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Jiang T, Bo S, You Y, Wang Y, Hou L, Tian S, Bai B, Cheng Y, Gao Y. ELAVL1 facilitates gastric cancer progression and metastasis through TL1A mRNA stabilization. Exp Cell Res 2025; 446:114491. [PMID: 40020895 DOI: 10.1016/j.yexcr.2025.114491] [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: 09/13/2024] [Revised: 01/23/2025] [Accepted: 02/26/2025] [Indexed: 03/03/2025]
Abstract
ELAV-like RNA-binding protein 1 (ELAVL1) is a key RNA-binding protein involved in tumor progression and metastasis. This study identifies a previously unrecognized interaction between ELAVL1 and TL1A mRNA, elucidating its role in promoting gastric cancer (GC) progression through the activation of the PI3K/Akt signaling pathway. Overexpression of ELAVL1 significantly enhances the proliferation and migration of GC cells, whereas silencing ELAVL1 leads to a marked reduction in these processes. Additionally, stable knockout of ELAVL1 significantly inhibits the growth of xenograft tumors derived from GC cells in nude mice. Mechanistically, ELAVL1 directly binds to TL1A mRNA through its RNA recognition motifs (RRM1 and RRM3). The binding sites on TL1A mRNA have been confirmed in two regions: one located between nucleotides 1605 and 1868, and the other between 4324 and 4587. ELAVL1 stabilizes TL1A mRNA expression and promotes GC progression by activating the downstream PI3K/Akt signaling pathway.Our findings highlight a novel regulatory axis involving ELAVL1, TL1A mRNA, and PI3K/Akt, providing new insights into RNA-mediated oncogenic signaling and establishing ELAVL1 as a potential therapeutic target for GC. This discovery lays the groundwork for developing targeted therapies against ELAVL1.
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Affiliation(s)
- Tao Jiang
- Department of Immunology, Basic Medical Institute, Chengde Medical University, Chengde 067000, Hebei, China; Department of Ultrasound, The First Affiliated Hospital of Anhui Medical University, Hefei, AH, 230000, China
| | - Sihan Bo
- Department of Immunology, Basic Medical Institute, Chengde Medical University, Chengde 067000, Hebei, China
| | - Yong You
- Department of Immunology, Basic Medical Institute, Chengde Medical University, Chengde 067000, Hebei, China
| | - Yongwei Wang
- Department of Anatomy, Basic Medical Institute, Chengde Medical University, Chengde 067000, Hebei, China
| | - Lei Hou
- Department of Gastrointestinal Surgery, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei, China
| | - Shuang Tian
- Department of Immunology, Basic Medical Institute, Chengde Medical University, Chengde 067000, Hebei, China
| | - Bing Bai
- Department of Immunology, Basic Medical Institute, Chengde Medical University, Chengde 067000, Hebei, China
| | - Yu Cheng
- Department of Pathology, Chengde Medical University, Chengde 067000, Hebei, China
| | - Yaxian Gao
- Department of Immunology, Basic Medical Institute, Chengde Medical University, Chengde 067000, Hebei, China.
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Wei X, He Y, Yu Y, Tang S, Liu R, Guo J, Jiang Q, Zhi X, Wang X, Meng D. The Multifaceted Roles of BACH1 in Disease: Implications for Biological Functions and Therapeutic Applications. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412850. [PMID: 39887888 PMCID: PMC11905017 DOI: 10.1002/advs.202412850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 12/22/2024] [Indexed: 02/01/2025]
Abstract
BTB domain and CNC homolog 1 (BACH1) belongs to the family of basic leucine zipper proteins and is expressed in most mammalian tissues. It can regulate its own expression and play a role in transcriptionally activating or inhibiting downstream target genes. It has a crucial role in various biological processes, such as oxidative stress, cell cycle, heme homeostasis, and immune regulation. Recent research highlights BACH1's significant regulatory roles in a series of conditions, including stem cell pluripotency maintenance and differentiation, growth, senescence, and apoptosis. BACH1 is closely associated with cardiovascular diseases and contributes to angiogenesis, atherosclerosis, restenosis, pathological cardiac hypertrophy, myocardial infarction, and ischemia/reperfusion (I/R) injury. BACH1 promotes tumor cell proliferation and metastasis by altering tumor metabolism and the epithelial-mesenchymal transition phenotype. Moreover, BACH1 appears to show an adverse role in diseases such as neurodegenerative diseases, gastrointestinal disorders, leukemia, pulmonary fibrosis, and skin diseases. Inhibiting BACH1 may be beneficial for treating these diseases. This review summarizes the role of BACH1 and its regulatory mechanism in different cell types and diseases, proposing that precise targeted intervention of BACH1 may provide new strategies for human disease prevention and treatment.
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Affiliation(s)
- Xiangxiang Wei
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Zhongshan Hospital Immunotherapy Translational Research Center, Fudan University, Shanghai, 200032, China
| | - Yunquan He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Zhongshan Hospital Immunotherapy Translational Research Center, Fudan University, Shanghai, 200032, China
| | - Yueyang Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Zhongshan Hospital Immunotherapy Translational Research Center, Fudan University, Shanghai, 200032, China
| | - Sichong Tang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Zhongshan Hospital Immunotherapy Translational Research Center, Fudan University, Shanghai, 200032, China
| | - Ruiwen Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Zhongshan Hospital Immunotherapy Translational Research Center, Fudan University, Shanghai, 200032, China
| | - Jieyu Guo
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Zhongshan Hospital Immunotherapy Translational Research Center, Fudan University, Shanghai, 200032, China
| | - Qingjun Jiang
- Department of Vascular & Endovascular Surgery, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Xiuling Zhi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Zhongshan Hospital Immunotherapy Translational Research Center, Fudan University, Shanghai, 200032, China
| | - Xinhong Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Zhongshan Hospital Immunotherapy Translational Research Center, Fudan University, Shanghai, 200032, China
| | - Dan Meng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Zhongshan Hospital Immunotherapy Translational Research Center, Fudan University, Shanghai, 200032, China
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Jiang H, Cai Q, He P, Li F, Chen Q. LncRNA TUG1 Repressed Angiogenesis by Promoting the Ubiquitination of HuR and Inhibiting Its Nuclear Translocation in Cerebral Ischemic Reperfusion Injury. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413333. [PMID: 39887590 PMCID: PMC11948051 DOI: 10.1002/advs.202413333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 12/24/2024] [Indexed: 02/01/2025]
Abstract
Although both Taurine Upregulated Gene 1(TUG1) and Human Antigen R (HuR) play significant regulatory roles in Cerebral Ischemic Reperfusion Injury (CIRI), their potential pro-angiogenesis mechanisms in CIRI remain unclear. METHODS Herein, the biological roles of TUG1 and HuR in angiogenesis are first confirmed. Following that, HuR-binding VEGFA mRNAs are identified via the Fluorescence In Situ Hybridization (FISH), RNA Immunoprecipitation (RIP), and Cross-Linking Immunoprecipitation (CLIP) assays. Actinomycin D and polysomal assays are also employed to confirm VEGFA mRNA stability. The co-localization of TUG1 with HuR is confirmed using FISH, while the RIP and RNA pull-down assays are employed to elucidate their interplay. The direct binding between TUG1 and HuR is confirmed through the CLIP assay. Co-Immunoprecipitation (Co-IP) and rescue experiments are performed to further elucidate TUG1-HuR interactions. RESULTS While TUG1 repressed angiogenesis and aggravated CIRI, HuR exerted contrary effects. Specifically, HuR bound directly to VEGFA mRNA, a phenomenon that enhanced VEGFA mRNA stability. Conversely, TUG1 binds to HuR directly, inhibiting its nuclear translocation and promoting its ubiquitination, ultimately reducing VEGFA mRNA stability. CONCLUSIONS It is found that TUG1 can inhibit angiogenesis in CIRI through the HuR/VEGFA mRNA axis.
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Affiliation(s)
- Hongxiang Jiang
- Department of NeurosurgeryRenmin Hospital of Wuhan UniversityWuhanHubei Province430060China
| | - Qiang Cai
- Department of NeurosurgeryRenmin Hospital of Wuhan UniversityWuhanHubei Province430060China
| | - Peidong He
- First School of Clinical Medicine of Wuhan UniversityWuhanHubei Province430060China
| | - Fei Li
- Department of NeurosurgeryRenmin Hospital of Wuhan UniversityWuhanHubei Province430060China
| | - Qianxue Chen
- Department of NeurosurgeryRenmin Hospital of Wuhan UniversityWuhanHubei Province430060China
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Youness RA, Hassan HA, Abaza T, Hady AA, El Magdoub HM, Ali M, Vogel J, Thiersch M, Gassmann M, Hamdy NM, Aboouf MA. A Comprehensive Insight and In Silico Analysis of CircRNAs in Hepatocellular Carcinoma: A Step toward ncRNA-Based Precision Medicine. Cells 2024; 13:1245. [PMID: 39120276 PMCID: PMC11312109 DOI: 10.3390/cells13151245] [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: 05/22/2024] [Revised: 07/11/2024] [Accepted: 07/22/2024] [Indexed: 08/10/2024] Open
Abstract
Circular RNAs (circRNAs) are cardinal players in numerous physiological and pathological processes. CircRNAs play dual roles as tumor suppressors and oncogenes in different oncological contexts, including hepatocellular carcinoma (HCC). Their roles significantly impact the disease at all stages, including initiation, development, progression, invasion, and metastasis, in addition to the response to treatment. In this review, we discuss the biogenesis and regulatory functional roles of circRNAs, as well as circRNA-protein-mRNA ternary complex formation, elucidating the intricate pathways tuned by circRNAs to modulate gene expression and cellular processes through a comprehensive literature search, in silico search, and bioinformatics analysis. With a particular focus on the interplay between circRNAs, epigenetics, and HCC pathology, the article sets the stage for further exploration of circRNAs as novel investigational theranostic agents in the dynamic realm of HCC.
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Affiliation(s)
- Rana A. Youness
- Molecular Genetics Research Team (MGRT), Molecular Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (R.A.Y.); (H.A.H.); (T.A.)
| | - Hossam A. Hassan
- Molecular Genetics Research Team (MGRT), Molecular Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (R.A.Y.); (H.A.H.); (T.A.)
| | - Tasneem Abaza
- Molecular Genetics Research Team (MGRT), Molecular Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (R.A.Y.); (H.A.H.); (T.A.)
- Biotechnology Program, Institute of Basic and Applied Sciences (BAS), Egypt-Japan University of Science and Technology (E-JUST), New Borg El-Arab City 21934, Egypt
| | - Ahmed A. Hady
- Clinical Oncology Department, Faculty of Medicine, Mansoura University, Mansoura 35511, Egypt;
| | - Hekmat M. El Magdoub
- Biochemistry Department, Faculty of Pharmacy, Misr International University, Cairo 19648, Egypt;
| | - Mohamed Ali
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA;
- Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Johannes Vogel
- Zurich Center for Integrative Human Physiology and Institute of V. Physiology, University of Zurich, 8057 Zurich, Switzerland; (J.V.); (M.T.); (M.G.)
| | - Markus Thiersch
- Zurich Center for Integrative Human Physiology and Institute of V. Physiology, University of Zurich, 8057 Zurich, Switzerland; (J.V.); (M.T.); (M.G.)
| | - Max Gassmann
- Zurich Center for Integrative Human Physiology and Institute of V. Physiology, University of Zurich, 8057 Zurich, Switzerland; (J.V.); (M.T.); (M.G.)
| | - Nadia M. Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt
| | - Mostafa A. Aboouf
- Zurich Center for Integrative Human Physiology and Institute of V. Physiology, University of Zurich, 8057 Zurich, Switzerland; (J.V.); (M.T.); (M.G.)
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt
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Lan S, Zhong G. Identification of a novel survival and immune microenvironment related ceRNA regulatory network for hepatocellular carcinoma based on circHECTD1. Heliyon 2024; 10:e33763. [PMID: 39040406 PMCID: PMC11261882 DOI: 10.1016/j.heliyon.2024.e33763] [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: 04/27/2024] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 07/24/2024] Open
Abstract
Background CircHECTD1 (circ_0031450) is highly expressed in hepatocellular carcinoma (HCC) tissues and may act as an oncogene. Its specific competitive endogenous RNA (ceRNA) mechanism remains to be further elucidated. Methods Several databases and online platforms, including pathway activity, immune checkpoint, and overall survival analyses, were used to predict targets, download datasets, and perform online analyses. The R software was used for differential gene expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), clinical relevance, receiver operator characteristic curve, and single-cell analysis. Cytoscape software was used to construct ceRNAs, protein-protein interactions (PPI), and pivotal networks. Results The ceRNA, PPI, and pivotal networks were successfully constructed. Pathway enrichment analysis was mainly related to apoptosis, cell cycle, and epithelial-mesenchymal transition (EMT) pathways. Six pivotal targets related to survival, immune infiltration, immune checkpoints, clinical stage, and diagnosis of patients with HCC were identified. The recovery function and pathway enrichment results were consistent with previous results. Single-cell analysis suggested that the pivotal targets were highly expressed in T cells. Conclusion We successfully constructed a prognosis and immune microenvironment-related ceRNA network based on circHECTD1, providing new insights for diagnosing and treating HCC.
