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Liu YC, Ishikawa M, Sakakibara S, Kadi MA, Motooka D, Naito Y, Ito S, Imamura Y, Matsumoto H, Sugihara F, Hirata H, Ogura H, Okuzaki D. Full-length nanopore sequencing of circular RNA landscape in peripheral blood cells following sequential BNT162b2 mRNA vaccination. Gene 2025; 933:148971. [PMID: 39343185 DOI: 10.1016/j.gene.2024.148971] [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: 05/16/2024] [Revised: 09/25/2024] [Accepted: 09/26/2024] [Indexed: 10/01/2024]
Abstract
Circular RNAs (circRNA) lack 5' or 3' ends; their unique covalently closed structures prevent RNA degradation by exonucleases. These characteristics provide circRNAs with high pharmaceutical stability and biostability relative to current standard-of-care linear mRNAs. CircRNA levels are reportedly associated with certain human diseases, making them novel disease biomarkers and a noncanonical class of therapeutic targets. In this study, the endogenous circRNAs underlying the response to BNT162b2 mRNA vaccination were evaluated. To this end, peripheral blood samples were subjected to full-length sequencing of circRNAs via nanopore sequencing and transcriptome sequencing. Fifteen samples, comprising pre-, first, and second vaccination cohorts, were obtained from five healthcare workers with no history of SARS-CoV-2 infection or previous vaccination. A total of 4706 circRNAs were detected; following full-length sequencing, 4217 novel circRNAs were identified as being specifically expressed during vaccination. These circRNAs were enriched in the binding motifs of stress granule assemblies and SARS-CoV-2 RNA binding proteins, namely poly(A) binding protein cytoplasmic 1 (PABPC1), pumilio RNA binding family member 1 (PUM1), and Y box binding protein 1 (YBX1). Moreover, 489 circRNAs were identified as previously reported miRNA sponges. The differentially expressed circRNAs putatively originated from plasma B cells compared to circRNAs reported in human blood single-cell RNA sequencing datasets. The pre- and post-vaccination differences observed in the circRNA expression landscape in response to the SARS-CoV-2 BNT162b2 mRNA vaccine.
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Affiliation(s)
- Yu-Chen Liu
- Laboratory for Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, Osaka University, Japan; Center for Infectious Disease Education and Research (CiDER), OsakaUniversity, Osaka, Japan
| | - Masakazu Ishikawa
- Laboratory for Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, Osaka University, Japan; Center for Infectious Disease Education and Research (CiDER), OsakaUniversity, Osaka, Japan
| | - Shuhei Sakakibara
- Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Japan
| | - Mohamad Al Kadi
- Laboratory for Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, Osaka University, Japan; Center for Infectious Disease Education and Research (CiDER), OsakaUniversity, Osaka, Japan
| | - Daisuke Motooka
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Japan
| | - Yoko Naito
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Japan
| | - Shingo Ito
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Japan
| | - Yuko Imamura
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Japan
| | - Hisatake Matsumoto
- Center for Infectious Disease Education and Research (CiDER), OsakaUniversity, Osaka, Japan; Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Japan
| | - Fuminori Sugihara
- Center for Infectious Disease Education and Research (CiDER), OsakaUniversity, Osaka, Japan; Core Instrumentation Facility, Immunology Frontier Research Center and Research Institute for Microbial Disease, Osaka University, Japan
| | - Haruhiko Hirata
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Japan
| | - Hiroshi Ogura
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Japan
| | - Daisuke Okuzaki
- Laboratory for Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, Osaka University, Japan; Center for Infectious Disease Education and Research (CiDER), OsakaUniversity, Osaka, Japan; Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Japan; Institute for Open and Transdisciplinary Research Initiatives, OsakaUniversity, Osaka, Japan.
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Liu R, Zhou J, Chen X, Zhang J, Chen Q, Liu X, Yao K. Diagnostic and Therapeutic Advances of RNAs in Precision Medicine of Gastrointestinal Tumors. Biomedicines 2024; 13:47. [PMID: 39857631 PMCID: PMC11762367 DOI: 10.3390/biomedicines13010047] [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: 11/07/2024] [Revised: 12/01/2024] [Accepted: 12/10/2024] [Indexed: 01/27/2025] Open
Abstract
Gastrointestinal tumors present a significant challenge for precision medicine due to their complexity, necessitating the development of more specific diagnostic tools and therapeutic agents. Recent advances have positioned coding and non-coding RNAs as emerging biomarkers for these malignancies, detectable by liquid biopsies, and as innovative therapeutic agents. Many RNA-based therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotides (ASO), have entered clinical trials or are available on the market. This review provides a narrative examination of the diagnostic and therapeutic potential of RNA in gastrointestinal cancers, with an emphasis on its application in precision medicine. This review discusses the current challenges, such as drug resistance and tumor metastasis, and highlights how RNA molecules can be leveraged for targeted detection and treatment. Additionally, this review categorizes specific diagnostic biomarkers and RNA therapeutic targets based on tissue type, offering a comprehensive analysis of their role in advancing precision medicine for gastrointestinal tumors.
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Affiliation(s)
- Runhan Liu
- Department of Gastrointestinal Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, China
- School of Clinical Medicine, Henan University, Kaifeng 475004, China
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Jiaxin Zhou
- School of Life Sciences, Henan University, Kaifeng 475004, China
- School of Pharmacy, Henan University, Kaifeng 475004, China
| | - Xiaochen Chen
- School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Jie Zhang
- School of Life Sciences, Henan University, Kaifeng 475004, China
- School of Pharmacy, Henan University, Kaifeng 475004, China
| | - Qunzhi Chen
- School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Xiaoming Liu
- Department of Gastrointestinal Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, China
- School of Clinical Medicine, Henan University, Kaifeng 475004, China
| | - Kunhou Yao
- Department of Gastrointestinal Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, China
- School of Clinical Medicine, Henan University, Kaifeng 475004, China
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Li Y, Ma L, Li P. Circ_FNDC3B Promotes Cell Proliferation and Metastasis in Esophageal Squamous Cell Carcinoma via Regulating MAPK1 by Binding to miR-136-5p. Biochem Genet 2024; 62:3803-3820. [PMID: 38228844 DOI: 10.1007/s10528-023-10585-5] [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: 02/08/2023] [Accepted: 11/01/2023] [Indexed: 01/18/2024]
Abstract
A handful of circular RNAs (circRNAs) associated with cancer progression have been indicated in esophageal squamous cell carcinoma (ESCC). The current study aimed to investigate the functional mechanism of circular RNA Fibronectin type III domain containing 3B (circ_FNDC3B) in ESCC. Circ_FNDC3B, FNDC3B, microRNA-136-5p (miR-136-5p) and mitogen-activated protein kinase 1 (MAPK1) were examined via the quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) and colony formation assays. Transwell assay was performed to measure cell migration and invasion. Protein analysis was implemented by western blot. Cell apoptosis was assessed via flow cytometry. Target interaction was affirmed using dual-luciferase reporter assay. The function analysis of circ_FNDC3B in vivo was explored by xenograft models. The upregulation of circ_FNDC3B was detected in ESCC tissues and cells. Functionally, ESCC cell proliferation and metastasis were repressed but apoptosis was promoted by circ_FNDC3B knockdown. Besides, circ_FNDC3B silence inhibited ESCC progression through MAPK1 downregulation. Further target analysis identified miR-136-5p as a target of circ_FNDC3B and an upstream control of MAPK1. Additionally, the regulation of si-circ_FNDC3B in ESCC was also dependent on targeting miR-136-5p. Moreover, circ_FNDC3B targeted miR-136-5p to affect MAPK1 level. Tumorigenesis in vivo was also suppressed by downregulating circ_FNDC3B to regulate miR-136-5p/MAPK1 axis. Circ_FNDC3B downregulation impeded the development of ESCC via the mediation of miR-136-5p/MAPK1 axis. This report afforded a novel insight into the functional mechanism of circ_FNDC3B in ESCC.
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Affiliation(s)
- Yuwei Li
- Center of Medical Genetics, Northwest Women's and Children's Hospital, Xi'an, People's Republic of China
| | - Lieting Ma
- Department of Laboratory, First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China.
| | - Peng Li
- Department of Laboratory, First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China.
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Sharma A, Bansal C, Sharma KL, Kumar A. Circular RNA: The evolving potential in the disease world. World J Med Genet 2024; 12:93011. [DOI: 10.5496/wjmg.v12.i1.93011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 05/23/2024] [Accepted: 07/02/2024] [Indexed: 09/19/2024] Open
Abstract
Circular RNAs (circRNAs), a new star of noncoding RNAs, are a group of endogenous RNAs that form a covalently closed circle and occur widely in the mammalian genome. Most circRNAs are conserved throughout species and frequently show stage-specific expression during various stages of tissue development. CircRNAs were a mystery discovery, as they were initially believed to be a product of splicing errors; however, subsequent research has shown that circRNAs can perform various functions and help in the regulation of splicing and transcription, including playing a role as microRNA (miRNA) sponges. With the application of high throughput next-generation technologies, circRNA hotspots were discovered. There are emerging indications that explain the association of circRNAs with human diseases, like cancers, developmental disorders, and inflammation, and circRNAs may be a new potential biomarker for the diagnosis and treatment outcome of various diseases, including cancer. After the discoveries of miRNAs and long noncoding RNAs, circRNAs are now acting as a novel research entity of interest in the field of RNA disease biology. In this review, we aim to focus on major updates on the biogeny and metabolism of circRNAs, along with their possible/established roles in major human diseases.
