTX and Hela/PTX) were utilized. The levels of IL-10 mRNA, miR-944, and circ_ZFR were measured using qRT-PCR analyses. The CCK-8 assay was used to determine PTX resistance. The IL-10 expression was measured via the ELISA technique. The combination of miR-944 and circ_ZFR or IL-10 was validated using a dual-luciferase reporter (DLR) assay. Results The amount of circ_ZFR was increased in PTX-resistant CC cells and tissues. In PTX-resistant CC cells, knocking down circ_ZFR expression decreased PTX resistance. circ_ZFR knockdown significantly reduced IL-10 expression via sponging miR-944, increasing PTX sensitivity in PTX-resistant CC cells. Conclusion circ_ZFR knockdown has a considerable role in overwhelming CC-associated PTX resistance by modifying the axis of miR-944/IL-10 axis, suggesting that developing a circRNA target-based treatment could be considered prevent CC progression.
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Koppula A, Abdelgawad A, Guarnerio J, Batish M, Parashar V. CircFISH: A Novel Method for the Simultaneous Imaging of Linear and Circular RNAs. Cancers (Basel) 2022; 14:428. [PMID: 35053590 PMCID: PMC8773908 DOI: 10.3390/cancers14020428] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/09/2022] [Accepted: 01/12/2022] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) are regulatory RNAs which have recently been shown to have clinical significance in several diseases, including, but not limited to, various cancers, neurological diseases and cardiovascular diseases. The function of such regulatory RNAs is largely dependent on their subcellular localization. Several circRNAs have been shown to conduct antagonistic roles compared to the products of the linear isoforms, and thus need to be characterized distinctly from the linear RNAs. However, conventional fluorescent in situ hybridization (FISH) techniques cannot be employed directly to distinguish the signals from linear and circular isoforms because most circRNAs share the same sequence with the linear RNAs. In order to address this unmet need, we adapted the well-established method of single-molecule FISH by designing two sets of probes to differentiate the linear and circular RNA isoforms by virtue of signal colocalization. We call this method 'circular fluorescent in situ hybridization' (circFISH). Linear and circular RNAs were successfully visualized and quantified at a single-molecule resolution in fixed cells. RNase R treatment during the circFISH reduced the levels of linear RNAs while the circRNA levels remain unaltered. Furthermore, cells with shRNAs specific to circRNA showed the loss of circRNA levels, whereas the linear RNA levels were unaffected. The optimization of the in-situ RNase R treatment allowed the multiplexing of circFISH to combine it with organelle staining. CircFISH was found to be compatible with multiple sample types, including cultured cells and fresh-frozen and formalin-fixed tissue sections. Thus, we present circFISH as a versatile method for the simultaneous visualization and quantification of the distribution and localization of linear and circular RNA in fixed cells and tissue samples.
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Affiliation(s)
- Aakash Koppula
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; (A.K.); (A.A.)
- Department of Medical and Molecular Sciences, University of Delaware, Newark, DE 19716, USA
| | - Ahmed Abdelgawad
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; (A.K.); (A.A.)
- Department of Medical and Molecular Sciences, University of Delaware, Newark, DE 19716, USA
| | - Jlenia Guarnerio
- Samuel Oschin Comprehensive Cancer Institute, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Mona Batish
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; (A.K.); (A.A.)
- Department of Medical and Molecular Sciences, University of Delaware, Newark, DE 19716, USA
| | - Vijay Parashar
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; (A.K.); (A.A.)
- Department of Medical and Molecular Sciences, University of Delaware, Newark, DE 19716, USA
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Wang N, Yao F, Liu D, Jiang H, Xia X, Xiong S. RNA N6-methyladenosine in nonocular and ocular disease. J Cell Physiol 2021; 237:1686-1710. [PMID: 34913163 DOI: 10.1002/jcp.30652] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 10/27/2021] [Accepted: 11/12/2021] [Indexed: 12/23/2022]
Abstract
N6 -methyladenosine (m6 A), the sixth N methylation of adenylate (A) in RNA, is the most abundant transcriptome modification in eukaryotic messenger RNA (mRNAs). m6 A modification exists in both coding mRNA and noncoding RNAs, and its functions are controlled by methyltransferase, demethylase, and m6 A reading proteins. Methylation modification of m6 A can regulate RNA cleavage, transport, stability, and expression. This review summarizes the enzymes involved in RNA m6 A methylation and the commonly used detection methods. The role of m6 A modification in physiological processes is described, and its impact on tumorigenesis, viral infection, and diabetes is further highlighted. Moreover, up-to-date knowledge of the implications of RNA m6 A modification in ocular diseases such as uveal melanoma and diabetic retinopathy is introduced. Clarifying the mechanism of RNA m6 A methylation will help elucidate the pathogenesis of various diseases, providing options for subsequent treatment.