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Affiliation(s)
- Shuiqing Lan
- Department of Pain Management, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, China
| | - Guoqiang Zhong
- The Graduate School, Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, China
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Qin C, Liu S, Chen W, Xue D, Guo T, Wu B. HuR-induced circ_0082319 contributes to hepatocellular carcinoma by elevating PTK2 through miR-505-3p. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:3111-3126. [PMID: 37878047 DOI: 10.1007/s00210-023-02793-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/13/2023] [Indexed: 10/26/2023]
Abstract
The aim of the present research is to explore the biological function and mechanism of circ_0082319 in HCC progression. Circ_0082319, microRNA-505-3p (miR-505-3p), protein tyrosine kinase 2 (PTK2), and human antigen R (HuR, also known as ELAVL1) level were detected by real-time quantitative polymerase chain reaction. Cell viability, proliferation, apoptosis, invasion, and angiogenesis were measured using (4-5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and tube formation assays. Protein levels of c-Myc, MMP2, PTK2, and HuR were examined using western blot. The glycolysis levels were assessed using specific kits. Binding between miR-505-3p and circ_0082319 or PTK2 was predicted by Starbase and verified by a dual-luciferase reporter and RNA immunoprecipitation assays. The biological role of circ_0082319 on HCC tumor growth was examined using xenograft tumor model in vivo. Circ_0082319, PTK2, and HuR were highly expressed, and miR-505-3p was reduced in HCC samples and cell lines. Moreover, the knockdown of circ_0082319 might repress HCC cell proliferation, invasion, angiogenesis, and induce apoptosis in vitro. In mechanism, circ_0082319 served as a sponge of miR-505-3p to regulate PTK2 expression. HuR expedited circ_0082319 expression in HCC cells. HuR-mediated circ_0082319 might accelerate HCC cell proliferation, invasion, angiogenesis, and suppress apoptosis by the miR-505-3p/PTK2 axis, hinting at a promising therapeutic target for HCC treatment.
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Affiliation(s)
- Chuntang Qin
- Department of Interventional, The First Affiliated Hospital of Henan Polytechnic University (Jiaozuo Second People's Hospital), Democratic South Road 17, Jiefang District, Jiaozuo, 454000, China.
| | - Shuyan Liu
- Department of Endocrinology, The First Affiliated Hospital of Henan Polytechnic University (Jiaozuo Second People's Hospital), Jiaozuo, 454000, China
| | - Weibin Chen
- Department of Interventional, The First Affiliated Hospital of Henan Polytechnic University (Jiaozuo Second People's Hospital), Democratic South Road 17, Jiefang District, Jiaozuo, 454000, China
| | - Dan Xue
- Department of Interventional, The First Affiliated Hospital of Henan Polytechnic University (Jiaozuo Second People's Hospital), Democratic South Road 17, Jiefang District, Jiaozuo, 454000, China
| | - Tianli Guo
- Department of Interventional, The First Affiliated Hospital of Henan Polytechnic University (Jiaozuo Second People's Hospital), Democratic South Road 17, Jiefang District, Jiaozuo, 454000, China
| | - Baojiang Wu
- Department of Interventional, The First Affiliated Hospital of Henan Polytechnic University (Jiaozuo Second People's Hospital), Democratic South Road 17, Jiefang District, Jiaozuo, 454000, China
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Wu L, Zhang Y, Ren J. Targeting non-coding RNAs and N 6-methyladenosine modification in hepatocellular carcinoma. Biochem Pharmacol 2024; 223:116153. [PMID: 38513741 DOI: 10.1016/j.bcp.2024.116153] [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: 02/09/2024] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancers, accounts for a significant portion of cancer-related death globally. However, the molecular mechanisms driving the onset and progression of HCC are still not fully understood. Emerging evidence has indicated that non-protein-coding regions of genomes could give rise to transcripts, termed non-coding RNA (ncRNA), forming novel functional driving force for aberrant cellular activity. Over the past decades, overwhelming evidence has denoted involvement of a complex array of molecular function of ncRNAs at different stages of HCC tumorigenesis and progression. In this context, several pre-clinical studies have highlighted the potentials of ncRNAs as novel therapeutic modalities in the management of human HCC. Moreover, N6-methyladenosine (m6A) modification, the most prevalent form of internal mRNA modifications in mammalian cells, is essential for the governance of biological processes within cells. Dysregulation of m6A in ncRNAs has been implicated in human carcinogenesis, including HCC. In this review, we will discuss dysregulation of several hallmark ncRNAs (miRNAs, lncRNAs, and circRNAs) in HCC and address the latest advances for their involvement in the onset and progression of HCC. We also focus on dysregulation of m6A modification and various m6A regulators in the etiology of HCC. In the end, we discussed the contemporary preclinical and clinical application of ncRNA-based and m6A-targeted therapies in HCC.
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Affiliation(s)
- Lin Wu
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Yingmei Zhang
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Jun Ren
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
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Dawoud A, Elmasri RA, Mohamed AH, Mahmoud A, Rostom MM, Youness RA. Involvement of CircRNAs in regulating The "New Generation of Cancer Hallmarks": A Special Depiction on Hepatocellular Carcinoma. Crit Rev Oncol Hematol 2024; 196:104312. [PMID: 38428701 DOI: 10.1016/j.critrevonc.2024.104312] [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: 10/06/2023] [Revised: 02/01/2024] [Accepted: 02/26/2024] [Indexed: 03/03/2024] Open
Abstract
The concept of 'Hallmarks of Cancer' is an approach of reducing the enormous complexity of cancer to a set of guiding principles. As the underlying mechanism of cancer are portrayed, we find that we gain insight and additional aspects of the disease arise. The understanding of the tumor microenvironment (TME) brought a new dimension and led to the discovery of novel hallmarks such as senescent cells, non-mutational epigenetic reprogramming, polymorphic microbiomes and unlocked phenotypic plasticity. Circular RNAs (circRNAs) are single-stranded, covalently closed RNA molecules that are ubiquitous across all species. Recent studies on the circRNAs have highlighted their crucial function in regulating the formation of human malignancies through a range of biological processes. The primary goal of this review is to clarify the role of circRNAs in the most common form of liver cancer, hepatocellular carcinoma (HCC). This review also addressed the topic of how circRNAs affect HCC hallmarks, including the new generation hallmarks. Finally, the enormous applications that these rapidly expanding ncRNA molecules serve in the functional and molecular development of effective HCC diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- A Dawoud
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, New Administrative Capital, Egypt; School of Medicine, University of North California, Chapel Hill, NC 27599, USA
| | - R A Elmasri
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, New Administrative Capital, Egypt
| | - A H Mohamed
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, New Administrative Capital, Egypt; Department of Chemistry, Faculty of Science, Cairo University, Cairo, Egypt
| | - A Mahmoud
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, New Administrative Capital, Egypt; Biotechnology School, Nile University, Giza 12677, Egypt
| | - M M Rostom
- Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - R A Youness
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, New Administrative Capital, Egypt.
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Wang S, Sun H, Chen G, Wu C, Sun B, Lin J, Lin D, Zeng D, Lin B, Huang G, Lu X, Lin H, Liang Y. RNA-binding proteins in breast cancer: Biological implications and therapeutic opportunities. Crit Rev Oncol Hematol 2024; 195:104271. [PMID: 38272151 DOI: 10.1016/j.critrevonc.2024.104271] [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: 06/27/2023] [Revised: 01/05/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024] Open
Abstract
RNA-binding proteins (RBPs) refer to a class of proteins that participate in alternative splicing, RNA stability, polyadenylation, localization and translation of RNAs, thus regulating gene expression in post-transcriptional manner. Dysregulation of RNA-RBP interaction contributes to various diseases, including cancer. In breast cancer, disorders in RBP expression and function influence the biological characteristics of tumor cells. Targeting RBPs has fostered the development of innovative therapies for breast cancer. However, the RBP-related mechanisms in breast cancer are not completely clear. In this review, we summarize the regulatory mechanisms of RBPs and their signaling crosstalk in breast cancer. Specifically, we emphasize the potential of certain RBPs as prognostic factors due to their effects on proliferation, invasion, apoptosis, and therapy resistance of breast cancer cells. Most importantly, we present a comprehensive overview of the latest RBP-related therapeutic strategies and novel therapeutic targets that have proven to be useful in the treatment of breast cancer.
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Affiliation(s)
- Shimeng Wang
- Department of Thyroid and Breast Surgery, Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College (SUMC), 57 Changping Road, Shantou 515041, China
| | - Hexing Sun
- Department of Thyroid and Breast Surgery, Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College (SUMC), 57 Changping Road, Shantou 515041, China
| | - Guanyuan Chen
- Department of Thyroid and Breast Surgery, Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College (SUMC), 57 Changping Road, Shantou 515041, China
| | - Chengyu Wu
- Department of Thyroid and Breast Surgery, Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College (SUMC), 57 Changping Road, Shantou 515041, China
| | - Bingmei Sun
- Department of Thyroid and Breast Surgery, Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College (SUMC), 57 Changping Road, Shantou 515041, China
| | - Jiajia Lin
- Department of Thyroid and Breast Surgery, Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College (SUMC), 57 Changping Road, Shantou 515041, China
| | - Danping Lin
- Department of Medical Oncology, Cancer Hospital of SUMC, Shantou 515000, China
| | - De Zeng
- Department of Medical Oncology, Cancer Hospital of SUMC, Shantou 515000, China
| | - Baohang Lin
- Department of Thyroid, Breast and Vascular Surgery, Longgang District Central Hospital of Shenzhen, Shenzhen 518116, China
| | - Guan Huang
- Department of Pathology, Longgang District Central Hospital of Shenzhen, Shenzhen 518116, China
| | - Xiaofeng Lu
- Department of Thyroid and Breast Surgery, Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College (SUMC), 57 Changping Road, Shantou 515041, China
| | - Haoyu Lin
- Department of Thyroid and Breast Surgery, Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College (SUMC), 57 Changping Road, Shantou 515041, China.
| | - Yuanke Liang
- Department of Thyroid and Breast Surgery, Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College (SUMC), 57 Changping Road, Shantou 515041, China.
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10
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Godet AC, Roussel E, Laugero N, Morfoisse F, Lacazette E, Garmy-Susini B, Prats AC. Translational control by long non-coding RNAs. Biochimie 2024; 217:42-53. [PMID: 37640229 DOI: 10.1016/j.biochi.2023.08.015] [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: 04/25/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 08/31/2023]
Abstract
Long non-coding (lnc) RNAs, once considered as junk and useless, are now broadly recognized to have major functions in the cell. LncRNAs are defined as non-coding RNAs of more than 200 nucleotides, regulate all steps of gene expression. Their origin is diverse, they can arise from intronic, intergenic or overlapping region, in sense or antisense direction. LncRNAs are mainly described for their action on transcription, while their action at the translational level is more rarely cited. However, the bibliography in the field is more and more abundant. The present synopsis of lncRNAs involved in the control of translation reveals a wide field of regulation of gene expression, with at least nine distinct molecular mechanisms. Furthermore, it appears that all these lncRNAs are involved in various pathologies including cancer, cardiovascular and neurodegenerative diseases.
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Affiliation(s)
- Anne-Claire Godet
- UMR 1297-I2MC, Inserm, Université de Toulouse, UT3, Toulouse, France; Threonin Design, 220 Chemin de Montabon, Le Touvet, France
| | - Emilie Roussel
- UMR 1297-I2MC, Inserm, Université de Toulouse, UT3, Toulouse, France
| | - Nathalie Laugero
- UMR 1297-I2MC, Inserm, Université de Toulouse, UT3, Toulouse, France
| | - Florent Morfoisse
- UMR 1297-I2MC, Inserm, Université de Toulouse, UT3, Toulouse, France
| | - Eric Lacazette
- UMR 1297-I2MC, Inserm, Université de Toulouse, UT3, Toulouse, France
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11
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Liao Q, Xia W, Chen J, Wang K, Xiao E. Circular RNA DNAH14 molecular mechanism in an experimental model of hepatocellular carcinoma treated with Cobalt chloride to mimic the hypoxia-like response of transcatheter arterial chemoembolization. Sci Rep 2024; 14:1992. [PMID: 38263208 PMCID: PMC10805718 DOI: 10.1038/s41598-024-52578-3] [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: 09/26/2023] [Accepted: 01/20/2024] [Indexed: 01/25/2024] Open
Abstract
Transcatheter arterial chemoembolization (TACE) is the primary local treatment for patients with unresectable hepatocellular carcinoma (HCC). Numerous studies have demonstrated the pivotal role of circular RNAs (circRNAs) in TACE efficacy. This study aimed to investigate the function of circular RNA DNAH14 (circDNAH14) in TACE for HCC and to elucidate its molecular mechanisms. To simulate hypoxia conditions experienced during TACE, HCC cells were treated with cobalt chloride. The expression levels of circDNAH14, microRNA-508-3p (miR-508-3p), and Prothymosin Alpha (PTMA) were modulated via transfection for knockdown or overexpression. Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays, flow cytometry, and Transwell assays, along with epithelial-mesenchymal transition (EMT) evaluations, were employed to assess cell proliferation, apoptosis, invasion, migration, and EMT. The results indicated that hypoxia treatment downregulated the expression of circDNAH14 and PTMA while upregulating miR-508-3p. Such treatment suppressed HCC cell proliferation, invasion, migration, and EMT, and induced apoptosis. Knockdown of circDNAH14 or PTMA intensified the suppressive effects of hypoxia on the malignant behaviors of HCC cells. Conversely, upregulation of miR-508-3p or PTMA mitigated the effects of circDNAH14 overexpression and knockdown, respectively. Mechanistically, circDNAH14 was found to competitively bind to miR-508-3p, thereby regulating PTMA expression. In vivo, nude mouse xenograft experiments demonstrated that circDNAH14 knockdown augmented the hypoxia-induced suppression of HCC tumor growth. In conclusion, circDNAH14 mitigates the suppressive effects of hypoxia on HCC, both in vitro and in vivo, by competitively binding to miR-508-3p and regulating PTMA expression.