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Affiliation(s)
- Aarti Sharma
- Department of Research, Mayo Clinic Arizona, Phoenix, AZ 85054, United States
| | - Cherry Bansal
- Department of Pathology, Dr. S Tantia Medical College, Hospital and Research Center, Sri Ganganagar 335002, Rajasthan, India
| | - Kiran Lata Sharma
- Department of Pathology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Shi R, Zhang L. Circ_0004771 regulates malignant biological behaviors and has clinical significance in oral squamous cell carcinoma. J Oral Pathol Med 2024; 53:502-510. [PMID: 38887835 DOI: 10.1111/jop.13566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 05/23/2024] [Accepted: 05/25/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND The incidence of oral squamous cell carcinoma (OSCC) is increasing, and more effective treatment protocols must rapidly be developed to prevent the death of patients and ensure favorable outcomes. CircRNAs are a unique class of noncoding ribonucleic acid (RNA) molecules unaffected by RNA exonucleases. CircRNAs have more stable expression than linear RNAs and are not readily degraded; therefore, they are the newest focus of RNA research. Here, we analyze the mechanism of hsa_circ_0004771 (circ_0004771) in OSCC to provide a clinical reference. METHODS Circ_0004771 expression was measured in peripheral blood, cancerous tissues and adjacent tissues of OSCC patients. Patients were followed up for 3 years. The diagnostic value of circ_0004771 for OSCC occurrence, prognosis, recurrence and survival was analyzed with receiver operating characteristic (ROC) curves. OSCC cells were lentivirally transduced with a circ_0004771-silencing or an empty vector to evaluate alterations in cell growth, invasion, and apoptosis. Apoptosis-related and epithelial-mesenchymal transition (EMT)-related protein expression was quantified. BALB/c nude mice were used for tumorigenesis experiments to evaluate tumor growth in vivo after silencing circ_0004771. RESULTS Circ_0004771 expression was higher in peripheral blood and cancerous tissue of OSCC patients than in control peripheral blood and paracancerous tissue, respectively, exhibiting excellent predictive value for OSCC occurrence, prognosis, recurrence and survival. Silencing circ_0004771 decreased the growth, invasiveness, and EMT capacity and increased the apoptosis of OCC cells. In mice implanted with OSCC cells transduced with the circ_0004771-silencing lentiviral vector, the tumor growth capacity was obviously decreased. CONCLUSION Silencing circ_0004771 inhibits the malignant growth of OSCC.
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Affiliation(s)
- Rongji Shi
- Department of Stomatology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lei Zhang
- Department of Stomatology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Lu P, Wang Y. RDGAN: Prediction of circRNA-Disease Associations via Resistance Distance and Graph Attention Network. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2024; 21:1445-1457. [PMID: 38787672 DOI: 10.1109/tcbb.2024.3402248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2024]
Abstract
As a series of single-stranded RNAs, circRNAs have been implicated in numerous diseases and can serve as valuable biomarkers for disease therapy and prevention. However, traditional biological experiments demand significant time and effort. Therefore, various computational methods have been proposed to address this limitation, but how to extract features more comprehensively remains a challenge that needs further attention in the future. In this study, we propose a unique approach to predict circRNA-disease associations based on resistance distance and graph attention network (RDGAN). First, the associations of circRNA and disease are obtained by fusing multiple databases, and resistance distance as a similarity matrix is used to further deal with the sparse of the similarity matrices. Then the circRNA-disease heterogeneous network is constructed based on the similiarity of circRNA-circRNA, disease-disease and the known circRNA-disease adjacency matric. Second, leveraging the three neural network modules-ResGatedGraphConv, GAT and MFConv-we gather node feature embeddings collected from the heterogeneous network. Subsequently, all the characteristics are supplied to the self-attention mechanism to predict new potential connections. Finally, our model obtains a remarkable AUC value of 0.9630 through five-fold cross-validation, surpassing the predictive performance of the other eight state-of-the-art models.
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Zhang L, Wang Y, Gao J, Zhou X, Huang M, Wang X, He Z. Non‑coding RNA: A promising diagnostic biomarker and therapeutic target for esophageal squamous cell carcinoma (Review). Oncol Lett 2024; 27:255. [PMID: 38646493 PMCID: PMC11027111 DOI: 10.3892/ol.2024.14388] [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: 11/04/2023] [Accepted: 03/22/2024] [Indexed: 04/23/2024] Open
Abstract
Esophageal cancer (EC) is a common form of malignant tumor in the digestive system that is classified into two types: Esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinoma. ESCC is known for its early onset of symptoms, which can be difficult to identify, as well as its rapid progression and tendency to develop drug resistance to chemotherapy and radiotherapy. These factors contribute to the high incidence of disease and low cure rate. Therefore, a diagnostic biomarker and therapeutic target need to be identified for ESCC. Non-coding RNAs (ncRNAs) are a class of molecules that are transcribed from DNA but do not encode proteins. Initially, ncRNAs were considered to be non-functional segments generated during transcription. However, with advancements in high-throughput sequencing technologies in recent years, ncRNAs have been associated with poor prognosis, drug resistance and progression of ESCC. The present study provides a comprehensive overview of the biogenesis, characteristics and functions of ncRNAs, particularly focusing on microRNA, long ncRNAs and circular RNAs. Furthermore, the ncRNAs that could potentially be used as diagnostic biomarkers and therapeutic targets for ESCC are summarized to highlight their application value and prospects in ESCC.
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Affiliation(s)
- Longze Zhang
- Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yanyang Wang
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Department of Cell Engineering Laboratory, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Jianmei Gao
- School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Xue Zhou
- Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Minglei Huang
- Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Xianyao Wang
- Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Zhixu He
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Department of Cell Engineering Laboratory, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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Qiu S, Zhang K, Chen S, Yin S. Circular RNA PRKCI (hsa_circ_0067934): a potential target in the pathogenesis of human malignancies. Front Oncol 2024; 14:1365032. [PMID: 38741779 PMCID: PMC11089142 DOI: 10.3389/fonc.2024.1365032] [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: 01/03/2024] [Accepted: 03/29/2024] [Indexed: 05/16/2024] Open
Abstract
Circular RNAs (circRNAs) are a new type of endogenous non-coding RNA formed by a covalent closed loop. CircRNAs are characterized by specificity, universality, conservation, and stability. They are abundant in eukaryotic cells and have biological regulatory roles at various transcriptional and post-transcriptional levels. The upregulation of circPRKCI has been observed in a variety of tumors and is directly related to the clinicopathological characteristics of tumors and prognosis. More importantly, circPRKCI can participate in the tumorigenesis, progression, recurrence, and metastasis of various tumors through many functional mechanisms, including the activation of signaling pathways, such as the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, and sponging of many microRNAs (miRNAs). This review summarizes the progress achieved in understanding the biological functions of circRNA PRKCI in various tumors. The goal is to inform the discovery of more functional mechanisms and new anticancer molecular targets.
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Affiliation(s)
- Shipei Qiu
- Department of General Surgery, Southeast University Affiliated Zhongda Hospital, Nanjing, China
| | - Kefan Zhang
- Department of Cardiothoracic Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Siyu Chen
- Department of Intensive Care Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Shuting Yin
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Wang L, Hong Z. Circular RNA circ-SLC7A5 Functions as a Competing Endogenous RNA to Impact Cell Biological Behaviors in Esophageal Squamous Cell Carcinoma (ESCC). Cell Biochem Biophys 2024; 82:139-151. [PMID: 37814151 DOI: 10.1007/s12013-023-01183-8] [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: 01/13/2023] [Accepted: 09/17/2023] [Indexed: 10/11/2023]
Abstract
BACKGROUND Circular RNAs (circRNAs) have profound effects on establishment and pathogenesis of esophageal squamous cell carcinoma (ESCC). Here, we defined whether circRNA solute carrier family 7 member 5 (circ-SLC7A5, also called hsa_circ_0040796) is causally involved in the pathogenesis of ESCC. METHODS Circ-SLC7A5, microRNA (miR)-874-3p and coronin-1C (CORO1C) expression levels were gauged by qRT-PCR or immunoblotting. Cell functional phenotypes were tested by colony formation, EdU, flow cytometry, transwell and wound-healing assays. RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were applied to ascertained circ-SLC7A5/miR-874-3p and miR-874-3p/CORO1C relationships. RESULTS Circ-SLC7A5 was highly expressed in human ESCC. Circ-SLC7A5 depletion impaired cell growth, migration, invasiveness, and promoted apoptosis. Circ-SLC7A5 knockdown diminished ESCC cell tumorigenicity. Mechanistically, circ-SLC7A5 contained a binding site for miR-874-3p. Also, miR-874-3p was responsible for circ-SLC7A5's function in ESCC cells. CORO1C was a direct miR-874-3p target. Circ-SLC7A5 functioned as a competing endogenous RNA (ceRNA) to control CORO1C by competing for shared miR-874-3p. Furthermore, CORO1C knockdown phenocopied miR-874-3p overexpression in impacting the biological behaviors of ESCC cells. CONCLUSION These findings identify circ-SLC7A5 as a crucial modulator of ESCC cells and establish a novel circ-SLC7A5/miR-874-3p/CORO1C ceRNA network in ESCC.