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Affiliation(s)
- Nan Wang
- Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Opthalmology, Central South University, Changsha, China
| | - Fei Yao
- Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Opthalmology, Central South University, Changsha, China
| | - Die Liu
- Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Opthalmology, Central South University, Changsha, China
| | - Haibo Jiang
- Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Opthalmology, Central South University, Changsha, China
| | - Xiaobo Xia
- Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Opthalmology, Central South University, Changsha, China
| | - Siqi Xiong
- Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Opthalmology, Central South University, Changsha, China
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Das A, Das D, Panda AC. Validation of Circular RNAs by PCR. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2021; 2392:103-114. [PMID: 34773618 DOI: 10.1007/978-1-0716-1799-1_8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
High-throughput RNA-sequencing (RNA-seq) technologies combined with novel bioinformatic algorithms discovered a large class of covalently closed single-stranded RNA molecules called circular RNAs (circRNAs ). Although RNA-seq has identified more than a million circRNAs, only a handful of them is validated with other techniques, including northern blotting, gel-trap electrophoresis, exonuclease treatment assays, and polymerase chain reaction (PCR). Reverse transcription (RT) of total RNA followed by PCR amplification is the most widely used technique for validating circRNAs identified in RNA-seq. RT-PCR is a highly reproducible, sensitive, and quantitative method for the detection and quantitation of circRNAs. This chapter details the basic guidelines for designing suitable primers for PCR amplification and validation of circRNAs .
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Affiliation(s)
- Aniruddha Das
- Institute of Life Sciences, Bhubaneswar, Odisha, India.,School of Biotechnology, KIIT University, Bhubaneswar, Odisha, India
| | - Debojyoti Das
- Institute of Life Sciences, Bhubaneswar, Odisha, India.,School of Biotechnology, KIIT University, Bhubaneswar, Odisha, India
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Liu X, Tong Y, Xia D, Peng E, Yang X, Liu H, Ye T, Wang X, He Y, Ye Z, Chen Z, Tang K. Circular RNAs in prostate cancer: Biogenesis,biological functions, and clinical significance. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:1130-1147. [PMID: 34820150 PMCID: PMC8585584 DOI: 10.1016/j.omtn.2021.10.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Circular RNAs (circRNAs) are covalently closed RNA molecules that play important regulatory roles in various tumors. Prostate cancer (PCa) is one of the most common malignant tumors in the world, with high morbidity and mortality. In recent years, more and more circRNAs have been found to be abnormally expressed and involved in the occurrence and development of PCa, including cell proliferation, apoptosis, invasion, migration, metastasis, chemotherapy resistance, and radiotherapy resistance. Most of the circRNAs regulate biological behaviors of cancer through a competitive endogenous RNA (ceRNA) regulatory mechanism, and some can exert their functions by binding to proteins. circRNAs are also associated with many clinicopathological features of PCa, including tumor grade, lymph node metastasis, and distant metastasis. In addition, circRNAs are potential diagnostic and prognostic biomarkers for PCa. Considering their critical regulatory roles in the progression of PCa, circRNAs would be the potential therapeutic targets. In this paper, the current research status of circRNAs in PCa is briefly reviewed.
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Affiliation(s)
- Xiao Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yonghua Tong
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ding Xia
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ejun Peng
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaoqi Yang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hailang Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Tao Ye
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xinguang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yu He
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhangqun Ye
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhiqiang Chen
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Kun Tang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Wu J, Yuan XH, Jiang W, Lu YC, Huang QL, Yang Y, Qie HJ, Liu JT, Sun HY, Tang LJ. Genome-wide map of N 6-methyladenosine circular RNAs identified in mice model of severe acute pancreatitis. World J Gastroenterol 2021; 27:7530-7545. [PMID: 34887647 PMCID: PMC8613746 DOI: 10.3748/wjg.v27.i43.7530] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/05/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Severe acute pancreatitis (SAP) is a deadly inflammatory disease with complex pathogenesis and lack of effective therapeutic options. N6-methyladenosine (m6A) modification of circRNAs plays important roles in physiological and pathological processes. However, the roles of m6A circRNA in the pathological process of SAP remains unknown.
AIM To identify transcriptome-wide map of m6A circRNAs and to determine their biological significance and potential mechanisms in SAP.
METHODS The SAP in C57BL/6 mice was induced using 4% sodium taurocholate salt. The transcriptome-wide map of m6A circRNAs was identified by m6A-modified RNA immunoprecipitation sequencing. The biological significance of circRNAs with differentially expressed m6A peaks was evaluated through gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The underlying mechanism of m6A circRNAs in SAP was analyzed by constructing of m6A circRNA-microRNA networks. The expression of demethylases was determined by quantitative polymerase chain reaction and western blot to deduce the possible mechanism of reversible m6A process in SAP.