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Affiliation(s)
- Qiuling Liao
- Department of Radiology, The Second Xiangya Hospital of Central South University, No. 139, Renmin Middle Road, Changsha City, 410011, Hunan Province, China
| | - Weiping Xia
- Department of Urology Surgery, Xiangya Hospital Central South University, No. 87 Xiangya Road, Kaifu District, Changsha City, 410008, Hunan Province, China
| | - Jiawen Chen
- Department of Urology Surgery, Xiangya Hospital Central South University, No. 87 Xiangya Road, Kaifu District, Changsha City, 410008, Hunan Province, China
| | - Kangning Wang
- Department of Urology Surgery, Xiangya Hospital Central South University, No. 87 Xiangya Road, Kaifu District, Changsha City, 410008, Hunan Province, China.
| | - Enhua Xiao
- Department of Radiology, The Second Xiangya Hospital of Central South University, No. 139, Renmin Middle Road, Changsha City, 410011, Hunan Province, China.
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12
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Xie C, Hao X, Yuan H, Wang C, Sharif R, Yu H. Crosstalk Between circRNA and Tumor Microenvironment of Hepatocellular Carcinoma: Mechanism, Function and Applications. Onco Targets Ther 2024; 17:7-26. [PMID: 38283733 PMCID: PMC10812140 DOI: 10.2147/ott.s437536] [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: 09/21/2023] [Accepted: 11/30/2023] [Indexed: 01/30/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common aggressive tumors in the world. Despite the availability of various treatments, its prognosis remains poor due to the lack of specific diagnostic indicators and the high heterogeneity of HCC cases. CircRNAs are noncoding RNAs with stable and highly specific expression. Extensive research evidence suggests that circRNAs mediate the pathogenesis and progression of HCC through acting as miRNA sponges, protein modulators, and translation templates. Tumor microenvironment (TME) has become a hotspot of immune-related research in recent years due to its effects on metabolism, secretion and immunity of HCC. Accordingly, understanding the role played by circRNAs in TME is important for the study of HCC. This review will discuss the crosstalk between circRNAs and TME in HCC. In addition, we will discuss the current deficiencies and controversies in research on circRNAs and predict future research directions.
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Affiliation(s)
- Chenxi Xie
- Hepatobiliary Center, Department of Hepatobiliary Surgery, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Xiaopei Hao
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, People’s Republic of China
| | - Hao Yuan
- Hepatobiliary Center, Department of Hepatobiliary Surgery, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Chongyu Wang
- The First Clinical Medical College of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Razinah Sharif
- Center for Healthy Ageing & Wellness, Faculty of Health Sciences, University Kebangsaan Malaysia, Kuala Lumpur, 50300, Malaysia
- Biocompatibility Laboratory, Centre for Research and Instrumentation, University Kebangsaan Malaysia, UKM, Bangi, Selangor Darul Ehsan, 43600, Malaysia
| | - Haibo Yu
- Hepatobiliary Center, Department of Hepatobiliary Surgery, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
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13
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Abaza T, El-Aziz MKA, Daniel KA, Karousi P, Papatsirou M, Fahmy SA, Hamdy NM, Kontos CK, Youness RA. Emerging Role of Circular RNAs in Hepatocellular Carcinoma Immunotherapy. Int J Mol Sci 2023; 24:16484. [PMID: 38003674 PMCID: PMC10671287 DOI: 10.3390/ijms242216484] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly fatal malignancy with limited therapeutic options and high recurrence rates. Recently, immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) have emerged as a new paradigm shift in oncology. ICIs, such as programmed cell death protein 1 (PD-1) inhibitors, have provided a new source of hope for patients with advanced HCC. Yet, the eligibility criteria of HCC patients for ICIs are still a missing piece in the puzzle. Circular RNAs (circRNAs) have recently emerged as a new class of non-coding RNAs that play a fundamental role in cancer pathogenesis. Structurally, circRNAs are resistant to exonucleolytic degradation and have a longer half-life than their linear counterparts. Functionally, circRNAs possess the capability to influence various facets of the tumor microenvironment, especially at the HCC tumor-immune synapse. Notably, circRNAs have been observed to control the expression of immune checkpoint molecules within tumor cells, potentially impeding the therapeutic effectiveness of ICIs. Therefore, this renders them potential cancer-immune biomarkers for diagnosis, prognosis, and therapeutic regimen determinants. In this review, the authors shed light on the structure and functional roles of circRNAs and, most importantly, highlight the promising roles of circRNAs in HCC immunomodulation and their potential as promising biomarkers and immunotherapeutic regimen determinants.
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Affiliation(s)
- Tasneem Abaza
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (T.A.); (M.K.A.E.-A.); (K.A.D.)
- Biotechnology and Biomolecular Chemistry Program, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Mostafa K. Abd El-Aziz
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (T.A.); (M.K.A.E.-A.); (K.A.D.)
- Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71631, Egypt
| | - Kerolos Ashraf Daniel
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (T.A.); (M.K.A.E.-A.); (K.A.D.)
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo 11835, Egypt
| | - Paraskevi Karousi
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (P.K.); (M.P.)
| | - Maria Papatsirou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (P.K.); (M.P.)
| | - Sherif Ashraf Fahmy
- Department of Chemistry, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, R5 New Garden City, New Capital, Cairo 11835, Egypt;
| | - Nadia M. Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt;
| | - Christos K. Kontos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (P.K.); (M.P.)
| | - Rana A. Youness
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (T.A.); (M.K.A.E.-A.); (K.A.D.)
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14
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Zou Q, Zhang Y, Zhu D, Liu X, Wang C, Xiang H. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma. Open Med (Wars) 2023; 18:20230803. [PMID: 38025527 PMCID: PMC10655683 DOI: 10.1515/med-2023-0803] [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: 11/18/2022] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 12/01/2023] Open
Abstract
As a high metastatic tumor, patients having hepatocellular carcinoma (HCC) show poor prognosis. The carcinogenic roles of circMMP11 are generally described in the development of other cancers. However, there is a lack of studies on its involvement in HCC. Therefore, we investigated the potential role and molecular mechanisms of CircMMP11 in the development of HCC in vitro, providing preliminary evidence for the clinical treatment of HCC. First, we examined the expression of CircMMP11 in HCC tissues and cell lines in both clinical and in vitro experiments. We then used a loss-of-function assay to determine CircMMP11's regulatory role on the malignant characteristics of HCC cells. The results showed that high expression of CircMMP11 in HCC was associated with patient overall survival. Serum CircMMP11 had good diagnostic efficacy in distinguishing HCC patients from the control group. In vitro, inhibiting CircMMP11 suppressed the malignant characteristics of human HCC cell lines by directly sequestering miR-361-3p, which further affected the downstream gene HMGB1 expression. In addition, we knocked down CircMMP11 and found that its deletion inhibited the malignant characteristics of HCC cells through the miR-361-3p/HMGB1 axis.
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Affiliation(s)
- Qiong Zou
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Yuping Zhang
- Department of The First General Surgery, Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road Avenue, Changsha, Hunan, 410013, China
| | - Daoqi Zhu
- Department of Oncology, Changsha Kexin Cancer Hospital, Changsha, Hunan, 410205, China
| | - Xinrong Liu
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Changfa Wang
- Department of The First General Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Hong Xiang
- Department of Central Lab, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
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15
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Gao P, Yang Y, Li X, Zhao Q, Liu Y, Dong C, Zhang Y, Liu D. Circular RNA hsa_circ_0098181 inhibits metastasis in hepatocellular carcinoma by activating the Hippo signaling pathway via interaction with eEF2. Ann Hepatol 2023; 28:101124. [PMID: 37286166 DOI: 10.1016/j.aohep.2023.101124] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 05/27/2023] [Accepted: 05/31/2023] [Indexed: 06/09/2023]
Abstract
INTRODUCTION AND OBJECTIVES The development of hepatocellular carcinoma (HCC) is a multi-step process that accumulates genetic and epigenetic alterations, including changes in circular RNA (circRNA). This study aimed to understand the alterations in circRNA expression in HCC development and metastasis and to explore the biological functions of circRNA. MATERIALS AND METHODS Ten pairs of adjacent chronic hepatitis tissues and HCC tissues from patients without venous metastases, and ten HCC tissues from patients with venous metastases were analyzed using human circRNA microarrays. Differentially expressed circRNAs were then validated by quantitative real-time PCR. In vitro and in vivo assays were performed to assess the roles of the circRNA in HCC progression. RNA pull-down assay, mass spectrometry analysis, and RNA-binding protein immunoprecipitation were conducted to explore the protein partners of the circRNA. RESULTS CircRNA microarrays revealed that the expression patterns of circRNAs across the three groups were significantly different. Among these, hsa_circ_0098181 was validated to be lowly expressed and associated with poor prognosis in HCC patients. Ectopic expression of hsa_circ_0098181 delayed HCC metastasis in vitro and in vivo. Mechanistically, hsa_circ_0098181 sequestered eukaryotic translation elongation factor 2 (eEF2) and dissociated eEF2 from filamentous actin (F-actin) to prevent F-actin formation, which blocked activation of the Hippo signaling pathway. In addition, the RNA binding protein Quaking-5 bound directly to hsa_circ_0098181 and induced its biogenesis. CONCLUSIONS Our study reveals changes in circRNA expression from chronic hepatitis, primary HCC, to metastatic HCC. Further, the QKI5-hsa_circ_0098181-eEF2-Hippo signaling pathway exerts a regulatory role in HCC.
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Affiliation(s)
- Ping Gao
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Environment and Human Health, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Yuan Yang
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xiaowei Li
- Changping District Center for Disease Control and Prevention of Beijing Municipality, Beijing, China
| | - Qi Zhao
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Environment and Human Health, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Yujin Liu
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Environment and Human Health, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Chunnan Dong
- Department of Pathogenic Biology, Hebei Medical University, Shijiazhuang, China
| | - Yanan Zhang
- Experimental Center for Teaching, Hebei Medical University, Shijiazhuang, China
| | - Dianwu Liu
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Environment and Human Health, School of Public Health, Hebei Medical University, Shijiazhuang, China.
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16
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Miao S, Zhang Q. Circulating circRNA: a social butterfly in tumors. Front Oncol 2023; 13:1203696. [PMID: 37546422 PMCID: PMC10401440 DOI: 10.3389/fonc.2023.1203696] [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: 04/11/2023] [Accepted: 06/20/2023] [Indexed: 08/08/2023] Open
Abstract
Circular RNAs (circRNAs) are a class of single-stranded non-coding RNAs that form circular structures through irregular splicing or post-splicing events. CircRNAs are abnormally expressed in many cancers and regulate the occurrence and development of tumors. Circulating circRNAs are cell-free circRNAs present in peripheral blood, they are considered promising biomarkers due to their high stability. In recent years, more and more studies have revealed that circulating circRNAs participate in various cellular communication and regulate the occurrence and development of tumors, which involve many pathological processes such as tumorigenesis, tumor-related immunity, tumor angiogenesis, and tumor metastasis. Understanding the role of cell communication mediated by circulating circRNAs in tumor will further reveal the value and significance behind their use as biomarkers and potential therapeutic targets. In this review, we summarize the recent findings and provide an overview of the cell-cell communication mediated by circulating circRNAs, aiming to explore the role and application value of circulating circRNAs in tumors.
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Affiliation(s)
- Shuo Miao
- Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, China
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Qingsong Zhang
- Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, China
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17
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Wang X, Dong FL, Wang YQ, Wei HL, Li T, Li J. Exosomal circTGFBR2 promotes hepatocellular carcinoma progression via enhancing ATG5 mediated protective autophagy. Cell Death Dis 2023; 14:451. [PMID: 37474520 PMCID: PMC10359294 DOI: 10.1038/s41419-023-05989-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 07/10/2023] [Accepted: 07/12/2023] [Indexed: 07/22/2023]
Abstract
Exosomes contribute substantially to the communication between tumor cells and normal cells. Benefiting from the stable structure, circular RNAs (circRNAs) are believed to serve an important function in exosome-mediated intercellular communication. Here, we focused on circRNAs enriched in starvation-stressed hepatocytic exosomes and further investigated their function and mechanism in hepatocellular carcinoma (HCC) progression. Differentially expressed circRNAs in exosomes were identified by RNA sequencing, and circTGFBR2 was identified and chosen for further study. The molecular mechanism of circTGFBR2 in HCC was demonstrated by RNA pulldown, RIP, dual-luciferase reporter assays, rescue experiments and tumor xenograft assay both in vitro and vivo. We confirmed exosomes with enriched circTGFBR2 led to an upregulated resistance of HCC cells to starvation stress. Mechanistically, circTGFBR2 delivered into HCC cells via exosomes serves as a competing endogenous RNA by binding miR-205-5p to facilitate ATG5 expression and enhance autophagy in HCC cells, resulting in resistance to starvation. Thus, we revealed that circTGFBR2 is a novel tumor promoter circRNA in hepatocytic exosomes and promotes HCC progression by enhancing ATG5-mediated protective autophagy via the circTGFBR2/miR-205-5p/ATG5 axis, which may be a potential therapeutic target for HCC.