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Affiliation(s)
- Lei Wang
- Department of Cardiothoracic Surgery, Tongde Hospital of Zhejiang Province, Hangzhou City, Zhejiang Province, China
| | - Zhipeng Hong
- Department of Thoracic Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming City, Yunnan Province, China.
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Wu J, Wang Y, Cheng Y, Cheng L, Zhang L. Comprehensive landscape and future perspectives of non-coding RNAs in esophageal squamous cell carcinoma, a bibliometric analysis from 2008 to 2023. Pathol Oncol Res 2024; 30:1611595. [PMID: 38450329 PMCID: PMC10915033 DOI: 10.3389/pore.2024.1611595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 02/07/2024] [Indexed: 03/08/2024]
Abstract
Objectives: Summarize the progress and hot topic evolution of non-coding RNAs (ncRNAs) research in esophageal squamous cell carcinoma (ESCC) in recent years and predict future research directions. Methods: Relevant articles from the Web of Science until 31 October 2023 were obtained. Bibliometric analysis of included articles was performed using software (VOSviewer, CiteSpace, and Bibliometrix). The volume and citation of publications, as well as the country, institution, author, journal, keywords of the articles were used as variables to analyze the research trends and hot spot evolution. Results: 1,118 literature from 2008 to 2023 were retrieved from database, with 25 countries/regions, 793 institutions, 5,426 authors, 261 journals involved. Global cooperation was centered on China, Japan, and the United States. Zhengzhou University, an institution from China, had the highest publication. The most prolific author was Guo Wei, and the most prolific journal was Oncology Letters. Analysis of keywords revealed that the research in this field revolved around the role of ncRNAs in the occurrence, development, diagnosis, treatment, and prognosis of ESCC, mainly including micro RNAs, long non-coding RNAs, and then circular RNAs. Conclusion: Overall, research on ncRNAs in ESCC remains strong. Previous research has mainly focused on the basic research, with a focus on the mechanism of ncRNAs in the occurrence, development, diagnosis, treatment, and prognosis of ESCC. Combining current research with emerging disciplines to further explore its mechanisms of action or shifting the focus of research from preclinical research to clinical research based on diagnosis, treatment, and prognosis, will be the main breakthrough in this field in the future.
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Affiliation(s)
- Jiaxin Wu
- Graduate School, Chengdu Medical College, Chengdu, China
| | - Yuanying Wang
- Graduate School, Chengdu Medical College, Chengdu, China
| | - Yi Cheng
- Department of Radiology, People’s Hospital of Lushan County, Ya’an, China
| | - Li Cheng
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, China
| | - Lushun Zhang
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, China
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Du L, Yang J, Qin S, Ding S, Guo Y, Wang J. Appraising the value of CircRNAs for the diagnosis and prognosis of esophageal squamous cell cancer: An updated meta-analysis. Pathol Res Pract 2024; 254:155074. [PMID: 38246036 DOI: 10.1016/j.prp.2023.155074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024]
Abstract
OBJECTIVE The purpose of this study was to thoroughly assess the relevance of circular RNAs (circRNAs) in the diagnosis and prognosis of esophageal squamous cell carcinoma (ESCC)， and design a systematic review and meta-analysis. METHODS Using Stata 14.0 software, a meta-analysis was carried out by looking for pertinent studies up to February 20, 2023, in the online databases PubMed, Embase, Web of Science, and CNKI. The clinicopathologic and prognostic data were evaluated using the combined advantage ratio (OR) and combined hazard ratio (HR), respectively. The threshold effects and publication bias were quantified using Spearman's correlation and the Deeks funnel plot asymmetry tests, respectively. RESULTS A total of 36 pertinent studies with a literature quality score of 7 or above were included in this study. Of them, 22 papers dealt with clinicopathological characterization, 15 dealt with prognostic analysis, and 13 dealt with diagnostic analysis. The findings demonstrated that high expression of upregulated circRNAs was associated with worse clinicopathological features (tumor size: OR=3.61, 95% CI:1.45-5.78; TNM stage: OR=2.12, 95% CI:1.41-2.83; lymph node metastasis: OR=2.87, 95% CI:1.67-4.07) and worse OS (HR=1.49, 95% CI:1.26-1.77). High downregulated circRNAs expression was linked to improved clinicopathologic characteristics (TNM staging: OR=0.35, 95% CI:0.13- 0.95) and longer survival (HR=0.48, 95% CI:0.27-0.84); combined sensitivity was 0.77 (95% CI: 0.71-0.82), specificity was 0.80 (95% CI:0.74-0.86), and area under the subject operating characteristic curve (AUC) was 0.86 (95% CI:0.82- 0.88). CONCLUSION CircRNAs are useful for ESCC patient diagnosis and prognosis, and they are anticipated to be unique potential biomarkers for ESCC clinical diagnosis.
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Affiliation(s)
- Lihong Du
- Changzhi Medical College Affiliated Heping Hospital, Changzhi, Shanxi Province, 046000, China; Department of Pathology, Changzhi Medical College, Changzhi, Shanxi Province 046000, China; First Clinical College of Changzhi Medical College, Changzhi, Shanxi Province 046000, China
| | - Jianzhou Yang
- Department of Public Health and Preventive Medicine, Changzhi Medical College, Changzhi, Shanxi Province 046000, China
| | - Shaoze Qin
- First Clinical College of Changzhi Medical College, Changzhi, Shanxi Province 046000, China
| | - Shuyu Ding
- First Clinical College of Changzhi Medical College, Changzhi, Shanxi Province 046000, China
| | - Yuwei Guo
- First Clinical College of Changzhi Medical College, Changzhi, Shanxi Province 046000, China
| | - Jinsheng Wang
- Changzhi Medical College Affiliated Heping Hospital, Changzhi, Shanxi Province, 046000, China; Department of Pathology, Changzhi Medical College, Changzhi, Shanxi Province 046000, China; Key Laboratory of Shanxi Provincial Health Commission, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi Province 046000, China.
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12
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Wang J, Yao W, Li J, Zhang Q, Wei L. Circ_0001944 depletion inhibits glycolysis and esophageal cancer progression by binding to miR-338-5p to reduce PDK1 expression. J Bioenerg Biomembr 2024; 56:73-85. [PMID: 37999809 DOI: 10.1007/s10863-023-09988-1] [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: 06/28/2023] [Accepted: 10/05/2023] [Indexed: 11/25/2023]
Abstract
Circular RNA (circRNA) plays multiple roles in the development of esophageal cancer (EC). Herein, we investigate the function of circ_0001944 in EC progression and the related mechanism. Expression of circ_0001944, microRNA-338-5p (miR-338-5p), pyruvate dehydrogenase kinase 1 (PDK1), E-cadherin and N-cadherin was analyzed by quantitative real-time polymerase chain reaction, Western blotting or immunohistochemistry assay. Cell viability, proliferation, apoptosis, invasion and migration were investigated by cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell invasion and wound-healing assays, respectively. Glucose consumption was detected by Glucose Assay Kit. Lactate production was analyzed by Lactate Assay Kit. ATP/ADP ratio was determined by ADP/ATP ratio Assay Kit. The associations among circ_0001944, miR-338-5p and PDK1 were identified by dual-luciferase reporter and RNA pull-down assays. Xenograft mouse model assay was used to explore the role of circ_0001944 on tumor tumorigenesis in vivo. Circ_0001944 and PDK1 expression were significantly upregulated, while miR-338-5p was downregulated in EC tissues and cells in contrast with normal esophageal tissues and cells. Circ_0001944 knockdown inhibited EC cell proliferation, invasion, migration and glycolysis but induced apoptosis. Meanwhile, circ_0001944 depletion suppressed tumor tumorigenesis in vivo. Mechanistically, circ_0001944 bound to miR-338-5p, and miR-338-5p targeted PDK1. In addition, miR-338-5p inhibitors attenuated circ_0001944 depletion-induced effects in EC cells. The regulation of miR-338-5p on EC progression involved the downregulation of PDK1. Further, circ_0001944 controlled PDK1 expression through miR-338-5p. Circ_0001944 knockdown inhibited EC development and glycolysis by regulating the miR-338-5p/PDK1 pathway, providing a promising target for EC therapy.