RESULTS Fifty-seven circRNAs with differentially expressed m6A peaks were identified by m6A-modified RNA immunoprecipitation sequencing, of which 32 were upregulated and 25 downregulated. Functional analysis of these m6A circRNAs in SAP found some important pathways involved in the pathogenesis of SAP, such as regulation of autophagy and protein digestion. In m6A circRNA–miRNA networks, several important miRNAs participated in the occurrence and progression of SAP were found to bind to these m6A circRNAs, such as miR-24-3p, miR-26a, miR-92b, miR-216b, miR-324-5p and miR-762. Notably, the total m6A level of circRNAs was reduced, while the demethylase alkylation repair homolog 5 was upregulated in SAP.
CONCLUSION m6A modification of circRNAs may be involved in the pathogenesis of SAP. Our findings may provide novel insights to explore the possible pathogenetic mechanism of SAP and seek new potential therapeutic targets for SAP.
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Affiliation(s)
- Jun Wu
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
- College of Medicine, Southwest Jiaotong University, Chengdu 610036, Sichuan Province, China
| | - Xiao-Hui Yuan
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
- College of Medicine, Southwest Jiaotong University, Chengdu 610036, Sichuan Province, China
| | - Wen Jiang
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
- College of Medicine, Southwest Jiaotong University, Chengdu 610036, Sichuan Province, China
| | - Yi-Chen Lu
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
- College of Medicine, Southwest Jiaotong University, Chengdu 610036, Sichuan Province, China
| | - Qi-Lin Huang
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
| | - Yi Yang
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
| | - Hua-Ji Qie
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
- College of Medicine, Southwest Jiaotong University, Chengdu 610036, Sichuan Province, China
| | - Jiang-Tao Liu
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
- College of Medicine, Southwest Jiaotong University, Chengdu 610036, Sichuan Province, China
| | - Hong-Yu Sun
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
- College of Medicine, Southwest Jiaotong University, Chengdu 610036, Sichuan Province, China
- Laboratory of Basic Medicine, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
| | - Li-Jun Tang
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
- College of Medicine, Southwest Jiaotong University, Chengdu 610036, Sichuan Province, China
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Grammatikakis I, Karreth FA, Panda AC. Editorial: Structural and Functional Characterization of Circular RNAs. Front Mol Biosci 2021; 8:795286. [PMID: 34796203 PMCID: PMC8592900 DOI: 10.3389/fmolb.2021.795286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 10/19/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
- Ioannis Grammatikakis
- National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Florian A. Karreth
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
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Yu J, Li F, Li Y, Li Z, Jia G, Ding B, Zhou Y. The effects of hsa_circ_0000517/miR-326 axis on the progression of breast cancer cells and the prediction of miR-326 downstream targets in breast cancer. Pathol Res Pract 2021; 227:153638. [PMID: 34619576 DOI: 10.1016/j.prp.2021.153638] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 09/21/2021] [Accepted: 09/27/2021] [Indexed: 12/16/2022]
Abstract
It has been proposed that circular RNAs (circRNAs) play crucial roles in the initiation and progression of various cancers including breast cancer. Our study aimed to determine the function and regulatory mechanism of hsa_circ_0000517 in breast cancer. qRT-PCR was applied to determine hsa_circ_0000517 expression in breast cancer cells. The circular structure of hsa_circ_0000517 was confirmed using RNase R digestion assay. The subcellular distribution of hsa_circ_0000517 was analyzed using nuclear mass separation assay. Effects of hsa_circ_0000517 on the malignant behaviors of breast cancer cells were determined using CCK-8, colony formation assay, flow cytometry analysis, caspase-3 activity assay, and Transwell invasion assay. Bioinformatics analysis, luciferase reporter assay, and RIP were used to predict and confirm the interaction between hsa_circ_0000517 and miR-326. Bioinformatics analysis was used to search the possible targets of miR-326. Hsa_circ_0000517 was upregulated in breast cancer tissues and cells. Hsa_circ_0000517 was a stable circularized transcript that was preferentially distributed in the cytoplasm. Hsa_circ_0000517 knockdown inhibited cell proliferation, colony formation ability, and invasion and triggered apoptosis in breast cancer cells. Hsa_circ_0000517 acted as a sponge of miR-326 to suppress its expression. miR-326 inhibition abolished the effects of hsa_circ_0000517 knockdown on the malignant behaviors of breast cancer cells. Totally 17 genes were identified as the potential targets of miR-326 in breast cancer. In conclusion, hsa_circ_0000517 silencing repressed breast cancer progression by upregulating miR-326 expression.