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Affiliation(s)
- Xin Wang
- Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, China
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
| | - Feng-Lin Dong
- Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, China
| | - Ying-Qiao Wang
- Department of Hematology, The Third Affiliated Hospital of Shandong First Medical University, Jinan, 250014, China
| | - Hong-Long Wei
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
| | - Tao Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China.
| | - Jie Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China.
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18
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Xia W, Chen W, Ni C, Meng X, Wu J, Yang Q, Tang H, Yuan H, Fang S. Chemotherapy-induced exosomal circBACH1 promotes breast cancer resistance and stemness via miR-217/G3BP2 signaling pathway. Breast Cancer Res 2023; 25:85. [PMID: 37461019 PMCID: PMC10351125 DOI: 10.1186/s13058-023-01672-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 06/07/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Chemoresistance involves metastasis and aggressiveness of breast cancer (BC). Chemotherapy-elicited exosomes have been reported to be associated with drug resistance and pro-metastatic capacity of BC cells. Non-coding RNAs (ncRNAs) are enriched in exosomes, which participated in generation, progression, and resistance of BC. However, the mechanism underlying the chemoresistance and metastasis in BC cells mediated by the BC-derived exosomal ncRNAs remained to be elucidated. METHODS The effects of PTX-induced exosomal circBACH1 on BC cell function were assessed using RNA Binding Protein Immunoprecipitation (RIP), dual luciferase reporter gene, tube formation, CCK-8, and Western Blot assays. The circBACH1 and miR-217 expression levels were detected using quantitative real-time PCR (RT-qPCR) and Immunohistochemistry (IHC) assays in BC tissues and precancerous tissues of BC patients. RESULTS CircBACH1 expression was increased in paclitaxel-treated BC-derived exosomes (PTX-EXO) and BC tissue. PTX-EXO was shown to promote PTX-resistance and angiogenesis through upregulation circBACH1. Downregulation of circBACH1 improved PTX-sensitiveness by suppressing the cell viability, stemness, migration, and angiogenesis of BC cells. Moreover, we found that miR-217 interacted with circBACH1 and targeted GTPase-activating SH3 domain-binding protein 2 (G3BP2) in BC cells. CircBACH1 combined miR-217 cotransfection suppressed the expression of G3BP2 proteins compared with circBACH1 treatment in MCF-7 cells. In addition, downregulation of G3BP2 suppressed BC cell migration. CONCLUSIONS These results demonstrated that PTX-induced exosomal circBACH1 promoted stemness and migration of BC cells by sponging miR-217 to upregulate the expression of G3BP2, which provided a new therapeutic target for PTX-resistance and progression of BC via circBACH1/miR-217/G3BP2 axis.
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Affiliation(s)
- Wenjie Xia
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Wuzhen Chen
- Department of Breast Surgery (Surgical Oncology), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chao Ni
- Department of Breast Surgery (Surgical Oncology), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuli Meng
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Jun Wu
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Qiong Yang
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Hongchao Tang
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Hongjun Yuan
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China.
| | - Shan Fang
- Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China.
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19
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Rao G, Peng X, Tian Y, Fu X, Zhang Y. Circular RNAs in hepatocellular carcinoma: biogenesis, function, and pathology. Front Genet 2023; 14:1106665. [PMID: 37485335 PMCID: PMC10361733 DOI: 10.3389/fgene.2023.1106665] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 06/16/2023] [Indexed: 07/25/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Both genetic and environmental factors through a multitude of underlying molecular mechanisms participate in the pathogenesis of HCC. Recently, numerous studies have shown that circular RNAs (circRNAs), an emerging class of non-coding RNAs characterized by the presence of covalent bonds linking 3' and 5' ends, play an important role in the initiation and progression of cancers, including HCC. In this review, we outline the current status of the field of circRNAs, with an emphasis on the functions and mechanisms of circRNAs in HCC and its microenvironment. We also summarize and discuss recent advances of circRNAs as biomarkers and therapeutic targets. These efforts are anticipated to throw new insights into future perspectives about circRNAs in basic, translational and clinical research, eventually advancing the diagnosis, prevention and treatment of HCC.
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Affiliation(s)
- Guocheng Rao
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Xi Peng
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Yan Tian
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xianghui Fu
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Yuwei Zhang
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
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Song Q, Mao X, Jing M, Fu Y, Yan W. Pathophysiological role of BACH transcription factors in digestive system diseases. Front Physiol 2023; 14:1121353. [PMID: 37228820 PMCID: PMC10203417 DOI: 10.3389/fphys.2023.1121353] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 04/26/2023] [Indexed: 05/27/2023] Open
Abstract
BTB and CNC homologous (BACH) proteins, including BACH1 and BACH2, are transcription factors that are widely expressed in human tissues. BACH proteins form heterodimers with small musculoaponeurotic fibrosarcoma (MAF) proteins to suppress the transcription of target genes. Furthermore, BACH1 promotes the transcription of target genes. BACH proteins regulate physiological processes, such as the differentiation of B cells and T cells, mitochondrial function, and heme homeostasis as well as pathogenesis related to inflammation, oxidative-stress damage caused by drugs, toxicants, or infections; autoimmunity disorders; and cancer angiogenesis, epithelial-mesenchymal transition, chemotherapy resistance, progression, and metabolism. In this review, we discuss the function of BACH proteins in the digestive system, including the liver, gallbladder, esophagus, stomach, small and large intestines, and pancreas. BACH proteins directly target genes or indirectly regulate downstream molecules to promote or inhibit biological phenomena such as inflammation, tumor angiogenesis, and epithelial-mesenchymal transition. BACH proteins are also regulated by proteins, miRNAs, LncRNAs, labile iron, and positive and negative feedback. Additionally, we summarize a list of regulators targeting these proteins. Our review provides a reference for future studies on targeted drugs in digestive diseases.
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Affiliation(s)
- Qianben Song
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xin Mao
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mengjia Jing
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yu Fu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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21
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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: 0] [Impact Index Per Article: 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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22
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Liu Z, Yang F, Xiao Z, Liu Y. Review of novel functions and implications of circular RNAs in hepatocellular carcinoma. Front Oncol 2023; 13:1093063. [PMID: 36890830 PMCID: PMC9986438 DOI: 10.3389/fonc.2023.1093063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/27/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent malignancies, with high incidence and mortality. As the majority of HCC patients are diagnosed at an advanced stage and die of recurrence and metastasis, its pathology and new biomarkers are needed. Circular RNAs (circRNAs) are a large subclass of long non-coding RNAs (lncRNAs) with covalently closed loop structures and abundant, conserved, stable, tissue-specific expression in mammalian cells. CircRNAs exert multiple functions in HCC initiation, growth and progression, serving as promising biomarkers for diagnosis, prognosis and therapeutic targets for this disease. This review briefly describes the biogenesis and biological functions of circRNAs and elucidates the roles of circRNAs in the development and progression of HCC, especially regarding epithelial-mesenchymal transition (EMT), drug resistance and interactions with epigenetic modifications. In addition, this review highlights the implications of circRNAs as potential biomarkers and therapeutic targets for HCC. We hope to provide novel insight into the roles of circRNAs in HCC.
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Affiliation(s)
- Zheng Liu
- Department of Combination of Traditional Chinese Medicine and Western Medicine, School of Medicine, Henan University of Chinese Medicine, Zhengzhou, China
| | - Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Yuexuan Liu
- Department of Combination of Traditional Chinese Medicine and Western Medicine, School of Medicine, Henan University of Chinese Medicine, Zhengzhou, China
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23
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Song R, Ma S, Xu J, Ren X, Guo P, Liu H, Li P, Yin F, Liu M, Wang Q, Yu L, Liu J, Duan B, Rahman NA, Wołczyński S, Li G, Li X. A novel polypeptide encoded by the circular RNA ZKSCAN1 suppresses HCC via degradation of mTOR. Mol Cancer 2023; 22:16. [PMID: 36691031 PMCID: PMC9869513 DOI: 10.1186/s12943-023-01719-9] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 01/09/2023] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND hsa_circ_0001727 (circZKSCAN1) has been reported to be a tumor-associated circRNA by sponging microRNAs. Intriguingly, we found that circZKSCAN1 encoded a secretory peptide (circZKSaa) in the liver. The present study aims to elucidate the potential role and molecular mechanism of circZKSaa in the regulation of hepatocellular carcinoma (HCC) progression. METHODS The circRNA profiling datasets (RNA-seq data GSE143233 and GSE140202) were reanalyzed and circZKSCAN1 was selected for further study. Mass spectrometry, polysome fractionation assay, dual-luciferase reporter, and a series of experiments showed that circZKSCAN1 encodes circZKSaa. Cell proliferation, apoptosis, and tumorigenesis in nude mice were examined to investigate the functions of circZKSaa. Mechanistically, the relationship between the circZKSaa and mTOR in HCC was verified by immunoprecipitation analyses, mass spectrometry, and immunofluorescence staining analyses. RESULTS Receiver operating characteristic (ROC) analysis demonstrated that the secretory peptide circZKSaa encoded by circZKSCAN1 might be the potential biomarker for HCC tissues. Through a series of experiments, we found that circZKSaa inhibited HCC progression and sensitize HCC cells to sorafenib. Mechanistically, we found that the sponge function of circZKSCAN1 to microRNA is weak in HCC, while overexpression of circZKSaa promoted the interaction of FBXW7 with the mammalian target of rapamycin (mTOR) to promote the ubiquitination of mTOR, thereby inhibiting the PI3K/AKT/mTOR pathway. Furthermore, we found that the high expression of cicZKSCAN1 in sorafenib-treated HCC cells was regulated by QKI-5. CONCLUSIONS These results reveal that a novel circZKSCAN1-encoded peptide acts as a tumor suppressor on PI3K/AKT/mTOR pathway, and sensitizes HCC cells to sorafenib via ubiquitination of mTOR. These findings demonstrated that circZKSaa has the potential to serve as a therapeutic target and biomarker for HCC treatment.
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Affiliation(s)
- Runjie Song
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Shuoqian Ma
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Jiajia Xu
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Xin Ren
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Peilan Guo
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Huijiao Liu
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Peng Li
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Fan Yin
- Department of Oncology, The Second Medical Centre & National Clinical Research Center of Geriatric Disease, Chinese PLA General Hospital, Beijing, 100071, China
| | - Mei Liu
- Department of Pathology, Chinese PLA General Hospital, Beijing, 100071, China
| | - Qiang Wang
- Department of Urology, Peking University People's Hospital, Beijing, 100044, China
| | - Lei Yu
- Department of Thoracic Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Jiali Liu
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Binwei Duan
- Department of General Surgery CenterBeijing You An Hospital, Clinical Center for Liver Cancer, Capital Medical University, Beijing, China
| | - Nafis A Rahman
- Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland
- Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland
| | - Sławomir Wołczyński
- Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland
| | - Guangming Li
- Department of General Surgery CenterBeijing You An Hospital, Clinical Center for Liver Cancer, Capital Medical University, Beijing, China
| | - Xiangdong Li
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
- Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland.
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24
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Liao J, Zhang Q, Huang J, He H, Lei J, Shen Y, Wang J, Xiao Y. The emerging role of circular RNAs in Parkinson's disease. Front Neurosci 2023; 17:1137363. [PMID: 36925739 PMCID: PMC10012279 DOI: 10.3389/fnins.2023.1137363] [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: 01/04/2023] [Accepted: 02/03/2023] [Indexed: 02/18/2023] Open
Abstract
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and the most common movement disorder. It involves a gradual loss of dopaminergic neurons in the substantia nigra. Although many studies have been conducted, the underlying molecular pathways of PD remain largely unknown. Circular RNAs (circRNAs), a novel class of non-coding RNAs with a covalently closed loop structure, are common in the brain. They are stable, conserved molecules that are widely expressed in eukaryotes in tissue-, cell-, and development-specific patterns. Many circRNAs have recently been identified in nervous system diseases, and some circRNA expression profiles have been linked to PD. Given that recent research has indicated the essential roles of various circRNAs in the development and progression of neurodegenerative diseases, the identification of individual circRNAs may be a promising strategy for finding new treatment targets for PD. Moreover, the search for circRNAs with high specificity and sensitivity will open up new avenues for the early diagnosis and treatment of PD. Herein, we address the biogenesis, properties, and roles of circRNAs and review their potential utility as biomarkers and therapeutic targets in PD.
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Affiliation(s)
- Jiajia Liao
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.,Department of Rehabilitation Medicine, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Qinxin Zhang
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jinjun Huang
- Department of Rehabilitation, Guiping People's Hospital, Guiping, China
| | - Honghu He
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jiang Lei
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yuefei Shen
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jin Wang
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yousheng Xiao
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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25
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Ishaq Y, Ikram A, Alzahrani B, Khurshid S. The Role of miRNAs, circRNAs and Their Interactions in Development and Progression of Hepatocellular Carcinoma: An Insilico Approach. Genes (Basel) 2022; 14:genes14010013. [PMID: 36672755 PMCID: PMC9858589 DOI: 10.3390/genes14010013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/06/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of malignant tumor. miRNAs are noncoding RNAs and their differential expression patterns are observed in HCC-induced by alcoholism, HBV and HCV infections. By acting as a competing endogenous RNA (ceRNA), circRNA regulates the miRNA function, indirectly controlling the gene expression and leading to HCC progression. In the present study, data mining was performed to screen out all miRNAs and circRNA involved in alcohol, HBV or HCV-induced HCC with statistically significant (≤0.05%) expression levels reported in various studies. Further, the interaction of miRNAs and circRNA was also investigated to explore their role in HCC due to various causative agents. Together, these study data provide a deeper understanding of the circRNA-miRNA regulatory mechanisms in HCC. These screened circRNA, miRNA and their interactions can be used as prognostic biomarkers or therapeutic targets for the treatment of HCC.