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Affiliation(s)
- Jianjun Wang
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, No. 7, Weiwu Road, Jinshui District, Zhengzhou City, Henan, 450003, China
| | - Wenjian Yao
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, No. 7, Weiwu Road, Jinshui District, Zhengzhou City, Henan, 450003, China
| | - Jiwei Li
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, No. 7, Weiwu Road, Jinshui District, Zhengzhou City, Henan, 450003, China
| | - Quan Zhang
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, No. 7, Weiwu Road, Jinshui District, Zhengzhou City, Henan, 450003, China
| | - Li Wei
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, No. 7, Weiwu Road, Jinshui District, Zhengzhou City, Henan, 450003, China.
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13
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Xu T, Hu Y, Zhao Y, Qi Y, Zhang S, Li P. Hsa_circ_0046534 accelerates esophageal squamous cell carcinoma proliferation and metastasis via regulating MMP2 expression by sponging miR-339-5p. Cell Signal 2023; 112:110906. [PMID: 37748540 DOI: 10.1016/j.cellsig.2023.110906] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/20/2023] [Accepted: 09/22/2023] [Indexed: 09/27/2023]
Abstract
Esophageal cancer is one of the most malignant gastrointestinal malignancies. Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer in China. In recent years, with developments in basic medicine, it has been demonstrated that the abnormal expression of circular RNA (circRNA) plays an important role in the progression and prognosis of ESCC. This study explored the role and downstream molecular mechanisms of circ_0046534 in ESCC. We identified circ_0046534, which was found to be highly expressed in ESCC tissues and cells. Moreover, the downregulation of circ_0046534 inhibited the proliferation, migration and invasion of ESCC cells and the growth and metastasis of ESCC tumours in vivo. Dual-luciferase reporter assays showed that circ_0046534 sponged miR-339-5p and inhibited the expression of miR-339-5p. Furthermore, MMP2 was identified to be a direct target of miR-339-5p through bioinformatics analysis. In addition, the knockdown of circ_0046534 inhibited the expression of the downstream target gene matrix metalloproteinase 2 (MMP2) by releasing the adsorption of miR-339-5p. Taken together, this study demonstrated that silencing circ_0046534 inhibited the growth and metastasis of ESCC through the miR-339-5p/MMP2 pathway. Circ_0046534 is expected to serve as a new biomarker and target for ESCC and provide a new direction for its diagnosis and treatment.
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Affiliation(s)
- Tingting Xu
- Department of Pathophysiology, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; Department of Pathology, Henan Provincial People's Hospital, Zhengzhou 450001, China
| | - Yanglin Hu
- Department of Pathophysiology, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yanyan Zhao
- Department of Pathophysiology, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yanan Qi
- Department of Pathophysiology, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Shanfeng Zhang
- Department of Basic Medical Experimental Center, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Pei Li
- Department of Pathophysiology, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; Department of Basic Medical Experimental Center, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
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14
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Luo Q, Li J, Miao H, Su S, Chen Y, Xu C, Zhao C, Huang J, Ling K, Lin C, Yan H, Zhang S. circSSPO boosts growth of esophageal squamous cell carcinoma through upregulation of micrRNA-6820-5p-mediated KLK8 and PKD1 expression. Cell Biol Toxicol 2023; 39:3219-3234. [PMID: 37812360 DOI: 10.1007/s10565-023-09828-3] [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: 01/31/2023] [Accepted: 08/13/2023] [Indexed: 10/10/2023]
Abstract
Investigation on a competitive endogenous RNA (ceRNA) network attracted lots of attention due its function in cancer regulation. Here, we probed into the possible molecular mechanism of circSSPO/microRNA-6820-5p (miR-6820-5p)/kallikrein-related peptidase 8 (KLK8)/PKD1 network in the esophageal squamous cell carcinoma (ESCC). Following whole-transcriptome sequencing and differential analysis in collected ESCC tissue samples, circRNA-miRNA-mRNA regulatory network affecting ESCC was investigated. After interaction measurement among circSSPO/miR-6820-5p/KLK8/PKD1, their regulatory roles in ESCC cell functions in vitro and xenograft tumor growth and lung metastasis in vivo were analyzed. The bioinformatics prediction and sequencing results screened that circSSPO, miR-6820-5p, KLK8, and PKD1 were associated with ESCC development. In ESCC, miR-6820-5p was expressed at very low levels, while circSSPO, KLK8, and PKD1 were highly expressed. In vitro cell experiments further proved that circSSPO competitively inhibited miR-6820-5p to induce ESCC cell malignant properties. Moreover, knockdown of KLK8 or PKD1 inhibited ESCC cell malignant properties. circSSPO also promoted the tumorigenic and metastasis of ESCC through the upregulation of KLK8 and PKD1 expression in vivo. We found that circSSPO was an oncogenic circRNA that was significantly abundant in ESCC tissues and circSSPO exhibited an oncogenic activity in ESCC by elevating expression of KLK8 and PKD1 through suppressing miR-6820-5p expression.
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Affiliation(s)
- Qianhua Luo
- Clinical Pharmacy Research Center, Shantou University Medical College, Shantou, 515041, People's Republic of China
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396, Tongfuzhong Road, Haizhu District, Guangzhou, 510220, People's Republic of China
| | - Junzheng Li
- Department of Otolaryngology-Head and Neck Surgery, Zhujiang Hospital of Southern Medical University, Guangzhou, 510280, China
| | - Haixiong Miao
- Department of Orthopaedics, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Guangzhou, 510220, People's Republic of China
| | - Siman Su
- Clinical Pharmacy Research Center, Shantou University Medical College, Shantou, 515041, People's Republic of China
| | - Yun Chen
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396, Tongfuzhong Road, Haizhu District, Guangzhou, 510220, People's Republic of China
| | - Chengcheng Xu
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396, Tongfuzhong Road, Haizhu District, Guangzhou, 510220, People's Republic of China
| | - Chengkuan Zhao
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396, Tongfuzhong Road, Haizhu District, Guangzhou, 510220, People's Republic of China
| | - Jianxiang Huang
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396, Tongfuzhong Road, Haizhu District, Guangzhou, 510220, People's Republic of China
| | - Kai Ling
- Clinical Pharmacy Research Center, Shantou University Medical College, Shantou, 515041, People's Republic of China
| | - Chaoxian Lin
- Clinical Pharmacy Research Center, Shantou University Medical College, Shantou, 515041, People's Republic of China.
- Shantou Chaonan Minsheng Hospital, Shantou, 515144, People's Republic of China.
| | - Hongfei Yan
- Department of Pathology, Cancer Hospital of Shantou University Medical College, Shantou, 515031, People's Republic of China.
| | - Shuyao Zhang
- Clinical Pharmacy Research Center, Shantou University Medical College, Shantou, 515041, People's Republic of China.
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396, Tongfuzhong Road, Haizhu District, Guangzhou, 510220, People's Republic of China.
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15
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Gao X, Yu S, Liu S, Zhang S, Sha X, Sun D, Jiang X. Circular RNA nuclear receptor interacting protein 1 promoted biliary tract cancer epithelial-mesenchymal transition and stemness by regulating the miR-515-5p/AKT2 axis and PI3K/AKT/mTOR signaling pathway. ENVIRONMENTAL TOXICOLOGY 2023; 38:2632-2644. [PMID: 37466171 DOI: 10.1002/tox.23898] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/17/2023] [Accepted: 06/29/2023] [Indexed: 07/20/2023]
Abstract
Biliary tract cancer (BTC) is a devastating malignancy that is notoriously difficult to diagnose and is associated with high mortality. Circular RNA (circRNA) is a class of endogenous non-coding RNA which has been regarded as the key regulator of tumor initiation and progression, including BTC. Circular RNA nuclear receptor interacting protein 1 (circ_NRIP1), as a circular RNA, is abnormally expressed in many human tumors and exhibits diverse functions in cancer progression. However, its biological significance in BTC has not been thoroughly investigated. In this research, we elucidated that circ_NRIP1 was notably overexpressed in both BTC tissues and cells. We further established a correlation between circ_NRIP1 expression and clinicopathological features in BTC patients, highlighting its clinical relevance. Through functional assays, we observed that knockdown of circ_NRIP1 significantly inhibited tumor cell proliferation, invasion, stemness maintenance, and epithelial-mesenchymal transition, indicating its active involvement in promoting BTC progression. Additionally, it attenuated growth of xenograft and metastasis models. Mechanically, we revealed that circ_NRIP1 served as the competing endogenous RNA to sequester miR-515-5p through complementary base pairing mechanism, thereby upregulated AKT2 expression and indirectly activated PI3K/AKT/mTOR signaling pathway. Generally, targeting the circ_NRIP1/miR-515-5p/AKT2 axis and aberrant activation of the PI3K/AKT/mTOR pathway may hold promising therapeutic strategies for BTC. Our research contributes to a better understanding of the underlying biological basis of BTC and paves the way for the development of innovative treatment approaches.