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Affiliation(s)
- Jinsong Yu
- Department of Thyroid and Breast Surgery, Nanyang First People's Hospital, Nanyang 473012, China; Key Laboratory of Thyroid Tumor Prevention and Treatment, Nanyang First People's Hospital, Nanyang 473012, China
| | - Fengbo Li
- Department of Respiratory Medicine, Nanshi Hospital of Nanyang, Nanyang 473000, China
| | - Yan Li
- Department of General Surgery, Nanyang First People's Hospital, Nanyang 473012, China
| | - Zhong Li
- Department of General Surgery, Nanyang First People's Hospital, Nanyang 473012, China
| | - Guangwei Jia
- Department of Thyroid and Breast Surgery, Nanyang First People's Hospital, Nanyang 473012, China
| | - Bo Ding
- Department of General Surgery, Nanyang First People's Hospital, Nanyang 473012, China
| | - Yeqi Zhou
- Department of Radiology, The Affiliated Huai'an Hospital of Xuzhou Medical University, The Second People's Hospital of Huai'an, Huai'an 223002, China.
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Reed KM, Mendoza KM, Abrahante JE, Velleman SG, Strasburg GM. Data Mining Identifies Differentially Expressed Circular RNAs in Skeletal Muscle of Thermally Challenged Turkey Poults. Front Physiol 2021; 12:732208. [PMID: 34512399 PMCID: PMC8424120 DOI: 10.3389/fphys.2021.732208] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 08/06/2021] [Indexed: 11/30/2022] Open
Abstract
Precise regulation of gene expression is critical for normal muscle growth and development. Changes in gene expression patterns caused by external stressors such as temperature can have dramatic effects including altered cellular structure and function. Understanding the cellular mechanisms that underlie muscle growth and development and how these are altered by external stressors are crucial in maintaining and improving meat quality. This study investigated circular RNAs (circRNAs) as an emerging aspect of gene regulation. We used data mining to identify circRNAs and characterize their expression profiles within RNAseq data collected from thermally challenged turkey poults of the RBC2 and F-lines. From sequences of 28 paired-end libraries, 8924 unique circRNAs were predicted of which 1629 were common to all treatment groups. Expression analysis identified significant differentially expressed circRNAs (DECs) in comparisons between thermal treatments (41 DECs) and between genetic lines (117 DECs). No intersection was observed between the DECs and differentially expressed gene transcripts indicating that the DECs are not simply the result of expression changes in the parental genes. Comparative analyses based on the chicken microRNA (miRNA) database suggest potential interactions between turkey circRNAs and miRNAs. Additional studies are needed to reveal the functional significance of the predicted circRNAs and their role in muscle development in response to thermal challenge. The DECs identified in this study provide an important framework for future investigation.
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Affiliation(s)
- Kent M Reed
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States
| | - Kristelle M Mendoza
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States
| | - Juan E Abrahante
- University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, MN, United States
| | - Sandra G Velleman
- Department of Animal Sciences, The Ohio State University, Ohio Agricultural Research and Development Center, Wooster, OH, United States
| | - Gale M Strasburg
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States
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Shen HY, Shi LX, Wang L, Fang LP, Xu W, Xu JQ, Fan BQ, Fan WF. Hsa_circ_0001361 facilitates the progress of lung adenocarcinoma cells via targeting miR-525-5p/VMA21 axis. J Transl Med 2021; 19:389. [PMID: 34507559 PMCID: PMC8434718 DOI: 10.1186/s12967-021-03045-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 08/17/2021] [Indexed: 12/13/2022] Open
Abstract
Background Lung adenocarcinoma (LUAD) is a common subtype of lung cancer with high recurrence rate and fatality. Circ_0001361 has been recognized as key regulators in various malignancies, but its roles in LUAD remain ambiguous. Methods Circ_0001361, miR-525-5p, and VMA21 levels were assessed by RT-qPCR. The growth and metastasis of LUAD cells were detected by MTT, colony formation, wound scratch, and transwell assays, respectively. The interaction between circ_0001361/VMA21 and miR-525-5p was detected by dual luciferase, RNA immunoprecipitation, and RNA pull-down assays. VMA21 protein level was detected by Western blotting. Nude mouse xenograft model was established to determine the role of circ_0001361 in tumor growth in vivo. Results Circ_0001361 was up-regulated, while miR-525-5p was down-regulated in LUAD tissues and cells. Functional experiments demonstrated that circ_0001361 drove LUAD cell growth and metastasis. Mechanistically, circ_0001361 functioned as a sponge of miR-525-5p to up-regulate downstream target VMA21 level. MiR-525-5p/VMA21 axis was involved in circ_0001361-mediated malignant phenotypes of LUAD cells. Finally, inhibition of circ_0001361 restrained in vivo xenograft tumor growth via regulating miR-525-5p/VMA21 axis. Conclusion Our findings elucidate that circ_0001361 facilitates the tumorigenesis and development of LUAD through miR-525-5p/VMA21 axis, providing evidence for circ_0001361 as a potential prognosis biomarker and therapeutic target for clinical treatment of LUAD. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-03045-4.