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Affiliation(s)
- Yasmeen Ishaq
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
| | - Aqsa Ikram
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
- Correspondence:
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, Jouf University, Sakaka 42421, Saudi Arabia
| | - Sana Khurshid
- Department of Molecular Biology, Virtual University of Pakistan, 1-Davis Road, Lahore 54000, Pakistan
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26
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Wu W, Zhou Z, Chen C, Chen M. Circ_0061395 functions as an oncogenic gene in hepatocellular carcinoma by acting as a miR-1182 sponge. Cell Cycle 2022; 21:2192-2205. [PMID: 35775884 PMCID: PMC9519000 DOI: 10.1080/15384101.2022.2092177] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 05/25/2022] [Indexed: 11/03/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in liver cancer, with a high rate of metastasis and recurrence. Circular RNA_0061395 (circ_0061395) has been shown to be involved in the advance of HCC. However, the interaction between circ_0061395 and microRNA (miRNA) in HCC has not been studied. Quantitative real-time polymerase-chain reaction (qRT-PCR) was used to detect the expression of related genes in liver cancer tissues and cells. The stability of circ_0061395 was verified by RNase R digestion. Through detection of cell malignant behavior and apoptosis, the capping experiment was carried out to verify the regulatory relationship between miR-1182 and circ_0061395 or SPARC/osteonectin, CWCV and Kazal-like domains proteoglycan 1 (SPOCK1). The expression of related proteins was detected by western blot. The interaction of miR-1182 with circ_0061395 or SPOCK1 has been notarized by Dual-luciferase reporter analysis and RNA immunoprecipitation (RIP) assay. Xenotransplantation experiments using BALB/C nude mice were used to confirm the function of circ_0061395 in vivo. Circ_0061395 and SPOCK1 were significantly expressed in liver cancer tissues and cells. Silencing circ_0061395 reduced the proliferation, migration, invasion, tube formation and tumor spheroid formation rate of Huh-7 and SNU-387 cells. MiR-1182 was a target of circ_0061395. Silencing circ_0061395 inhibited the malignant behavior of HCC cells by releasing miR-1182. In addition, SPOCK1 was the target of miR-1182. Overexpression of SPOCK1 partially restored the inhibitory effect of miR-1182 on cell proliferation. Animal experiments confirmed the anti-tumor effect of silence circ_0061395. Circ_0061395 induced the changes of the expression of SPOCK1 by regulating miR-1182, thereby mediating the process of HCC, and at least partially promoting the development of HCC cells, providing a novel targeted therapy for HCC.
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Affiliation(s)
- Wen Wu
- The First Affiliated Hospital, Department of Hepato-Biliary-Pancreatic Surgery, Hengyang Medical School, University of South China, Hengyang City, Hunan Province, China
| | - Zhenhua Zhou
- Department of Hepato-Biliary-Pancreatic Surgery, The First People's Hospital of Huaihua, Huaihua City, Hunan Province, China
| | - Chao Chen
- The First Affiliated Hospital, Department of Hepato-Biliary-Pancreatic Surgery, Hengyang Medical School, University of South China, Hengyang City, Hunan Province, China
| | - Ming Chen
- The First Affiliated Hospital, Department of Gastroenterology and Hepatology, Hengyang Medical School, University of South China, Hengyang City, Hunan Province, China
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27
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Yang L, Wang L, Tang Q, Liu Y, Meng C, Sun S, Chong Y, Zhang Y, Feng F. Hsa_circ_0093884 bound to RNA-binding protein RPS3 ameliorates hepatocyte inflammation in anti-tuberculosis drug-induced liver injury by competitively activating SIRT1. Int Immunopharmacol 2022; 110:109018. [PMID: 35816943 DOI: 10.1016/j.intimp.2022.109018] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/25/2022] [Accepted: 06/29/2022] [Indexed: 02/07/2023]
Abstract
Anti-tuberculosis drug-induced liver injury (ADLI) is one of the main factors hindering the efficacy of routine chemotherapy against tuberculosis. Understanding the mechanism of ADLI will aid in the effective treatment of patients with tuberculosis. Recently, we found that the expression of hsa_circ_0093884, a circular RNA derived from the NAD-dependent deacetylase, sirtuin-1 (SIRT1), was down-regulated in ADLI. Hsa_circ_0093884 was negatively correlated with the NLR family pyrin domain containing 3 (NLRP3) inflammasome and its overexpression increased the expression levels of NLRP3, interleukin-1β, and caspase-1. Mechanistically, RNA immunoprecipitation and immunofluorescence assays revealed that the ribosomal protein S3 (RPS3) could bind to hsa_circ_0093884 and SIRT1. Additionally, the expression of hsa_circ_0093884 was positively correlated with that of SIRT1, and the upregulation of hsa_circ_0093884 expression was crucial for the upregulation of SIRT1 expression. We confirmed that the mRNA and protein expression levels of SIRT1 were influenced by hsa_circ_0093884 and RPS3. Furthermore, hsa_circ_0093884 recruited RPS3 to increase SIRT1 mRNA and protein levels. Importantly, we found a marked decrease in the upregulating effect of hsa_circ_0093884 on SIRT1 owing to RPS3 depletion. To the best of our knowledge, this study is the first to reveal that hsa_circ_0093884 regulates SIRT1 expression and inhibits the inflammatory response by binding to RPS3 in ADLI, which may be used to develop novel strategies for ADLI treatment.
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Affiliation(s)
- Luming Yang
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei, 063210, China.
| | - Lin Wang
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei, 063210, China.
| | - Qinyan Tang
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei, 063210, China.
| | - Yue Liu
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei, 063210, China.
| | - Chunyan Meng
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei, 063210, China.
| | - Shufeng Sun
- College of Nursing and Rehabilitation, North China University of Science and Technology, Tangshan, Hebei, 063210, China.
| | - Yingzhi Chong
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei, 063210, China.
| | - Yiyang Zhang
- Lubei District Center for Disease Control and Prevention, Tangshan City, Tangshan, Hebei, 063000, China.
| | - Fumin Feng
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei, 063210, China; School of Life Science, North China University of Science and Technology, Tangshan, Hebei, 063210, China.
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28
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Niu ZS, Wang WH. Circular RNAs in hepatocellular carcinoma: Recent advances. World J Gastrointest Oncol 2022; 14:1067-1085. [PMID: 35949213 PMCID: PMC9244981 DOI: 10.4251/wjgo.v14.i6.1067] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/22/2021] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) have covalently closed loop structures at both ends, exhibiting characteristics dissimilar to those of linear RNAs. Emerging evidence suggests that aberrantly expressed circRNAs play crucial roles in hepatocellular carcinoma (HCC) by affecting the proliferation, apoptosis and invasive capacity of HCC cells. Certain circRNAs may be used as biomarkers to diagnose and predict the prognosis of HCC. Therefore, circRNAs are expected to become novel biomarkers and therapeutic targets for HCC. Herein, we briefly review the characteristics and biological functions of circRNAs, focusing on their roles in HCC to provide new insights for the early diagnosis and targeted therapy of HCC.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
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29
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Hu Antigen R (HuR) Protein Structure, Function and Regulation in Hepatobiliary Tumors. Cancers (Basel) 2022; 14:cancers14112666. [PMID: 35681645 PMCID: PMC9179498 DOI: 10.3390/cancers14112666] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/19/2022] [Accepted: 05/23/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Hepatobiliary tumors are a group of primary malignancies encompassing the liver, the intra- and extra-hepatic biliary tracts, and the gall bladder. Within the liver, hepatocellular carcinoma (HCC) is the most common type of primary cancer, which is, also, representing the third-most recurrent cause of cancer-associated death and the sixth-most prevalent type of tumor worldwide, nowadays. Although less frequent, cholangiocarcinoma (CCA) is, currently, a fatal cancer with limited therapeutic options. Here, we review the regulatory role of Hu antigen R (HuR), a ubiquitous member of the ELAV/Hu family of RNA-binding proteins (RBPs), in the pathogenesis, progression, and treatment of HCC and CCA. Overall, HuR is proposed as a valuable diagnostic and prognostic marker, as well as a therapeutic target in hepatobiliary cancers. Therefore, novel therapeutic approaches that can selectively modulate HuR function appear to be highly attractive for the clinical management of these types of tumors. Abstract Hu antigen R (HuR) is a 36-kDa ubiquitous member of the ELAV/Hu family of RNA-binding proteins (RBPs), which plays an important role as a post-transcriptional regulator of specific RNAs under physiological and pathological conditions, including cancer. Herein, we review HuR protein structure, function, and its regulation, as well as its implications in the pathogenesis, progression, and treatment of hepatobiliary cancers. In particular, we focus on hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), tumors where the increased cytoplasmic localization of HuR and activity are proposed, as valuable diagnostic and prognostic markers. An overview of the main regulatory axes involving HuR, which are associated with cell proliferation, invasion, metastasis, apoptosis, and autophagy in HCC, is provided. These include the transcriptional, post-transcriptional, and post-translational modulators of HuR function, in addition to HuR target transcripts. Finally, whereas studies addressing the relevance of targeting HuR in CCA are limited, in the past few years, HuR has emerged as a potential therapeutic target in HCC. In fact, the therapeutic efficacy of some pharmacological inhibitors of HuR has been evaluated, in early experimental models of HCC. We, further, discuss the major findings and future perspectives of therapeutic approaches that specifically block HuR interactions, either with post-translational modifiers or cognate transcripts in hepatobiliary cancers.
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30
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Cai H, Zheng D, Yao Y, Yang L, Huang X, Wang L. Roles of Embryonic Lethal Abnormal Vision-Like RNA Binding Proteins in Cancer and Beyond. Front Cell Dev Biol 2022; 10:847761. [PMID: 35465324 PMCID: PMC9019298 DOI: 10.3389/fcell.2022.847761] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 03/04/2022] [Indexed: 12/31/2022] Open
Abstract
Embryonic lethal abnormal vision-like (ELAVL) proteins are RNA binding proteins that were originally discovered as indispensable regulators of the development and functioning of the nervous system. Subsequent studies have shown that ELAVL proteins not only exist in the nervous system, but also have regulatory effects in other tissues. ELAVL proteins have attracted attention as potential therapeutic targets because they stabilize multiple mRNAs by binding within the 3′-untranslated region and thus promote the development of tumors, including hepatocellular carcinoma, pancreatic cancer, ovarian cancer, breast cancer, colorectal carcinoma and lung cancer. Previous studies have focused on these important relationships with downstream mRNAs, but emerging studies suggest that ELAVL proteins also interact with non-coding RNAs. In this review, we will summarize the relationship of the ELAVL protein family with mRNA and non-coding RNA and the roles of ELAVL protein family members in a variety of physiological and pathological processes.
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Affiliation(s)
| | | | | | - Lehe Yang
- *Correspondence: Lehe Yang, ; Xiaoying Huang, ; Liangxing Wang,
| | - Xiaoying Huang
- *Correspondence: Lehe Yang, ; Xiaoying Huang, ; Liangxing Wang,
| | - Liangxing Wang
- *Correspondence: Lehe Yang, ; Xiaoying Huang, ; Liangxing Wang,
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Wang P, Zhang Y, Deng L, Qu Z, Guo P, Liu L, Yu Z, Wang P, Liu N. The function and regulation network mechanism of circRNA in liver diseases. Cancer Cell Int 2022; 22:141. [PMID: 35361205 PMCID: PMC8973545 DOI: 10.1186/s12935-022-02559-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 03/22/2022] [Indexed: 12/04/2022] Open
Abstract
Circular RNA (circRNA), a new type of endogenous non-coding RNA, is abundantly present in eukaryotic cells, and characterized as stable high conservation and tissue specific expression. It has been generated increasing attention because of their close association with the progress of diseases. The liver is the vital organ of humans, while it is prone to acute and chronic diseases due to the influence of multiple pathogenic factors. Moreover, hepatocellular carcinoma (HCC) is the one of most common cancer and the leading cause of cancer death worldwide. Overwhelming evidences indicate that some circRNAs are differentially expressed in liver diseases, such as, HCC, chronic hepatitis B, hepatic steatosis and hepatoblastoma tissues, etc. Additionally, these circRNAs are related to proliferation, invasion, migration, angiogenesis, apoptosis, and metastasis of cell in liver diseases and act as oncogenic agents or suppressors, and linked to clinical manifestations. In this review, we briefly summarize the biogenesis, characterization and biological functions, recent detection and identification technologies of circRNA, and regulation network mechanism of circRNA in liver diseases, and discuss their potential values as biomarkers or therapeutic targets for liver diseases, especially on HCC.