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Affiliation(s)
- Xin Gao
- Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shaobo Yu
- Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Sidi Liu
- Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Siyuan Zhang
- Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiangjun Sha
- Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dongsheng Sun
- Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xingming Jiang
- Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
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16
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Gao X, Yu Y, Wang H, Liu G, Sun X, Wang Z, Jiang X. Emerging roles of circ_NRIP1 in tumor development and cancer therapy (Review). Oncol Lett 2023; 26:321. [PMID: 37332333 PMCID: PMC10272956 DOI: 10.3892/ol.2023.13907] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 05/15/2023] [Indexed: 06/20/2023] Open
Abstract
Circular RNA (circRNA) is a class of endogenous non-coding RNA, a type of single-stranded covalently closed RNA molecule formed by alternative splicing of exons or introns. Previous studies have demonstrated that circRNA participates in modulating biological processes such as cell proliferation, differentiation and apoptosis, and plays key roles in tumor occurrence and development. CircRNA nuclear receptor interacting protein 1 (circ_NRIP1), a form of circRNA, is abnormally expressed in certain human tumor types. It is present at a higher abundance compared with cognate linear transcripts and can regulate malignant biological behaviors such as tumor proliferation, invasion and migration, revealing a currently unexplored frontier in cancer progression. The present review presents a pattern of circ_NRIP1 expression in various malignant tumor types and highlights its significance in cancer development, in addition to its potential as a disease indicator or future therapeutic agent.
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Affiliation(s)
- Xin Gao
- General Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Yongbo Yu
- General Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Haicun Wang
- General Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Guanglin Liu
- General Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Xinyu Sun
- General Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Zhidong Wang
- General Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Xingming Jiang
- General Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
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17
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Li X, Lu J, Liu L, Li F, Xu T, Chen L, Yan Z, Li Y, Guo W. FOXK1 regulates malignant progression and radiosensitivity through direct transcriptional activation of CDC25A and CDK4 in esophageal squamous cell carcinoma. Sci Rep 2023; 13:7737. [PMID: 37173384 PMCID: PMC10182098 DOI: 10.1038/s41598-023-34979-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 05/10/2023] [Indexed: 05/15/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a serious malignancy with poor prognosis, necessitating identification of oncogenic mechanisms for novel therapeutic strategies. Recent studies have highlighted the significance of the transcription factor forkhead box K1 (FOXK1) in diverse biological processes and carcinogenesis of multiple malignancies, including ESCC. However, the molecular pathways underlying FOXK1's role in ESCC progression are not fully understood, and its potential role in radiosensitivity remains unclear. Here, we aimed to elucidate the function of FOXK1 in ESCC and explore the underlying mechanisms. Elevated FOXK1 expression levels were found in ESCC cells and tissues, positively correlated with TNM stage, invasion depth, and lymph node metastasis. FOXK1 markedly enhanced the proliferative, migratory and invasive capacities of ESCC cells. Furthermore, silencing FOXK1 resulted in heightened radiosensitivity by impeding DNA damage repair, inducing G1 arrest, and promoting apoptosis. Subsequent studies demonstrated that FOXK1 directly bound to the promoter regions of CDC25A and CDK4, thereby activating their transcription in ESCC cells. Moreover, the biological effects mediated by FOXK1 overexpression could be reversed by knockdown of either CDC25A or CDK4. Collectively, FOXK1, along with its downstream target genes CDC25A and CDK4, may serve as a promising set of therapeutic and radiosensitizing targets for ESCC.
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Affiliation(s)
- Xiaoxu Li
- Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Juntao Lu
- Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China
| | - Lei Liu
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Fei Li
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Tongxin Xu
- Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China
| | - Liying Chen
- Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China
| | - Zhaoyang Yan
- Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China
| | - Yan Li
- Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China
| | - Wei Guo
- Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China.
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18
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Ji X, Lv C, Huang J, Dong W, Sun W, Zhang H. ALKBH5-induced circular RNA NRIP1 promotes glycolysis in thyroid cancer cells by targeting PKM2. Cancer Sci 2023. [PMID: 36851875 DOI: 10.1111/cas.15772] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/14/2023] [Accepted: 02/21/2023] [Indexed: 03/01/2023] Open
Abstract
Although circular RNAs (circRNAs) are involved in cell proliferation, differentiation, apoptosis, and invasion, the underlying regulatory mechanisms of circRNAs in thyroid cancer have not been fully elucidated. This article aimed to study the role of circRNA regulated by N6-methyladenosine modification in papillary thyroid cancer (PTC). Quantitative real-time PCR, western blotting, and immunohistochemistry were used to investigate the expressions of circRNA nuclear receptor-interacting protein 1 (circNRIP1) in PTC tissues and adjacent noncancerous thyroid tissues. In vitro and in vivo assays were carried out to assess the effects of circNRIP1 on PTC glycolysis and growth. The N6-methyladenosine mechanisms of circNRIP1 were evaluated by methylated RNA immunoprecipitation sequencing, luciferase reporter gene, and RNA stability assays. Results showed that circNRIP1 levels were significantly upregulated in PTC tissues. Furthermore, elevated circNRIP1 levels in PTC patients were correlated with high tumor lymph node metastasis stage and larger tumor sizes. Functionally, circNRIP1 significantly promoted glycolysis, PTC cell proliferation in vitro, and tumorigenesis in vivo. Mechanistically, circNRIP1 acted as a sponge for microRNA (miR)-541-5p and miR-3064-5p and jointly upregulated pyruvate kinase M2 (PKM2) expression. Knockdown of m6 A demethylase α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) significantly enhanced circNRIP1 m6 A modification and upregulated its expression. These results show that ALKBH5 knockdown upregulates circNRIP1, thus promoting glycolysis in PTC cells. Therefore, circNRIP1 can be a prognostic biomarker and therapeutic target for PTC by acting as a sponge for oncogenic miR-541-5p and miR-3064-5p to upregulate PKM2 expression.
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Affiliation(s)
- Xiaoyu Ji
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Chengzhou Lv
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Jiapeng Huang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Wenwu Dong
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Wei Sun
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Hao Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
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19
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Zhao L, Yu L, Wang X, He J, Zhu X, Zhang R, Yang A. Mechanisms of function and clinical potential of exosomes in esophageal squamous cell carcinoma. Cancer Lett 2023; 553:215993. [PMID: 36328162 DOI: 10.1016/j.canlet.2022.215993] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/05/2022] [Accepted: 10/27/2022] [Indexed: 11/20/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) remains one of the most lethal and widespread malignancies in China. Exosomes, a subset of tiny extracellular vesicles manufactured by all cells and present in all body fluids, contribute to intercellular communication and have become a focus of the search for new therapeutic strategies for cancer. A number of global analyses of exosome-mediated functions and regulatory mechanism in malignant diseases have recently been reported. There is extensive evidence that exosomes can be used as diagnostic and prognostic markers for cancer. However, our understanding of their clinical value and mechanisms of action in ESCC is still limited and has not been systematically reviewed. Here, we review current research specifically focused on the functions and mechanisms of action of ESCC tumor-derived exosomes and non-ESCC-derived exosomes in ESCC progression and describe opportunities and challenges in the clinical translation of exosomes.
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Affiliation(s)
- Lijun Zhao
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Lili Yu
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Xiangpeng Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Jangtao He
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Xiaofei Zhu
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
| | - Rui Zhang
- The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Angang Yang
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China; The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
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20
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Xu P, Wang L, Liu Q, Gao P, Hu F, Xie X, Jiang L, Bi R, Ding F, Yang Q, Xiao H. The abnormal expression of circ-ARAP2 promotes ESCC progression through regulating miR-761/FOXM1 axis-mediated stemness and the endothelial-mesenchymal transition. Lab Invest 2022; 20:318. [PMID: 35842667 PMCID: PMC9287963 DOI: 10.1186/s12967-022-03507-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 06/24/2022] [Indexed: 12/15/2022]
Abstract
Circular RNAs (circRNAs) belong to a novel class of noncoding RNA that gained more attention in human cancer pathogenesis. The role of circRNA in esophageal squamous cell carcinoma (ESCC) is largely unclear. Present investigation was to characterize new circRNAs regulating ESCC progression and explore the regulatory mechanisms in ESCC. In this study, circRNAs differentially expressed in ESCC and adjacent normal tissues were characterized via high-throughput sequencing. Then the differentially expressed circRNA between ESCC and adjacent normal tissues were investigated using Rt-qPCR. The role of circ-ARAP2 expression on tumor progression were detected in both in vivo and in vitro. Luciferase reporter assays were used to identify the relationships among circ-ARAP2, microRNA (miR)-761 and the cell cycle regulator Forkhead Box M1 (FOXM1). The result of the expression profile analyses regarding human circRNAs in ESCC demonstrated that circ-ARAP2 was up-regulated significantly in both ESCC tissues and cell lines. Downregulation circ-ARAP2 suppressed ESCC proliferation, tumor growth and metastasis in both in vivo and in vitro. The data also suggested that miR-761 and FOXM1 were circ-ARAP2 downstream targets which were confirmed through luciferase reporter analysis. Overexpression of FOXM1 or inhibiting miR-761 restored ESCC cell proliferation and invasion ability after silencing circ-ARAP2. The study also found that circ-ARAP2 influenced the endothelial-mesenchymal transition (EMT) and cancer stem cells differently by regulating miR-761/FOXM1. In one word, the results demonstrated that abnormal circ-ARAP2 expression promoted ESCC progression by regulating miR-761/FOXM1 axis-mediated stemness and EMT.