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Affiliation(s)
- Hong-Yu Shen
- Department of Hematology and Oncology, Department of Geriatric Lung Cancer Laboratory, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, No.65 Jiangsu Road, Gulou District, Nanjing, 210000, Jiangsu Province, People's Republic of China
| | - Liu-Xi Shi
- GCP office, The Second Affiliated Hospital of Soochow University, Suzhou, 215000, Jiangsu Province, People's Republic of China
| | - Lin Wang
- Department of Hematology and Oncology, Department of Geriatric Lung Cancer Laboratory, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, No.65 Jiangsu Road, Gulou District, Nanjing, 210000, Jiangsu Province, People's Republic of China
| | - Le-Ping Fang
- Department of Hematology and Oncology, Department of Geriatric Lung Cancer Laboratory, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, No.65 Jiangsu Road, Gulou District, Nanjing, 210000, Jiangsu Province, People's Republic of China
| | - Wei Xu
- Department of Hematology and Oncology, Department of Geriatric Lung Cancer Laboratory, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, No.65 Jiangsu Road, Gulou District, Nanjing, 210000, Jiangsu Province, People's Republic of China
| | - Ju-Qing Xu
- Department of Hematology and Oncology, Department of Geriatric Lung Cancer Laboratory, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, No.65 Jiangsu Road, Gulou District, Nanjing, 210000, Jiangsu Province, People's Republic of China
| | - Bo-Qiang Fan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu Province, People's Republic of China.
| | - Wei-Fei Fan
- Department of Hematology and Oncology, Department of Geriatric Lung Cancer Laboratory, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, No.65 Jiangsu Road, Gulou District, Nanjing, 210000, Jiangsu Province, People's Republic of China.
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Zhou R, Jia W, Gao X, Deng F, Fu K, Zhao T, Li Z, Fu W, Liu G. CircCDYL Acts as a Tumor Suppressor in Wilms' Tumor by Targeting miR-145-5p. Front Cell Dev Biol 2021; 9:668947. [PMID: 34485273 PMCID: PMC8415843 DOI: 10.3389/fcell.2021.668947] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 06/03/2021] [Indexed: 11/13/2022] Open
Abstract
Circular RNAs (circRNA) have been reported to exert evident functions in many human carcinomas. However, the possible mechanisms concerning the circRNA in various tumors are still elusive. In this research, we analyzed the expression profile and biological functions of circular RNA CDYL (circCDYL, circBase ID: hsa_circ_0008285) in Wilms' tumor. Here, miRNA and gene expression were examined by real-time PCR in Wilms' tumor tissues and cell lines. The functions of circCDYL and its potential targets to influence cell proliferation, migration, and invasion in Wilms' tumor cells were determined by biological functional experiments in vitro and in vivo. We predicted and analyzed potential miRNA targets through online bioinformatic tools. To validate the interactions between circCDYL and its targets, we performed RNA fluorescence in situ hybridization, biotin-coupled miRNA capture assay, and biotin-coupled probe pull-down assay. Tight junction protein l (TJP1) was proved to be the target gene of the predicted miRNA by dual-luciferase reporter assay. The expression level of TJP1 in Wilms' tumor cells was identified via Western blot. We showed that circCDYL was downregulated in WT tissue compared with adjacent non-tumor tissue. Upregulation of circCDYL could reduce cell proliferation, migration, and invasion. Mechanically, circCDYL, functioning as a miRNA sponge, decreased the expression level of miR-145-5p and TJP1 3'UTR was validated as the target of miR-145-5p, facilitating the circCDYL/miR-145-5p/TJP1 axis. In conclusion, our study suggested circCDYL as a novel biomarker and therapeutic target for WT treatment.