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Affiliation(s)
- Panpan Wang
- College of Public Health, Zhengzhou University, Zhengzhou, 540001, People's Republic of China.,South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, People's Republic of China
| | - Yunhuan Zhang
- Institute of Chronic Disease Risks Assessment, School of Nursing and Health, Henan University, Kaifeng, 475004, People's Republic of China
| | - Lugang Deng
- South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, People's Republic of China
| | - Zhi Qu
- Institute of Chronic Disease Risks Assessment, School of Nursing and Health, Henan University, Kaifeng, 475004, People's Republic of China.
| | - Peisen Guo
- College of Public Health, Zhengzhou University, Zhengzhou, 540001, People's Republic of China.,South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, People's Republic of China
| | - Limin Liu
- College of Public Health, Zhengzhou University, Zhengzhou, 540001, People's Republic of China.,Institute of Chronic Disease Risks Assessment, School of Nursing and Health, Henan University, Kaifeng, 475004, People's Republic of China.,South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, People's Republic of China
| | - Zengli Yu
- College of Public Health, Zhengzhou University, Zhengzhou, 540001, People's Republic of China.
| | - Peixi Wang
- Institute of Chronic Disease Risks Assessment, School of Nursing and Health, Henan University, Kaifeng, 475004, People's Republic of China
| | - Nan Liu
- College of Public Health, Zhengzhou University, Zhengzhou, 540001, People's Republic of China. .,Institute of Chronic Disease Risks Assessment, School of Nursing and Health, Henan University, Kaifeng, 475004, People's Republic of China. .,South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, People's Republic of China.
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Chen G, Long C, Wang S, Wang Z, Chen X, Tang W, He X, Bao Z, Tan B, Zhao J, Xie Y, Li Z, Yang D, Xiao G, Peng S. Circular RNA circStag1 promotes bone regeneration by interacting with HuR. Bone Res 2022; 10:32. [PMID: 35361779 PMCID: PMC8971384 DOI: 10.1038/s41413-022-00208-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 01/29/2022] [Accepted: 02/28/2022] [Indexed: 12/11/2022] Open
Abstract
Postmenopausal osteoporosis is a common bone metabolic disorder characterized by deterioration of the bone microarchitecture, leading to an increased risk of fractures. Recently, circular RNAs (circRNAs) have been demonstrated to play pivotal roles in regulating bone metabolism. However, the underlying functions of circRNAs in bone metabolism in postmenopausal osteoporosis remain obscure. Here, we report that circStag1 is a critical osteoporosis-related circRNA that shows significantly downregulated expression in osteoporotic bone marrow mesenchymal stem cells (BMSCs) and clinical bone tissue samples from patients with osteoporosis. Overexpression of circStag1 significantly promoted the osteogenic capability of BMSCs. Mechanistically, we found that circStag1 interacts with human antigen R (HuR), an RNA-binding protein, and promotes the translocation of HuR into the cytoplasm. A high cytoplasmic level of HuR led to the activation of the Wnt signaling pathway by stabilizing and enhancing low-density lipoprotein receptor-related protein 5/6 (Lrp5/6) and β-catenin expression, thereby stimulating the osteogenic differentiation of BMSCs. Furthermore, overexpression of circStag1 in vivo by circStag1-loaded adeno-associated virus (circStag1-AAV) promoted new bone formation, thereby preventing bone loss in ovariectomized rats. Collectively, we show that circStag1 plays a pivotal role in promoting the regeneration of bone tissue via HuR/Wnt signaling, which may provide new strategies to prevent bone metabolic disorders such as postmenopausal osteoporosis.
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Affiliation(s)
- Gaoyang Chen
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Canling Long
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Shang Wang
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Zhenmin Wang
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Xin Chen
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Wanze Tang
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Xiaoqin He
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Zhiteng Bao
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Baoyu Tan
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Jin Zhao
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Yongheng Xie
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Zhizhong Li
- The First Affiliated Hospital, Jinan University, Guangzhou, 510630, China
| | - Dazhi Yang
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China.
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China.
| | - Guozhi Xiao
- School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China.
| | - Songlin Peng
- Department of Spine Surgery and Institute for Orthopaedic Research, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, China.
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518055, China.
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Pitolli C, Marini A, Sette C, Pagliarini V. Non-Canonical Splicing and Its Implications in Brain Physiology and Cancer. Int J Mol Sci 2022; 23:ijms23052811. [PMID: 35269953 PMCID: PMC8911335 DOI: 10.3390/ijms23052811] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 02/28/2022] [Accepted: 03/02/2022] [Indexed: 02/01/2023] Open
Abstract
The advance of experimental and computational techniques has allowed us to highlight the existence of numerous different mechanisms of RNA maturation, which have been so far unknown. Besides canonical splicing, consisting of the removal of introns from pre-mRNA molecules, non-canonical splicing events may occur to further increase the regulatory and coding potential of the human genome. Among these, splicing of microexons, recursive splicing and biogenesis of circular and chimeric RNAs through back-splicing and trans-splicing processes, respectively, all contribute to expanding the repertoire of RNA transcripts with newly acquired regulatory functions. Interestingly, these non-canonical splicing events seem to occur more frequently in the central nervous system, affecting neuronal development and differentiation programs with important implications on brain physiology. Coherently, dysregulation of non-canonical RNA processing events is associated with brain disorders, including brain tumours. Herein, we summarize the current knowledge on molecular and regulatory mechanisms underlying canonical and non-canonical splicing events with particular emphasis on cis-acting elements and trans-acting factors that all together orchestrate splicing catalysis reactions and decisions. Lastly, we review the impact of non-canonical splicing on brain physiology and pathology and how unconventional splicing mechanisms may be targeted or exploited for novel therapeutic strategies in cancer.
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Affiliation(s)
- Consuelo Pitolli
- Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168 Rome, Italy; (C.P.); (C.S.)
- GSTEP-Organoids Research Core Facility, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168 Rome, Italy;
| | - Alberto Marini
- GSTEP-Organoids Research Core Facility, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168 Rome, Italy;
| | - Claudio Sette
- Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168 Rome, Italy; (C.P.); (C.S.)
- GSTEP-Organoids Research Core Facility, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168 Rome, Italy;
| | - Vittoria Pagliarini
- Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168 Rome, Italy; (C.P.); (C.S.)
- GSTEP-Organoids Research Core Facility, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168 Rome, Italy;
- Correspondence:
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Li X, Wang C, Chen G, Zou W, Deng Y, Zhou F. EIF4A3-induced circCCNB1 (hsa_circ_0001495) promotes glioma progression by elevating CCND1 through interacting miR-516b-5p and HuR. Metab Brain Dis 2022; 37:819-833. [PMID: 35038081 DOI: 10.1007/s11011-021-00899-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 12/26/2021] [Indexed: 01/29/2023]
Abstract
To explore the functions of circRNA cyclin B1 (circCCNB1) in glioma and its possible mechanisms. The expression of circCCNB1, eukaryotic translation initiation factor 4A3 (EIF4A3), cyclin D1 (CCND1) and miR-516b-5p was determined by qRT-PCR, western blot or immunohistochemistry (IHC) assay. The feature of circCCNB1 was analyzed by Actinomycin D (ActD), RNase R and subcellular fraction assays. The molecule relationships were analyzed by RIP, dual-luciferase reporter and RNA pull-down assays. CCK-8, EdU and colony formation assays were performed to analyze cell proliferation. Flow cytometry analysis was executed to estimate the cell cycle. Murine xenograft model assay was used for the role of circCCNB1 in vivo. CircCCNB1 was overexpressed in glioma tissues and cells. EIF4A3 positively regulated circCCNB1 expression. CircCCNB1 knockdown repressed glioma cell proliferation and cell cycle process in vitro and blocked tumor growth in vivo. CircCCNB1 knockdown reduced CCND1 expression in glioma cells and CCND1 overexpression bated the effect of circCCNB1 knockdown on glioma cell growth. CircCCNB1 interacted with HuR to elevate CCND1 expression. miR-516b-5p could interact with circCCNB1 and CCND1. CircCCNB1 regulated glioma cell progression and CCND1 expression by miR-516b-5p and HuR. CircCCNB1 aggravated glioma cell growth by elevating CCND1 through targeting miR-516b-5p and HuR.
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Affiliation(s)
- Xiaoli Li
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, No. 39, Chaoyang Middle Road, Maojian District, Shiyan, 442000, China
| | - Chengmou Wang
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, No. 39, Chaoyang Middle Road, Maojian District, Shiyan, 442000, China
| | - Guanghui Chen
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, No. 39, Chaoyang Middle Road, Maojian District, Shiyan, 442000, China
| | - Wenqin Zou
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, No. 39, Chaoyang Middle Road, Maojian District, Shiyan, 442000, China
| | - Yanqing Deng
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, No. 39, Chaoyang Middle Road, Maojian District, Shiyan, 442000, China
| | - Faming Zhou
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, No. 39, Chaoyang Middle Road, Maojian District, Shiyan, 442000, China.
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Louis C, Leclerc D, Coulouarn C. Emerging roles of circular RNAs in liver cancer. JHEP Rep 2022; 4:100413. [PMID: 35036887 PMCID: PMC8749337 DOI: 10.1016/j.jhepr.2021.100413] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma and cholangiocarcinoma are the most common primary liver tumours, whose incidence and associated mortality have increased over recent decades. Liver cancer is often diagnosed late when curative treatments are no longer an option. Characterising new molecular determinants of liver carcinogenesis is crucial for the development of innovative treatments and clinically relevant biomarkers. Recently, circular RNAs (circRNAs) emerged as promising regulatory molecules involved in cancer onset and progression. Mechanistically, circRNAs are mainly known for their ability to sponge and regulate the activity of microRNAs and RNA-binding proteins, although other functions are emerging (e.g. transcriptional and post-transcriptional regulation, protein scaffolding). In liver cancer, circRNAs have been shown to regulate tumour cell proliferation, migration, invasion and cell death resistance. Their roles in regulating angiogenesis, genome instability, immune surveillance and metabolic switching are emerging. Importantly, circRNAs are detected in body fluids. Due to their circular structure, circRNAs are often more stable than mRNAs or miRNAs and could therefore serve as promising biomarkers - quantifiable with high specificity and sensitivity through minimally invasive methods. This review focuses on the role and the clinical relevance of circRNAs in liver cancer, including the development of innovative biomarkers and therapeutic strategies.
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Key Words
- ASO, antisense oligonucleotide
- CCA, cholangiocarcinoma
- CLIP, cross-linking immunoprecipitation
- EMT, epithelial-to-mesenchymal transition
- EVs, extracellular vesicles
- HCC, hepatocellular carcinoma
- HN1, haematopoietic- and neurologic-expressed sequence 1
- IRES, internal ribosome entry sites
- NGS, next-generation sequencing
- QKI, Quaking
- RBP, RNA-binding protein
- RISC, RNA-induced silencing complex
- TAM, tumour-associated macrophage
- TSB, target site blockers
- biomarker
- cancer hallmarks
- cholangiocarcinoma
- circRNA
- circRNA, circular RNA
- hepatocellular carcinoma
- miRNA, microRNA
- shRNA, small-hairpin RNA
- snRNP, small nuclear ribonuclear proteins
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Affiliation(s)
- Corentin Louis
- Inserm, Univ Rennes 1, COSS (Chemistry, Oncogenesis Stress Signaling), UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
| | - Delphine Leclerc
- Inserm, Univ Rennes 1, COSS (Chemistry, Oncogenesis Stress Signaling), UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
| | - Cédric Coulouarn
- Inserm, Univ Rennes 1, COSS (Chemistry, Oncogenesis Stress Signaling), UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
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Yun BD, Choi YJ, Son SW, Cipolla GA, Berti FCB, Malheiros D, Oh TJ, Kuh HJ, Choi SY, Park JK. Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers. Int J Mol Sci 2022; 23:ijms23020930. [PMID: 35055115 PMCID: PMC8781283 DOI: 10.3390/ijms23020930] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/12/2022] [Accepted: 01/13/2022] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) are differentially expressed in gastrointestinal cancers. These noncoding RNAs (ncRNAs) regulate a variety of cellular activities by physically interacting with microRNAs and proteins and altering their activity. It has also been suggested that exosomes encapsulate circRNAs and lncRNAs in cancer cells. Exosomes are then discharged into the extracellular environment, where they are taken up by other cells. As a result, exosomal ncRNA cargo is critical for cell-cell communication within the cancer microenvironment. Exosomal ncRNAs can regulate a range of events, such as angiogenesis, metastasis, immune evasion, drug resistance, and epithelial-to-mesenchymal transition. To set the groundwork for developing novel therapeutic strategies against gastrointestinal malignancies, a thorough understanding of circRNAs and lncRNAs is required. In this review, we discuss the function and intrinsic features of oncogenic circRNAs and lncRNAs that are enriched within exosomes.