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Affiliation(s)
- Pei Xu
- Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Lei Wang
- Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Qingtao Liu
- Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Pengkai Gao
- Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Fengqing Hu
- Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Xiao Xie
- Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Lianyong Jiang
- Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Rui Bi
- Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Fangbao Ding
- Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China.
| | - Qi Yang
- Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China.
| | - Haibo Xiao
- Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China.
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21
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Ju C, He J, Wang C, Sheng J, Jia J, Du D, Li H, Zhou M, He F. Current advances and future perspectives on the functional roles and clinical implications of circular RNAs in esophageal squamous cell carcinoma: more influential than expected. Biomark Res 2022; 10:41. [PMID: 35672804 PMCID: PMC9171998 DOI: 10.1186/s40364-022-00388-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/29/2022] [Indexed: 11/24/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive gastrointestinal cancers with high incidence and mortality. Therefore, it is necessary to identify novel sensitive and specific biomarkers for ESCC detection and treatment. Circular RNAs (circRNAs) are a type of noncoding RNAs featured by their covalently closed circular structure. This special structure makes circRNAs more stable in mammalian cells, coupled with their great abundance and tissue specificity, suggesting circRNAs may present enormous potential to be explored as valuable prognostic and diagnostic biomarkers for tumor. Mounting studies verified the critical roles of circRNAs in regulating ESCC cells malignant behaviors. Here, we summarized the current progresses in a handful of aberrantly expressed circRNAs, and elucidated their biological function and clinical significance in ESCC, and introduced a series of databases for circRNA research. With the improved advancement in high-throughput sequencing and bioinformatics technique, new frontiers of circRNAs will pave the path for the development of precision treatment in ESCC.
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Affiliation(s)
- Chenxi Ju
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jing He
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Chang Wang
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jinxiu Sheng
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jinlin Jia
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Dan Du
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hongle Li
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, China.
| | - Mingxia Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Fucheng He
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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22
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Feng H, Wang D, Liu J, Zou L, Xu S, Liang Z, Qin G. Diagnostic and prognostic value of circRNAs expression in head and neck squamous cell carcinoma: A meta-analysis. J Clin Lab Anal 2022; 36:e24496. [PMID: 35595945 PMCID: PMC9280010 DOI: 10.1002/jcla.24496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 04/16/2022] [Accepted: 04/27/2022] [Indexed: 12/22/2022] Open
Abstract
Background Circular RNAs (circRNAs) have been found to have potential biological applications against tumors in humans. This study aimed to evaluate the diagnostic, prognostic, and clinicopathological value of circRNAs in head and neck squamous cell carcinoma (HNSCC). Methods The PubMed, Web of Science, EMBASE, and the Cochrane Library were comprehensively searched for the relevant studies before October 20, 2021. Statistical analysis was performed based on STATA 15.0, Meta‐DiSc 1.4, and RevMan 5.3 software. Results A total of 55 reports regarding 56 kinds of circRNA were studied in this meta‐analysis, including 23, 38, and 26 articles on diagnosis, prognosis, and clinicopathological features, respectively. The pooled sensitivity, specificity, and area under the curve (AUC) of the summary receiver‐operating characteristic curve (SROC) were 0.78, 0.84, and 0.87, respectively. Besides, the upregulation of oncogenic circRNAs was significantly associated with poorer overall survival (OS) (HR=2.25, p < 0.05) and disease‐free interval (DFS) (HR=1.92, p < 0.05). In contrast, the elevated expression of tumor suppressor circRNAs was associated with a favorable prognosis (HR=0.50, p < 0.05). In addition, the high expression of oncogenic circRNAs was associated with the tumor size (OR=3.59, p < 0.05), degree of differentiation (OR=1.89, p < 0.05), TNM stage (OR=2.35, p < 0.05), lymph node metastasis (OR=1.85, p < 0.05), and distant metastasis (OR=3.42, p < 0.05). Moreover, the expression of tumor suppressor circRNAs was associated with improved clinicopathological features (lymph node metastasis: OR=0.25, p < 0.05). Conclusions CircRNAs could serve as potential predictive indicators and be useful for the diagnosis, prognosis, and identification of clinicopathological features in HNSCC.
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Affiliation(s)
- Huajun Feng
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Dingting Wang
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jinping Liu
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Longfei Zou
- Department of Orthopedic Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Shengen Xu
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zhuoping Liang
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Gang Qin
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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23
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CircNRIP1 Exerts Oncogenic Functions in Papillary Thyroid Carcinoma by Sponging miR-653-5p and Regulating PBX3 Expression. JOURNAL OF ONCOLOGY 2022; 2022:2081501. [PMID: 35646117 PMCID: PMC9135513 DOI: 10.1155/2022/2081501] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/18/2022] [Accepted: 04/22/2022] [Indexed: 12/04/2022]
Abstract
Background Circular RNA circ_0004771 (termed circNRIP1) was identified by RNA-Seq previously and was elevated in papillary thyroid carcinoma (PTC) tissues. A series of studies also showed that circNRIP1 was upregulated in some tumors and could promote the malignant progression of tumors. This research intended to focus on the role of circNRIP1 in PTC progression and explore the mechanisms underlying circNRIP1 functions. Methods RT-PCR or western blot determined circNRIP1, miR-653-5p, and pre-B-cell leukemia homeobox 3 (PBX3) expression. EdU, CCK-8, Tunel, and transwell assays determined cell proliferation, apoptosis, invasion, and migration, respectively. Luciferase reporter assay, RNA immunoprecipitation (RIP), and RNA pull down assays clarified the target relation between miR-653-5p and circNRIP1 or PBX3. Xenograft models were applied to explore the role of circNRIP1 in vivo. Results circNRIP1 significantly increased in PTC tissues and PTC cell lines than that in normal ones. Higher circNRIP1 expression was associated with the TNM stage and poorer overall survival. circNRIP1 knockdown attenuated the malignant progression of PTC, specifically by inhibiting proliferation and invasion/migration and promoting apoptosis. circNRIP1 was a miR-653-5p sponge; miR-653-5p knockdown reversed the suppressive role of circNRIP1 silence in PTC progression. PBX3, a target of miR-653-5p, was positively medicated through circNRIP1 via competitively sponging miR-653-5p. Knockdown of circNRIP1 attenuated the PTC tumor progression via miR-653-5p/PBX3 axis. Conclusion Silencing of circNRIP1 suppressed PTC development via miR-653-5p elevation and PBX3 reduction, providing a novel perspective for understanding PTC pathogenesis.
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24
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Weidle UH, Sela T, Brinkmann U, Niewoehner J. Circular RNAs With Efficacy in Preclinical In Vitro and In Vivo Models of Esophageal Squamous Cell Carcinoma. Cancer Genomics Proteomics 2022; 19:283-298. [PMID: 35430563 DOI: 10.21873/cgp.20320] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/02/2022] [Accepted: 03/03/2022] [Indexed: 02/06/2023] Open
Abstract
Esophageal cancer is associated with a dismal prognosis. The armamentarium of approved drugs is focused on chemotherapy with modest therapeutic benefit. Recently, checkpoint inhibitory monoclonal antibody Pembrolizumab was approved. In order to identify new targets and modalities for the treatment of esophagus squamous cell carcinoma (ESCC) we searched the literature for circRNAs involved in the pathogenesis of ESCC. We identified two down-regulated and 17 up-regulated circRNAs as well as a synthetic circRNA with efficacy in preclinical in vivo systems. Down-regulated circRNAs sponge microRNAs directed against tumor suppressor genes. Up-regulated circRNAs sponge microRNAs directed against mRNAs, which encode proteins with pro-tumoral functions. We discuss issues such as reconstitution of down-regulated circRNAs and inhibition of up-regulated circRNAs with short interfering RNA (siRNA)- related entities. Also, we address druggability issues of the identified targets.
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Affiliation(s)
- Ulrich H Weidle
- Roche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany
| | - Tatjana Sela
- Roche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany
| | - Ulrich Brinkmann
- Roche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany
| | - Jens Niewoehner
- Roche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany
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25
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Wang J, Yao W, Li J, Zhang Q, Wei L. Identification of a novel circ_0001946/miR-1290/SOX6 ceRNA network in esophageal squamous cell cancer. Thorac Cancer 2022; 13:1299-1310. [PMID: 35411716 PMCID: PMC9058308 DOI: 10.1111/1759-7714.14381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 02/23/2022] [Indexed: 12/24/2022] Open
Abstract
Background Circular RNAs (circRNAs) can function as competing endogenous RNAs (ceRNAs) to impact the development of esophageal squamous cell cancer (ESCC). Human circ_0001946 has been identified as a potential anticancer factor in ESCC, yet our understanding of its molecular basis remains limited. Methods Circ_0001946, microRNA (miR)‐1290 and SRY‐box transcription factor 6 (SOX6) were quantified by quantitative reasl‐time PCR (qRT‐PCR) or immunoblotting. Cell proliferation was assessed by CCK‐8 and EDU assays. Cell apoptosis and invasion were evaluated by flow cytometry and transwell assays, respectively. Cell migration was detected by transwell and wound‐healing assays. The direct relationship between miR‐1290 and circ_0001946 or SOX6 was determined by dual‐luciferase reporter and RNA immunoprecipitation (RIP) assays. Xenograft model assays were used to assess the role of circ_0001946 in tumor growth. Results Circ_0001946 expression was attenuated in human ESCC, and circ_0001946 increase impeded cell proliferation, invasion, migration and enhanced apoptosis in vitro. Moreover, circ_0001946 increase diminished xenograft growth in vivo. Mechanistically, circ_0001946 bound to miR‐1290, and re‐expression of miR‐1290 reversed circ_0001946‐dependent cell properties. SOX6 was a miR‐1290 target and it was responsible for the regulation of miR‐1290 in cell properties. Furthermore, circ_0001946 functioned as a ceRNA to regulate SOX6 expression via miR‐1290. Conclusion Our findings uncover an undescribed molecular mechanism, the circ_0001946/miR‐1290/SOX6 ceRNA crosstalk, for the anti‐ESCC activity of circ_0001946.