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Affiliation(s)
- Rui Zhou
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wei Jia
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Xiaofeng Gao
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fuming Deng
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Kai Fu
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Tianxin Zhao
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Zhongmin Li
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wen Fu
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Guochang Liu
- Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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Systematic Identification of circRNAs in Alzheimer's Disease. Genes (Basel) 2021; 12:genes12081258. [PMID: 34440432 PMCID: PMC8391980 DOI: 10.3390/genes12081258] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/25/2021] [Accepted: 08/10/2021] [Indexed: 12/13/2022] Open
Abstract
Mammalian circRNAs are covalently closed circular RNAs often generated through backsplicing of precursor linear RNAs. Although their functions are largely unknown, they have been found to influence gene expression at different levels and in a wide range of biological processes. Here, we investigated if some circRNAs may be differentially abundant in Alzheimer’s Disease (AD). We identified and analyzed publicly available RNA-sequencing data from the frontal lobe, temporal cortex, hippocampus, and plasma samples reported from persons with AD and persons who were cognitively normal, focusing on circRNAs shared across these datasets. We identified an overlap of significantly changed circRNAs among AD individuals in the various brain datasets, including circRNAs originating from genes strongly linked to AD pathology such as DOCK1, NTRK2, APC (implicated in synaptic plasticity and neuronal survival) and DGL1/SAP97, TRAPPC9, and KIF1B (implicated in vesicular traffic). We further predicted the presence of circRNA isoforms in AD using specialized statistical analysis packages to create approximations of entire circRNAs. We propose that the catalog of differentially abundant circRNAs can guide future investigation on the expression and splicing of the host transcripts, as well as the possible roles of these circRNAs in AD pathogenesis.
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Chen F, Guo L, Di J, Li M, Dong D, Pei D. Circular RNA ubiquitin-associated protein 2 enhances autophagy and promotes colorectal cancer progression and metastasis via miR-582-5p/FOXO1 signaling. J Genet Genomics 2021; 48:1091-1103. [PMID: 34416339 DOI: 10.1016/j.jgg.2021.07.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 12/27/2022]
Abstract
Numerous circular RNAs (circRNAs) have been identified as vital regulators in various cancers. The newly reported circular RNA ubiquitin-associated protein 2 (circUBAP2) is a critical player in cell growth and metastasis in various types of cancers, although its role in colorectal cancer (CRC) has yet to be fully elucidated. We find that circUBAP2 is upregulated in CRC tissues and cell lines to induce autophagy both in vitro and in vivo. The effects of circUBAP2 on migration, invasion, and proliferation may be partially related to autophagy. Mechanistically, we uncover that circUBAP2 can directly interact with miR-582-5p and subsequently act as a microRNA sponge to regulate the expression of the miR-582-5p target gene forkhead box protein O1 (FOXO1) and downstream signaling molecules, which collectively advance the progression and metastasis of CRC. These results suggest that circUBAP2 acts as an oncogene via a novel circUBAP2/miR-582-5p/FOXO1 axis, providing a potential biomarker and therapeutic target for CRC management.
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Affiliation(s)
- Feifei Chen
- Department of Cell Biology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
| | - Lei Guo
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
| | - Jiehui Di
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
| | - Man Li
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
| | - Dong Dong
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
| | - Dongsheng Pei
- Department of Cell Biology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China.
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Zhang Z, Mou Z, Xu C, Wu S, Dai X, Chen X, Ou Y, Chen Y, Yang C, Jiang H. Autophagy-associated circular RNA hsa_circ_0007813 modulates human bladder cancer progression via hsa-miR-361-3p/IGF2R regulation. Cell Death Dis 2021; 12:778. [PMID: 34365465 PMCID: PMC8349354 DOI: 10.1038/s41419-021-04053-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 01/07/2023]
Abstract
Circular RNAs (circRNAs) drive several cellular processes including proliferation, survival, and differentiation. Here, we identified a circRNA hsa_circ_0007813, whose expression was upregulated in bladder cancer. High hsa_circ_0007813 expression was associated with larger tumor size, higher primary tumor T stage, and higher pathologic grade. Survival analysis showed that patients with high hsa_circ_0007813 expression levels had a poorer prognosis. Based on these findings from clinical tissue samples and cell lines, we assumed that hsa_circ_0007813 functioned a vital role in bladder cancer progression. Next, functional experiments revealed that knockdown of hsa_circ_0007813 inhibited proliferation, migration, and invasiveness of bladder cancer cells both in vitro and in vivo. Through extensive bioinformatic prediction and RNA pull-down assays, we identified hsa-miR-361-3p as a competing endogenous RNA of hsa_circ_0007813. Further bioinformatic studies narrowed targets to 35 possible downstream genes. We then found that knockdown of hsa_circ_0007813 led to altered cell autophagy, bringing our attention to IGF2R, one of the possible downstream genes. IGF2R was also known as cation-independent mannose-6-phosphate receptor (CI-M6PR), was discovered to participate in both autophagy and tumor biology. Regarding autophagy has a dominant role in the survival of tumor cells overcoming cellular stress and correlates with tumor progression, investigations were made to prove that hsa_circ_0007813 could regulate IGF2R expression via hsa-miR-361-3p sponging. The potential of hsa_circ_0007813 in regulating IGF2R expression explained its influence on cell behavior and clinical outcomes. Collectively, our data could offer new insight into the biology of circRNA in bladder cancer.