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Affiliation(s)
- Ba Da Yun
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
| | - Ye Ji Choi
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
| | - Seung Wan Son
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
| | - Gabriel Adelman Cipolla
- Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba 81531-990, Brazil; (G.A.C.); (F.C.B.B.); (D.M.)
| | - Fernanda Costa Brandão Berti
- Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba 81531-990, Brazil; (G.A.C.); (F.C.B.B.); (D.M.)
| | - Danielle Malheiros
- Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba 81531-990, Brazil; (G.A.C.); (F.C.B.B.); (D.M.)
| | - Tae-Jin Oh
- Department of Pharmaceutical Engineering and Biotechnology, SunMoon University, 70 Sunmoon-ro 221, Tangjeong-myeon, Asan-si 31460, Korea;
- Genome-Based BioIT Convergence Institute, 70 Sunmoon-ro 221, Tangjeong-myeon, Asan-si 31460, Korea
| | - Hyo Jeong Kuh
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Soo Young Choi
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
| | - Jong Kook Park
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
- Correspondence: ; Tel.: +82-33-248-2114
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Ji Y, Yang S, Yan X, Zhu L, Yang W, Yang X, Yu F, Shi L, Zhu X, Lu Y, Zhang C, Lu H, Zhang F. CircCRIM1 Promotes Hepatocellular Carcinoma Proliferation and Angiogenesis by Sponging miR-378a-3p and Regulating SKP2 Expression. Front Cell Dev Biol 2021; 9:796686. [PMID: 34869393 PMCID: PMC8634842 DOI: 10.3389/fcell.2021.796686] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 10/28/2021] [Indexed: 12/17/2022] Open
Abstract
Mounting evidence has demonstrated that circular RNAs have an important function in tumorigenesis and cancer evolvement. CircCRIM1 has been shown to be a poor prognostic element in multiple human malignancies. However, the clinical significance and mechanism of circCRIM1 in hepatocellular carcinoma (HCC) is still unclear. The present study confirmed the expression level of circCRIM1 using quantitative real-time PCR. In addition, circCRIM1 siRNA and overexpression vectors were used for transfection into LM3 or Huh7 cells to down- or up-regulate the expression of circCRIM1. In vitro and in vivo experiments were performed to explore the function of circCRIM1 in HCC. RNA pull-down, RNA immunoprecipitation, fluorescent in situ hybridization, and luciferase reporter assays were conducted to confirm the relationship between miR-378a-3p and circCRIM1 or S-phase kinase-associated protein 2 (SKP2) in HCC. Then, circCRIM1 was up-regulated in HCC and its expression level was significantly associated with poor prognosis and clinicopathologic characteristics. CircCRIM1 enhanced the proliferation and angiogenesis of HCC cells in vitro and promoted xenograft growth in vivo. Moreover, circCRIM1 upregulated the expression of SKP2 by functioning as a sponge for miR-378a-3p. These findings suggest that circCRIM1 boosts the HCC progression via the miR-378-3p/SKP2 axis and may act as a crucial epigenetic therapeutic molecule target in HCC.
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Affiliation(s)
- Yang Ji
- Key Laboratory of Liver Transplantation, Hepatobiliary/Liver Transplantation Center, Chinese Academy of Medical Sciences, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shikun Yang
- Key Laboratory of Liver Transplantation, Hepatobiliary/Liver Transplantation Center, Chinese Academy of Medical Sciences, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xueqi Yan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Li Zhu
- Department of Hepatobiliary Surgery, The Third Hospital Affiliated to Soochow University, Changzhou, China
| | - Wenjie Yang
- Key Laboratory of Liver Transplantation, Hepatobiliary/Liver Transplantation Center, Chinese Academy of Medical Sciences, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinchen Yang
- Key Laboratory of Liver Transplantation, Hepatobiliary/Liver Transplantation Center, Chinese Academy of Medical Sciences, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fei Yu
- Key Laboratory of Liver Transplantation, Hepatobiliary/Liver Transplantation Center, Chinese Academy of Medical Sciences, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Longqing Shi
- Department of Hepatobiliary Surgery, The Third Hospital Affiliated to Soochow University, Changzhou, China
| | - Xi Zhu
- Department of Infectious Disease, The First People's Hospital of Kunshan Affliated with Jiangsu University, Zhenjiang, China
| | - Yunjie Lu
- Department of Hepatobiliary Surgery, The Third Hospital Affiliated to Soochow University, Changzhou, China
| | - Chuanyong Zhang
- Key Laboratory of Liver Transplantation, Hepatobiliary/Liver Transplantation Center, Chinese Academy of Medical Sciences, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Lu
- Key Laboratory of Liver Transplantation, Hepatobiliary/Liver Transplantation Center, Chinese Academy of Medical Sciences, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Zhang
- Key Laboratory of Liver Transplantation, Hepatobiliary/Liver Transplantation Center, Chinese Academy of Medical Sciences, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Hui Y, Jin D, Leng J, Liu D, Yuan P, Tang C, Wang Q. Hsa_circ_0007059 sponges miR-421 to repress cell growth and stemness in hepatocellular carcinoma by the PTEN-AKT/mTOR pathway. Pathol Res Pract 2021; 229:153692. [PMID: 34847369 DOI: 10.1016/j.prp.2021.153692] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 11/01/2021] [Accepted: 11/16/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a substantial health concern worldwide. Increasing studies have suggested that circle RNAs (circRNAs) function as new regulators in HCC progression. The present work explored the role of hsa_circ_0007059 (circ_0007059) in the developing process of hepatocarcinogenesis. METHODS The circ_0007059 level in HCC was determined by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and northern blot. Its biological role in HCC cells was assessed using 3-(4,5-Dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT), colony formation, flow cytometry, Transwell, sphere formation and western blotting analyses. Bioinformatics analysis, luciferase reporter, and RNA immunoprecipitation (RIP) assays were used to test the regulatory mechanisms of circ_0007059. RESULTS Our results revealed that circ_0007059 expression was downregulated in HCC samples and cells. Moreover, circ_0007059 overexpression inhibited HCC cell proliferation, migration, invasion, and stem cell-like property, and strengthened cell apoptosis. In mechanism, circ_0007059 suppressed AKT/mTOR pathway by positively regulating phosphatase and tensin homolog (PTEN) expression. Additionally, circ_0007059 acted as a positive regulator of PTEN through controlling the availability of miR-421. Rescue assays demonstrated that PTEN knockdown or SC79 (AKT agonist) eliminated the effect of circ_0007059 on HCC cell phenotypes. CONCLUSION Circ_0007059 sponges miR-421 to inhibit oncogenic cellular process in HCC by mediating the PTEN-AKT/mTOR pathway.
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Affiliation(s)
- Yongfeng Hui
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, PR China
| | - Dong Jin
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, PR China
| | - Junzhi Leng
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, PR China
| | - Di Liu
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, PR China
| | - Peng Yuan
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, PR China
| | - Chaofeng Tang
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, PR China
| | - Qi Wang
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, PR China.
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Li LY, Yang JF, Rong F, Luo ZP, Hu S, Fang H, Wu Y, Yao R, Kong WH, Feng XW, Chen BJ, Li J, Xu T. ZEB1 serves an oncogenic role in the tumourigenesis of HCC by promoting cell proliferation, migration, and inhibiting apoptosis via Wnt/β-catenin signaling pathway. Acta Pharmacol Sin 2021; 42:1676-1689. [PMID: 33514855 PMCID: PMC8463676 DOI: 10.1038/s41401-020-00575-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 11/05/2020] [Indexed: 02/06/2023]
Abstract
Zinc finger E-box-binding homeobox 1 (ZEB1), a functional protein of zinc finger family, was aberrant expressed in many kinds of liver disease including hepatic fibrosis and Hepatitis C virus. Bioinformatics results showed that ZEB1 was abnormally expressed in HCC tissues. However, to date, the potential regulatory role and molecular mechanisms of ZEB1 are still unclear in the occurrence and development of HCC. This study demonstrated that the expression level of ZEB1 was significantly elevated both in liver tissues of HCC patients and cell lines (HepG2 and SMMC-7721 cells). Moreover, ZEB1 could promote the proliferation, migration, and invasion of HCC cells. On the downstream regulation mechanism, ZEB1 could activate the Wnt/β-catenin signaling pathway by upregulating the protein expression levels of β-catenin, c-Myc, and cyclin D1. Novel studies showed that miR-708 particularly targeted ZEB1 3'-UTR regions and inhibited the HCC cell proliferation, migration, and invasion. Furthermore, results of nude mice experiments of HCC model indicated that miR-708 could inhibit tumor growth and xenograft metastasis model was established to validate that miR-708 could inhibit HCC cell metastasis through tail-vein injection in vivo. Together, the study suggested that ZEB1 modulated by miR-708 might be a potential therapeutic target for HCC therapy.
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Affiliation(s)
- Liang-Yun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China
| | - Jun-Fa Yang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China
| | - Fan Rong
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China
- Lujiang County People's Hospital of Anhui Province, Hefei, 231500, China
| | - Zhi-Pan Luo
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China
- The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Shuang Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China
| | - Hui Fang
- Department of Pharmocology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, 310015, China
| | - Ying Wu
- The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Rui Yao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China
| | - Wei-Hao Kong
- The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Xiao-Wen Feng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China
| | - Bang-Jie Chen
- First Clinical Medical College of Anhui Medical University, Hefei, 230032, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China
| | - Tao Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
- Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China.
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Huang Z, Xia H, Liu S, Zhao X, He R, Wang Z, Shi W, Chen W, Kang P, Su Z, Cui Y, Yam JWP, Xu Y. The Mechanism and Clinical Significance of Circular RNAs in Hepatocellular Carcinoma. Front Oncol 2021; 11:714665. [PMID: 34540684 PMCID: PMC8445159 DOI: 10.3389/fonc.2021.714665] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/09/2021] [Indexed: 01/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. In view of the lack of early obvious clinical symptoms and related early diagnostic biomarkers with high specificity and sensitivity, most HCC patients are already at the advanced stages at the time of diagnosis, and most of them are accompanied by distant metastasis. Furthermore, the unsatisfactory effect of the follow-up palliative care contributes to the poor overall survival of HCC patients. Therefore, it is urgent to identify effective early diagnosis and prognostic biomarkers and to explore novel therapeutic approaches to improve the prognosis of HCC patients. Circular RNA (CircRNA), a class of plentiful, stable, and highly conserved ncRNA subgroup with the covalent closed loop, is dysregulated in HCC. Increasingly, emerging evidence have confirmed that dysregulated circRNAs can regulate gene expression at the transcriptional or post-transcriptional level, mediating various malignant biological behaviors of HCC cells, including proliferation, invasion, metastasis, immune escape, stemness, and drug resistance, etc.; meanwhile, they are regarded as potential biomarkers for early diagnosis and prognostic evaluation of HCC. This article reviews the research progress of circRNAs in HCC, expounding the potential molecular mechanisms of dysregulated circRNAs in the carcinogenesis and development of HCC, and discusses those application prospects in the diagnosis and prognosis of HCC.
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Affiliation(s)
- Ziyue Huang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Haoming Xia
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shuqiang Liu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xudong Zhao
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Risheng He
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhongrui Wang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenguang Shi
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wangming Chen
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Pengcheng Kang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhilei Su
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong, SAR China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong, SAR China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
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Shen H, Liu B, Xu J, Zhang B, Wang Y, Shi L, Cai X. Circular RNAs: characteristics, biogenesis, mechanisms and functions in liver cancer. J Hematol Oncol 2021; 14:134. [PMID: 34461958 PMCID: PMC8407006 DOI: 10.1186/s13045-021-01145-8] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 08/21/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignancies globally. Despite aggressive and multimodal treatment regimens, the overall survival of HCC patients remains poor. MAIN: Circular RNAs (circRNAs) are noncoding RNAs (ncRNAs) with covalently closed structures and tissue- or organ-specific expression patterns in eukaryotes. They are highly stable and have important biological functions, including acting as microRNA sponges, protein scaffolds, transcription regulators, translation templates and interacting with RNA-binding protein. Recent advances have indicated that circRNAs present abnormal expression in HCC tissues and that their dysregulation contributes to HCC initiation and progression. Furthermore, researchers have revealed that some circRNAs might serve as diagnostic biomarkers or drug targets in clinical settings. In this review, we systematically evaluate the characteristics, biogenesis, mechanisms and functions of circRNAs in HCC and further discuss the current shortcomings and potential directions of prospective studies on liver cancer-related circRNAs. CONCLUSION CircRNAs are a novel class of ncRNAs that play a significant role in HCC initiation and progression, but their internal mechanisms and clinical applications need further investigation.
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Affiliation(s)
- Hao Shen
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
| | - Boqiang Liu
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
| | - Junjie Xu
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Bin Zhang
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Yifan Wang
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
| | - Liang Shi
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
| | - Xiujun Cai
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang University, Hangzhou, 310016, China.
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang University, Hangzhou, 310016, China.
- Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310016, 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: 50] [Impact Index Per Article: 12.5] [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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Jiang MP, Xu WX, Hou JC, Xu Q, Wang DD, Tang JH. The Emerging Role of the Interactions between Circular RNAs and RNA-binding Proteins in Common Human Cancers. J Cancer 2021; 12:5206-5219. [PMID: 34335937 PMCID: PMC8317540 DOI: 10.7150/jca.58182] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 06/09/2021] [Indexed: 12/24/2022] Open
Abstract
Circular RNAs (circRNAs) are a unique family of noncoding RNAs that could regulate multiple biological processes, which play a crucial role in carcinogenesis, progression and chemotherapy resistance of cancers. Growing studies have demonstrated that circRNAs act as novel biomarkers and therapeutic targets for cancers by sponging microRNAs (miRNAs). Up to date, another function of circRNAs, combining with RNA-binding proteins (RBPs), was uncovered. However, there is limit studies illustrating the underlying mechanism of circRNAs-RBPs interactions, as well as showing its roles in diverse types of cancers. In this review, we collected the biogenesis, properties of circRNAs, and then synthesize the connection between circRNAs and RBPs, and try to clarify its molecular mechanisms involving in the pathogenesis and progression of several common cancers, aiming to provide a brand-new insight to the prognosis and treatment strategy for cancers.