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Affiliation(s)
- Jianjun Wang
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
| | - Wenjian Yao
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
| | - Jiwei Li
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
| | - Quan Zhang
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
| | - Li Wei
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
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26
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Novel circular RNA circ_0086722 drives tumor progression by regulating the miR-339-5p/STAT5A axis in prostate cancer. Cancer Lett 2022; 533:215606. [DOI: 10.1016/j.canlet.2022.215606] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 02/09/2022] [Accepted: 02/23/2022] [Indexed: 12/31/2022]
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Zhang B, Chu W, Li Z, Zhang Y, Zhen Q, Lv B, Liu J, Lu C, Zhao X. Circ-ATIC Serves as a Sponge of miR-326 to Accelerate Esophageal Squamous Cell Carcinoma Progression by Targeting ID1. Biochem Genet 2022; 60:1585-1600. [DOI: 10.1007/s10528-021-10167-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 12/06/2021] [Indexed: 02/07/2023]
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Lara-Chica M, Correa-Sáez A, Jiménez-Izquierdo R, Garrido-Rodríguez M, Ponce FJ, Moreno R, Morrison K, Di Vona C, Arató K, Jiménez-Jiménez C, Morrugares R, Schmitz ML, de la Luna S, de la Vega L, Calzado MA. A novel CDC25A/DYRK2 regulatory switch modulates cell cycle and survival. Cell Death Differ 2022; 29:105-117. [PMID: 34363019 PMCID: PMC8738746 DOI: 10.1038/s41418-021-00845-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 06/30/2021] [Accepted: 07/26/2021] [Indexed: 02/07/2023] Open
Abstract
The cell division cycle 25A (CDC25A) phosphatase is a key regulator of cell cycle progression that acts on the phosphorylation status of Cyclin-Cyclin-dependent kinase complexes, with an emergent role in the DNA damage response and cell survival control. The regulation of CDC25A activity and its protein level is essential to control the cell cycle and maintain genomic integrity. Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. CDC25A in turn is able to control the phosphorylation of DYRK2 at several residues outside from its activation loop, thus affecting DYRK2 localization and activity. An inverse correlation between DYRK2 and CDC25A protein amounts was observed during cell cycle progression and in response to DNA damage, with CDC25A accumulation responding to the manipulation of DYRK2 levels or activity in either physiological scenario. Functional data show that the pro-survival activity of CDC25A and the pro-apoptotic activity of DYRK2 could be partly explained by the mutual regulation between both proteins. Moreover, DYRK2 modulation of CDC25A expression and/or activity contributes to the DYRK2 role in cell cycle regulation. Altogether, we provide evidence suggesting that DYRK2 and CDC25A mutually control their activity and stability by a feedback regulatory loop, with a relevant effect on the genotoxic stress pathway, apoptosis, and cell cycle regulation.
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Affiliation(s)
- Maribel Lara-Chica
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
- Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Alejandro Correa-Sáez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
- Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Rafael Jiménez-Izquierdo
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
- Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Martín Garrido-Rodríguez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
- Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Francisco J Ponce
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
- Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Rita Moreno
- Division of Cellular Medicine, School of Medicine, University of Dundee, Scotland, UK
| | - Kimberley Morrison
- Division of Cellular Medicine, School of Medicine, University of Dundee, Scotland, UK
| | - Chiara Di Vona
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Barcelona, Spain
| | - Krisztina Arató
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Barcelona, Spain
| | - Carla Jiménez-Jiménez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
- Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Rosario Morrugares
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
- Hospital Universitario Reina Sofía, Córdoba, Spain
| | - M Lienhard Schmitz
- Institute of Biochemistry, Justus-Liebig-University, Member of the German Center for Lung Research, Giessen, Germany
| | - Susana de la Luna
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Laureano de la Vega
- Division of Cellular Medicine, School of Medicine, University of Dundee, Scotland, UK
| | - Marco A Calzado
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain.
- Hospital Universitario Reina Sofía, Córdoba, Spain.
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Xu P, Xu X, Wu X, Zhang L, Meng L, Chen Z, Han W, Yao J, Xu AM. CircTMC5 promotes gastric cancer progression and metastasis by targeting miR-361-3p/RABL6. Gastric Cancer 2022; 25:64-82. [PMID: 34296378 DOI: 10.1007/s10120-021-01220-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 07/15/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer (GC) is common in East Asia, yet its molecular and pathogenic mechanisms remain unclear. Circular RNAs (circRNAs) are differentially expressed in GC and may be promising biomarkers. Here, we investigated the role and regulatory mechanism of circTMC5 in GC. METHODS CircTMC5 expression was detected in human GC and adjacent tissues using microarray assays and qRT-PCR, while the clinicopathological characteristics of patients with GC were used to assess its diagnostic and prognostic value. The circTMC5/miR-361-3p/RABL6 axis was examined in vitro and vivo, and the immune roles of RABL6 were evaluated using bioinformatics analyses and immunohistochemistry (IHC). RESULTS CircTMC5 was highly expressed in GC tissues, plasma, and cell lines, and was closely related to histological grade, pathological stage, and T classification in patients with GC. CircTMC5 expression was also an independent prognostic factor for GC and its combined detection with carcinoembryonic antigen may improve GC diagnosis. Low circTMC5 expression correlated with good prognosis, inhibited GC cell proliferation, and promoted apoptosis. Mechanistically, circTMC5 overexpression promoted GC cell proliferation, invasion, and metastasis but inhibited apoptosis by sponging miR-361-3p and up-regulating RABL6 in vitro and vivo, whereas miR-361-3p up-regulation had the opposite effects. RABL6 was highly expressed in GC and was involved in immune regulation and infiltration in GC. CONCLUSIONS CircTMC5 promotes GC and sponges miR-361-3p to up-regulate RABL6 expression, thus may have diagnostic and prognostic value in GC. RABL6 also displays therapeutic promise due to its role in the immune regulation of GC.
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Affiliation(s)
- Peng Xu
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, No. 100 Huaihai Avenue, Xinzhan District, Hefei City, 230000, Anhui Province, China.,Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, No. 98, Nantong West Road, Yangzhou City, 225001, Jiangsu Province, China
| | - XiaoLan Xu
- Department of Critical Care Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
| | - Xiao Wu
- Department of Pathophysiology, Basic Medical College of Anhui Medical University, Anhui Provincial Key Laboratory of Pathophysiology, Hefei, 230022, China
| | - LiXiang Zhang
- Department of General Surgery, The First Affiliated Hospital of Anhui, Medical University, Hefei, 230022, China
| | - Lei Meng
- Department of General Surgery, The First Affiliated Hospital of Anhui, Medical University, Hefei, 230022, China
| | - ZhangMing Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui, Medical University, Hefei, 230022, China
| | - WenXiu Han
- Department of General Surgery, The First Affiliated Hospital of Anhui, Medical University, Hefei, 230022, China
| | - Jie Yao
- Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, No. 98, Nantong West Road, Yangzhou City, 225001, Jiangsu Province, China.
| | - AMan Xu
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, No. 100 Huaihai Avenue, Xinzhan District, Hefei City, 230000, Anhui Province, China. .,Department of General Surgery, The First Affiliated Hospital of Anhui, Medical University, Hefei, 230022, China.
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30
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Xi SJ, Cai WQ, Wang QQ, Peng XC. Role of circular RNAs in gastrointestinal tumors and drug resistance. World J Clin Cases 2021; 9:10400-10417. [PMID: 35004973 PMCID: PMC8686142 DOI: 10.12998/wjcc.v9.i34.10400] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/26/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023] Open
Abstract
The incidence of gastrointestinal cancers has increased significantly over the past decade and gastrointestinal malignancies now rank among the leading causes of mortality globally. Although newer therapeutic strategies such as targeted therapies have greatly improved patient outcomes, their clinical success is limited by drug resistance, treatment failure and recurrence of metastatic disease. Therefore, there is an urgent need for further research identifying accurate and reliable biomarkers for precise treatment strategies. Circular RNAs (circRNAs) exhibit a covalently closed structure, high stability and biological conservation, and their expression is associated with the occurrence and development of gastrointestinal tumors. Moreover, circRNAs may significantly influence drug resistance of gastrointestinal cancers. In this article, we review the role of circRNAs in the occurrence and development of gastrointestinal cancer, their association with drug resistance, and potential application for early diagnosis, treatment and prognosis in gastrointestinal malignancies. Furthermore, we summarize characteristics of circRNA, including mechanism of formation and biological effects via mRNA sponging, chromatin replication, gene regulation, translational modification, signal transduction, and damage repair. Finally, we discuss whether circRNA-related noninvasive testing may be clinically provided in the future. This review provides new insights for the future development of diagnostics and therapeutics based on circRNAs in gastrointestinal tumors.