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Affiliation(s)
- Zheyu Zhang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Zezhong Mou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chenyang Xu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Siqi Wu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiyu Dai
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xinan Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxi Ou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yiling Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chen Yang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China.
| | - Haowen Jiang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China.
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Das A, Sinha T, Shyamal S, Panda AC. Emerging Role of Circular RNA-Protein Interactions. Noncoding RNA 2021; 7:48. [PMID: 34449657 PMCID: PMC8395946 DOI: 10.3390/ncrna7030048] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/26/2021] [Accepted: 07/29/2021] [Indexed: 12/17/2022] Open
Abstract
Circular RNAs (circRNAs) are emerging as novel regulators of gene expression in various biological processes. CircRNAs regulate gene expression by interacting with cellular regulators such as microRNAs and RNA binding proteins (RBPs) to regulate downstream gene expression. The accumulation of high-throughput RNA-protein interaction data revealed the interaction of RBPs with the coding and noncoding RNAs, including recently discovered circRNAs. RBPs are a large family of proteins known to play a critical role in gene expression by modulating RNA splicing, nuclear export, mRNA stability, localization, and translation. However, the interaction of RBPs with circRNAs and their implications on circRNA biogenesis and function has been emerging in the last few years. Recent studies suggest that circRNA interaction with target proteins modulates the interaction of the protein with downstream target mRNAs or proteins. This review outlines the emerging mechanisms of circRNA-protein interactions and their functional role in cell physiology.
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Affiliation(s)
- Arundhati Das
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, India; (A.D.); (T.S.); (S.S.)
- School of Biotechnology, KIIT University, Bhubaneswar 751024, India
| | - Tanvi Sinha
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, India; (A.D.); (T.S.); (S.S.)
| | - Sharmishtha Shyamal
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, India; (A.D.); (T.S.); (S.S.)
| | - Amaresh Chandra Panda
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, India; (A.D.); (T.S.); (S.S.)
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Sinha T, Panigrahi C, Das D, Chandra Panda A. Circular RNA translation, a path to hidden proteome. WILEY INTERDISCIPLINARY REVIEWS-RNA 2021; 13:e1685. [PMID: 34342387 DOI: 10.1002/wrna.1685] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 11/06/2022]
Abstract
Functional proteins in the cell are translated from the messenger RNA (mRNA) molecules, constituting less than 5% of the cellular transcriptome. The majority of the RNA molecules in the cell are noncoding RNAs, including rRNA, tRNA, snRNA, piRNA, lncRNA, microRNA, and poorly characterized circular RNAs (circRNAs). Recent studies established that circRNAs regulate gene expression by associating with RNA-binding proteins and microRNAs. With the growing understanding of circRNA functions, a subset of circRNAs has been reported to translate into proteins. Interestingly, the presence of Open Reading Frames (ORFs), N6-methyladenosine (m6A) modifications, and internal ribosomal entry sites (IRES) in the circRNA sequences indicate their coding potential through the cap-independent translation initiation mechanism. The purpose of this review is to highlight the mechanism of circRNA translation and the importance of circRNA-encoded proteins (circ-proteins) in cellular physiology and pathology. Here, we discuss the computational and molecular methods currently utilized to systematically identify translatable circRNAs and the functional characterization of the circ-proteins. We foresee that the ongoing and future studies on circRNA translation will uncover the hidden proteome and their therapeutic implications in human health. This article is categorized under: RNA Methods > RNA Analyses in Cells Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs Translation > Mechanisms.
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Affiliation(s)
- Tanvi Sinha
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, India
| | - Chirag Panigrahi
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, India
| | - Debojyoti Das
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, India.,School of Biotechnology, KIIT University, Bhubaneswar, Odisha, India
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Zhang Y, Chen Y, Wan Y, Zhao Y, Wen Q, Tang X, Shen J, Wu X, Li M, Li X, Li J, Li W, Xiao Z, Du F. Circular RNAs in the Regulation of Oxidative Stress. Front Pharmacol 2021; 12:697903. [PMID: 34385919 PMCID: PMC8353126 DOI: 10.3389/fphar.2021.697903] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 07/13/2021] [Indexed: 12/29/2022] Open
Abstract
Oxidative stress caused by an imbalance between the production and elimination of reactive metabolites and free radicals can lead to the development of a variety of diseases. Over the past years, with the development of science and technology, circular RNA (circRNA) has been found to be closely associated with oxidative stress, which plays an important role in the process of oxidative stress. Currently, the understanding of circRNAs in the mechanism of oxidative stress is limited. In this review, we described the relationship between oxidative stress and circRNAs, the circRNAs related to oxidative stress, and the role of circRNAs in promoting or inhibiting the occurrence and development of diseases associated with the oxidative stress system.