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Affiliation(s)
- Meng-Ping Jiang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wen-Xiu Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jun-Chen Hou
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qi Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dan-Dan Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jin-Hai Tang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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New Molecular Mechanisms and Clinical Impact of circRNAs in Human Cancer. Cancers (Basel) 2021; 13:cancers13133154. [PMID: 34202482 PMCID: PMC8268751 DOI: 10.3390/cancers13133154] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Circular RNAs (circRNAs) belong to a new class of non-coding RNAs implicated in cellular physiological functions but also in the evolution of various human pathologies. Due to their circular shape, circRNAs are resistant to degradation by exonuclease activity, making them more stable than linear RNAs. Several findings reported that circRNAs are aberrantly modulated in human cancer tissues, thus affecting carcinogenesis and metastatization. We aim to report the most recent and relevant results about novel circRNA functions and molecular regulation, to dissert about their role as reliable cancer biomarkers, and to hypothesize their contribution to multiple hallmarks of cancer. Abstract Next generation RNA sequencing techniques, implemented in the recent years, have allowed us to identify circular RNAs (circRNAs), covalently closed loop structures resulting in RNA molecules that are more stable than linear RNAs. This class of non-coding RNA is emerging to be involved in a variety of cell functions during development, differentiation, and in many diseases, including cancer. Among the described biological activities, circRNAs have been implicated in microRNA (miRNA) sequestration, modulation of protein–protein interactions and regulation of mRNA transcription. In human cancer, circRNAs were implicated in the control of oncogenic activities such as tumor cell proliferation, epithelial-mesenchymal transition, invasion, metastasis and chemoresistance. The most widely described mechanism of action of circRNAs is their ability to act as competing endogenous RNAs (ceRNAs) for miRNAs, lncRNAs and mRNAs, thus impacting along their axis, despite the fact that a variety of additional mechanisms of action are emerging, representing an open and expanding field of study. Furthermore, research is currently focusing on understanding the possible implications of circRNAs in diagnostics, prognosis prediction, effectiveness of therapies and, eventually, therapeutic intervention in human cancer. The purpose of this review is to discuss new knowledge on the mechanisms of circRNA action, beyond ceRNA, their impact on human cancer and to dissect their potential value as biomarkers and therapeutic targets.
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Liu B, Tian Y, Chen M, Shen H, Xia J, Nan J, Yan T, Wang Y, Shi L, Shen B, Yu H, Cai X. CircUBAP2 Promotes MMP9-Mediated Oncogenic Effect via Sponging miR-194-3p in Hepatocellular Carcinoma. Front Cell Dev Biol 2021; 9:675043. [PMID: 34239873 PMCID: PMC8258265 DOI: 10.3389/fcell.2021.675043] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/31/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The physiological regulatory functions of circRNAs have become a topic of intensive research in recent years. Increasing evidence supports a significant role of circRNAs during cancer initiation and progression, including hepatocellular carcinoma (HCC). MATERIALS AND METHODS A bioinformatics analysis from three independent Gene Expression Omnibus (GEO) databases was performed to profile and screen the dysregulated circRNAs in HCC. RT-qPCR was used to examine the expression level of circUBAP2 in HCC and adjacent non-tumor tissues. Then, proliferation assays (CCK8 and colony formation) and migration assays (transwell and wound healing) were performed to examine effect of circUBAP2 in vitro. Immunoprecipitation, RNA pulldown, FISH, and dual-luciferase reporter assay was conducted to explore the circUBAP2-related mechanism for regulating HCC progression. Moreover, a mouse xenograft model and a mouse lung metastasis model confirmed the effect of circUBAP2 in vivo. RESULTS In this study, we found a novel circRNA: circUBAP2, which was identified by bioinformatics analysis. Among 91 HCC patients, circUBAP2 was significantly upregulated in HCC tissues, and negatively correlated with aggressive clinical characteristics and prognosis. Functional assays demonstrated that circUBAP2 promoted cell proliferation, colony formation, migration, and invasion in vitro. Moreover, circUBAP2 enhanced tumor growth and pulmonary metastasis in vivo. Mechanistically, circUBAP2 acts as a competing endogenous RNA (ceRNA) for miR-194-3p, a tumor suppressor in HCC. We confirmed that MMP9 was direct target for miR-194-3p, which was regulated by circUBAP2. CONCLUSION CircUBAP2 plays a significant role in promoting HCC via the miR-194-3p/MMP9 pathway and could serve as a promising prognostic biomarker and novel therapeutic target for HCC patients.
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Affiliation(s)
- Boqiang Liu
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yuanshi Tian
- Department of Diagnostic Ultrasound and Echocardiography, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Mingyu Chen
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hao Shen
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiafeng Xia
- State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Junjie Nan
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tingting Yan
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yifan Wang
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Liang Shi
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bo Shen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hong Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiujun Cai
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang University, Hangzhou, China
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang University, Hangzhou, China
- Zhejiang University Cancer Center, Zhejiang University, Hangzhou, China
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Large-scale circular RNA deregulation in T-ALL: unlocking unique ectopic expression of molecular subtypes. Blood Adv 2021; 4:5902-5914. [PMID: 33259601 DOI: 10.1182/bloodadvances.2020002337] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 10/20/2020] [Indexed: 12/25/2022] Open
Abstract
Circular RNAs (circRNAs) are stable RNA molecules that can drive cancer through interactions with microRNAs and proteins and by the expression of circRNA encoded peptides. The aim of the study was to define the circRNA landscape and potential impact in T-cell acute lymphoblastic leukemia (T-ALL). Analysis by CirComPara of RNA-sequencing data from 25 T-ALL patients, immature, HOXA overexpressing, TLX1, TLX3, TAL1, or LMO2 rearranged, and from thymocyte populations of human healthy donors disclosed 68 554 circRNAs. Study of the top 3447 highly expressed circRNAs identified 944 circRNAs with significant differential expression between malignant T cells and normal counterparts, with most circRNAs displaying increased expression in T-ALL. Next, we defined subtype-specific circRNA signatures in molecular genetic subgroups of human T-ALL. In particular, circZNF609, circPSEN1, circKPNA5, and circCEP70 were upregulated in immature, circTASP1, circZBTB44, and circBACH1 in TLX3, circHACD1, and circSTAM in HOXA, circCAMSAP1 in TLX1, and circCASC15 in TAL-LMO. Backsplice sequences of 14 circRNAs ectopically expressed in T-ALL were confirmed, and overexpression of circRNAs in T-ALL with specific oncogenic lesions was substantiated by quantification in a panel of 13 human cell lines. An oncogenic role of circZNF609 in T-ALL was indicated by decreased cell viability upon silencing in vitro. Furthermore, functional predictions identified circRNA-microRNA gene axes informing modes of circRNA impact in molecular subtypes of human T-ALL.
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Zhang Y, Wang Y. Circular RNAs in Hepatocellular Carcinoma: Emerging Functions to Clinical Significances. Front Oncol 2021; 11:667428. [PMID: 34055634 PMCID: PMC8160296 DOI: 10.3389/fonc.2021.667428] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 04/26/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and carries high morbidity and mortality. Diagnosing HCC at an early stage is challenging. Therefore, finding new, highly sensitive and specific diagnostic biomarkers for the diagnosis and prognosis of HCC patients is extremely important. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently closed loop structures. They are characterized by remarkable stability, long half-life, abundance and evolutionary conservation. Recent studies have shown that many circRNAs are expressed aberrantly in HCC tissues and have important regulatory roles during the development and progression of HCC. Hence, circRNAs are promising biomarkers for the diagnosis and prognosis of HCC. This review: (i) summarizes the biogenesis, categories, and functions of circRNAs; (ii) focuses on current progress of dysregulated expression of circRNAs in HCC with regard to regulation of the tumor hallmarks, “stemness” of cancer cells, and immunotherapy; (iii) highlights circRNAs as potential biomarkers and therapeutic targets for HCC; and (iv) discusses some of the challenges, questions and future perspectives of circRNAs research in HCC.
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Affiliation(s)
- Yucheng Zhang
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yali Wang
- Department of Blood Transfusion, China-Japan Union Hospital of Jilin University, Changchun, China
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Wang X, Sheng W, Xu T, Xu J, Gao R, Zhang Z. CircRNA hsa_circ_0110102 inhibited macrophage activation and hepatocellular carcinoma progression via miR-580-5p/PPARα/CCL2 pathway. Aging (Albany NY) 2021; 13:11969-11987. [PMID: 33891564 PMCID: PMC8109088 DOI: 10.18632/aging.202900] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 03/02/2021] [Indexed: 04/26/2023]
Abstract
Circular RNAs (circRNAs) have critical regulatory roles in tumor biology. However, their contributions in hepatocellular carcinoma (HCC) still remain enigmatic. The present study aimed to investigate the molecular mechanisms underlying the involvement of hsa_circ_0110102 in the occurrence and development of HCC. The expression level of hsa_circ_0110102 was significantly downregulated in HCC cell lines and tissues, which was associated with poor prognosis. Knockdown hsa_circ_0110102 significantly promoted cell proliferation, migration, and invasion. Moreover, the interaction between hsa_circ_0110102 and miR-580-5p was predicted and verified by luciferase assay and RNA pull-down. The findings indicated that hsa_circ_0110102 functioned as a sponge for miR-580-5p. Moreover, miR-580-5p directly bound to the 3' UTR of PPARα, which decreased the production and release of C-C chemokine ligand 2 (CCL2) in HCC cells. CCL2 could activate the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway in macrophage via FoxO1 in a p38 MAPK-dependent manner. Furthermore, the Δ256 mutant of FoxO1 showed no activation effect. These results concluded that hsa_circ_0110102 acted as a sponge for miR-580-5p and inhibited CCL2 secretion into tumor microenvironment by decrease the expression of PPARα in HCC cells, then inhibited the pro-inflammatory cytokine release from macrophages by regulating the COX-2/PGE2 pathway. In conclusion, hsa_circ_0110102 served as a potential prognostic predictor or therapeutic target for HCC.
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Affiliation(s)
- Xinxing Wang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Wei Sheng
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Tao Xu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Jiawen Xu
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Ruyi Gao
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Zhenhai Zhang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
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Circular RNA circE2F2 promotes malignant progression of ovarian cancer cells by upregulating the expression of E2F2 protein via binding to HuR protein. Cell Signal 2021; 84:110014. [PMID: 33894314 DOI: 10.1016/j.cellsig.2021.110014] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/20/2021] [Accepted: 04/20/2021] [Indexed: 12/14/2022]
Abstract
Ovarian cancer (OC) is a gynecological malignancy with a poor prognosis and low survival rate. E2F2 is a transcription activator that plays an indispensable role in cell proliferation and cell cycle progression. The preliminary analysis indicated that the E2F2 gene could produce three circular RNAs (circRNAs). This study aimed to investigate whether these circRNAs would be involved in OC tumorigenesis. The results showed that one of the circRNAs (termed circE2F2) was significantly upregulated in OC tissues and cell lines, and high circE2F2 expression was associated with poor survival in OC patients. The knockdown of circE2F2 in OC cells suppressed cell proliferation, migration, invasion, and cellular glucose metabolism. In circE2F2-deficient cells, the half-life of the E2F2 mRNA was significantly shorter than that in the control group, indicating that sufficient circE2F2 expression could strengthen the stability of the E2F2 mRNA. Further analysis revealed that circE2F2 could bind to RNA-binding protein Hu antigen R (HuR). Moreover, circE2F2 enhanced the stability of the E2F2 mRNA via binding to the HuR protein. Also, E2F2 overexpression significantly enhanced the mobility, invasiveness, and glucose metabolism of OC cells with insufficient circE2F2 expression, suggesting that circE2F2 induced OC cell growth and metastasis by upregulating E2F2. In conclusion, circE2F2 promoted OC cell proliferation, metastasis, and glucose metabolism by stabilizing the E2F2 mRNA via binding to the HuR protein. These findings suggest a novel regulatory mechanism for the oncogenic effects of circE2F2, E2F2, and HuR on ovarian carcinogenesis.
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Fang N, Ding GW, Ding H, Li J, Liu C, Lv L, Shi YJ. Research Progress of Circular RNA in Gastrointestinal Tumors. Front Oncol 2021; 11:665246. [PMID: 33937077 PMCID: PMC8082141 DOI: 10.3389/fonc.2021.665246] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 03/15/2021] [Indexed: 01/17/2023] Open
Abstract
circular RNA (circRNA) is a closed ring structure formed by cyclic covalent bonds connecting the 5’-end and 3’-end of pre-mRNA. circRNA is widely distributed in eukaryotic cells. Recent studies have shown that circRNA is involved in the pathogenesis and development of multiple types of diseases, including tumors. circRNA is specifically expressed in tissues. And the stability of circRNA is higher than that of linear RNA, which can play biological roles through sponge adsorption of miRNA, interaction with RNA binding protein, regulation of gene transcription, the mRNA and protein translation brake, and translation of protein and peptides. These characteristics render circRNAs as biomarkers and therapeutic targets of tumors. Gastrointestinal tumors are common malignancies worldwide, which seriously threaten human health. In this review, we summarize the generation and biological characteristics of circRNA, molecular regulation mechanism and related effects of circRNA in gastrointestinal tumors.
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Affiliation(s)
- Na Fang
- Department of Oncology, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
| | - Guo-Wen Ding
- Department of Thoracic and Cardiovascular Surgery, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
| | - Hao Ding
- Department of Respiratory, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
| | - Juan Li
- Department of Oncology, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
| | - Chao Liu
- Department of Thoracic and Cardiovascular Surgery, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
| | - Lu Lv
- Department of Thoracic and Cardiovascular Surgery, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
| | - Yi-Jun Shi
- Department of Thoracic and Cardiovascular Surgery, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
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