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Affiliation(s)
- Yao Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yue Wan
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Qinglian Wen
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiaolong Tang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Xiang Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jing Li
- Department of Oncology and Hematology, Hospital (T.C.M) Affiliated to Southwest Medical University, Luzhou, China
| | - Wanping Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
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Wu J, Guo X, Wen Y, Huang S, Yuan X, Tang L, Sun H. N6-Methyladenosine Modification Opens a New Chapter in Circular RNA Biology. Front Cell Dev Biol 2021; 9:709299. [PMID: 34368159 PMCID: PMC8342999 DOI: 10.3389/fcell.2021.709299] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/06/2021] [Indexed: 01/22/2023] Open
Abstract
As the most abundant internal modification in eukaryotic cells, N6-methyladenosine (m6A) in mRNA has shown widespread regulatory roles in a variety of physiological processes and disease progressions. Circular RNAs (circRNAs) are a class of covalently closed circular RNA molecules and play an essential role in the pathogenesis of various diseases. Recently, accumulating evidence has shown that m6A modification is widely existed in circRNAs and found its key biological functions in regulating circRNA metabolism, including biogenesis, translation, degradation and cellular localization. Through regulating circRNAs, studies have shown the important roles of m6A modification in circRNAs during immunity and multiple diseases, which represents a new layer of control in physiological processes and disease progressions. In this review, we focused on the roles played by m6A in circRNA metabolism, summarized the regulatory mechanisms of m6A-modified circRNAs in immunity and diseases, and discussed the current challenges to study m6A modification in circRNAs and the possible future directions, providing a comprehensive insight into understanding m6A modification of circRNAs in RNA epigenetics.
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Affiliation(s)
- Jun Wu
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, China.,College of Medicine, Southwest Jiaotong University, Chengdu, China
| | - Xin Guo
- Laboratory of Basic Medicine, The General Hospital of Western Theater Command, Chengdu, China
| | - Yi Wen
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, China
| | - Shangqing Huang
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, China.,College of Medicine, Southwest Jiaotong University, Chengdu, China
| | - Xiaohui Yuan
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, China.,College of Medicine, Southwest Jiaotong University, Chengdu, China
| | - Lijun Tang
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, China.,College of Medicine, Southwest Jiaotong University, Chengdu, China
| | - Hongyu Sun
- Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, China.,College of Medicine, Southwest Jiaotong University, Chengdu, China.,Laboratory of Basic Medicine, The General Hospital of Western Theater Command, Chengdu, China
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Natural antisense transcript of Period2, Per2AS, regulates the amplitude of the mouse circadian clock. Genes Dev 2021; 35:899-913. [PMID: 34016691 PMCID: PMC8168560 DOI: 10.1101/gad.343541.120] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 04/26/2021] [Indexed: 12/20/2022]
Abstract
In mammals, a set of core clock genes form transcription-translation feedback loops to generate circadian oscillations. We and others recently identified a novel transcript at the Period2 (Per2) locus that is transcribed from the antisense strand of Per2 This transcript, Per2AS, is expressed rhythmically and antiphasic to Per2 mRNA, leading to our hypothesis that Per2AS and Per2 mutually inhibit each other's expression and form a double negative feedback loop. By perturbing the expression of Per2AS, we found that Per2AS transcription, but not transcript, represses Per2 However, Per2 does not repress Per2AS, as Per2 knockdown led to a decrease in the Per2AS level, indicating that Per2AS forms a single negative feedback loop with Per2 and maintains the level of Per2 within the oscillatory range. Per2AS also regulates the amplitude of the circadian clock, and this function cannot be solely explained through its interaction with Per2, as Per2 knockdown does not recapitulate the phenotypes of Per2AS perturbation. Overall, our data indicate that Per2AS is an important regulatory molecule in the mammalian circadian clock machinery. Our work also supports the idea that antisense transcripts of core clock genes constitute a common feature of circadian clocks, as they are found in other organisms.
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Hoogstrate Y, French PJ. You spin me right 'round. Neuro Oncol 2021; 23:707-708. [PMID: 33704479 DOI: 10.1093/neuonc/noab032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Youri Hoogstrate
- Department of Neurology, Brain Tumor Center at Erasmus MC Cancer Institute Rotterdam, University Medical Center Rotterdam, the Netherlands
| | - Pim J French
- Department of Neurology, Brain Tumor Center at Erasmus MC Cancer Institute Rotterdam, University Medical Center Rotterdam, the Netherlands
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