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Affiliation(s)
- Shi-Jun Xi
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Wen-Qi Cai
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Qin-Qi Wang
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Xiao-Chun Peng
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
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31
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Fang X, Shrestha SM, Ren L, Shi R. Biological and clinical implications of metastasis-associated circular RNAs in oesophageal squamous cell carcinoma. FEBS Open Bio 2021; 11:2870-2887. [PMID: 34510785 PMCID: PMC8564336 DOI: 10.1002/2211-5463.13297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 08/29/2021] [Accepted: 09/10/2021] [Indexed: 12/20/2022] Open
Abstract
Oesophageal squamous cell carcinoma (OSCC) is a prevalent malignancy with high morbidity and mortality as a result of early metastasis and poor prognosis. Metastasis is a multistep process, involving various signalling pathways. Circular RNAs (circRNAs) are a class of covalently closed noncoding RNAs, the aberrant expression of which is reported to be involved in several biological events, including cell transformation, proliferation, migration, invasion, apoptosis and metastasis. Several studies have reported interactions between circRNAs and metastasis-associated signalling pathways. The abundance, stability and highly specific expression of candidate circRNAs make them potential biomarkers and therapeutic targets in OSCC. In this review article, we comprehensively describe metastasis-related circRNAs and their interactions with epithelial-mesenchymal transition-associated molecules. We also describe the molecular mechanisms and clinical relevance of circRNAs in OSCC progression and metastasis.
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Affiliation(s)
- Xin Fang
- Medical CollegeSoutheast UniversityNanjingChina
| | | | - Li‐Hua Ren
- Medical CollegeSoutheast UniversityNanjingChina
- Department of GastroenterologyZhongda HospitalAffiliated Hospital of Southeast UniversityNanjingChina
| | - Rui‐hua Shi
- Medical CollegeSoutheast UniversityNanjingChina
- Department of GastroenterologyZhongda HospitalAffiliated Hospital of Southeast UniversityNanjingChina
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Guo C, Mi J, Li H, Su P, Nie H. Dysregulated circular RNAs as novel biomarkers in esophageal squamous cell carcinoma: a meta-analysis. Cancer Med 2021; 10:7895-7908. [PMID: 34704390 PMCID: PMC8607254 DOI: 10.1002/cam4.3703] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 10/18/2020] [Indexed: 01/10/2023] Open
Abstract
Introduction Circular RNAs (circRNAs) play critical roles in tumorigenesis, but their clinical efficacy in esophageal squamous cell carcinoma (ESCC) still retains controversial. This meta‐analysis aims at evaluating the associations between circRNA expressions and clinicopathologic features as well as the diagnostic and prognostic values of circRNAs in ESCC. Materials & Methods PubMed, EMBASE, and other online databases were systematically searched to collect studies on circRNAs and clinicopathological features, diagnostic, and/or prognostic assessments of ESCC. The quality of included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS‐2) and Newcastle‐Ottawa Scale (NOS) scales. The included studies were quantitatively weighted and merged, and diagnostic indicators, hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were calculated. P values were merged by Fisher᾽s method. Sources of heterogeneity were traced using subgroup, sensitivity, and meta‐regression analyses. Results As a result, 12 studies were included, representing 769 ESCC patients. The meta‐analysis showed that abnormal expressions of circRNAs were associated to TNM stage as well as lymph node and distant metastases in ESCC cases. CircRNA was used to distinguish ESCC patients from healthy controls, and the merged sensitivity, specificity, and the area under the curve (AUC) of ESCC were 0.78 (95% CI: 0.74–0.81), 0.79 (95% CI: 0.75–0.83), and 0.86, respectively. The survival analysis showed that upregulated oncogenic circRNA levels in ESCC tissues was associated with the shorter overall survival (OS) of the patients (univariate analysis: HR = 2.25, 95% CI: 1.71–2.95, p = 0.000, I2 = 0.0%; multivariate analysis: HR = 2.50, 95% CI: 1.61–3.89, p = 0.000, I2 = 0.0%), while the OS of ESCC patients presenting overexpressions of tumor‐suppressive circRNAs was significantly ameliorated (HR = 0.29, 95% CI: 0.20–0.42, p = 0.000, I2 = 0.0%). The subgroup analyses based on circRNA biofunctions, sample size, and reference gene also revealed robust results. Conclusion CircRNAs can be used as promising molecular biomarkers for the early diagnosis and prognosis monitoring of ESCC.
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Affiliation(s)
- Chengcheng Guo
- Department of Pathology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Jianqiang Mi
- Department of Pathology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Haike Li
- Faculty of Basic Medicine, Henan Vocational College of Tuina, Luoyang, China
| | - Panke Su
- Department of Pathology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - He Nie
- Department of Nuclear Medicine, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
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Li C, Zhu L, Fu L, Han M, Li Y, Meng Z, Qiu X. CircRNA NRIP1 promotes papillary thyroid carcinoma progression by sponging mir-195-5p and modulating the P38 MAPK and JAK/STAT pathways. Diagn Pathol 2021; 16:93. [PMID: 34689819 PMCID: PMC8543861 DOI: 10.1186/s13000-021-01153-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 09/23/2021] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) have become a hot topic in the area of tumor biology due to its closed structure and the post-transcriptional regulatory effect. This study aims to clarify the roles of circRNA nuclear receptor-interacting protein 1 (NRIP1; circNRIP1) and the possible mechanisms in papillary thyroid carcinoma (PTC). METHODS The real-time PCR was used to detect the expression level of CircRNA NRIP1 in PTC specimens and cell lines. The effects of CircRNA NRIP1 and miR-195-5p on the PTC cell functions were detected by MTT, transwell, and flow cytometry assays. Dual-luciferase reporter assays and pull down assays were used to verify the association between circRNA NRIP1 and miR-195-5p. The murine xenograft models were constructed to detect the roles of CircRNA NRIP1 and miR-195-5p. Western blot was applied to detect the effects of CircRNA NRIP1 and miR-195-5p on the P38 MAPK and JAK/STAT singling pathways. RESULTS CircRNA NRIP1 was over-expressed in PTC tissues and cells and the high levels of CircRNA NRIP1 were correlated with advanced PTC stage. Depletion of CircRNA NRIP1 inhibited PTC cell proliferation, invasion, while accelerated apoptosis. miR-195-5p upregulation repressed proliferation and invasion capabilities, and accelerated apoptosis of PTC cell lines and restraining the growth of tumor xenografts, while the functions were reversed following CircRNA NRIP1 overexpression in PTC cells and tumor xenografts. Besides, the protein levels of p-p38, p-JAK2 and p-STAT1 were remarkably down-regulated in miR-195-5p overexpressed PTC cells and tumor xenografts, whereas CircRNA NRIP1 up-regulation overturned the impacts. CONCLUSIONS In conclusion, CircRNA NRIP1 promoted PTC progression by accelerating PTC cells proliferation, invasion and tumor growth, while impeding apoptosis by way of sponging miR-195-5p and regulating the P38 MAPK and JAK/STAT pathways.
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Affiliation(s)
- Chuang Li
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, 450052, Zhengzhou, China
- Department of Thyroid and Neck, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, 450000, Zhengzhou, China
| | - Lijuan Zhu
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China
| | - Lijun Fu
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, 450052, Zhengzhou, China
| | - Mingli Han
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China
| | - Ya Li
- Institute for Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, 450000, Zhengzhou, China
| | - Zhaozhong Meng
- Department of Thyroid and Neck, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, 450000, Zhengzhou, China
| | - Xinguang Qiu
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, 450052, Zhengzhou, China.
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Shi Z, Wang K, Xing Y, Yang X. CircNRIP1 Encapsulated by Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicles Aggravates Osteosarcoma by Modulating the miR-532-3p/AKT3/PI3K/AKT Axis. Front Oncol 2021; 11:658139. [PMID: 34660257 PMCID: PMC8511523 DOI: 10.3389/fonc.2021.658139] [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: 01/25/2021] [Accepted: 07/22/2021] [Indexed: 12/24/2022] Open
Abstract
Emerging evidence indicates that extracellular vesicle (EV)-encapsulated circRNAs have the potential diagnostic and prognostic values for malignancies. However, the role of circNRIP1 in osteosarcoma remains unclear. We herein investigated the therapeutic potential of circNRIP1 delivered by bone marrow mesenchymal stem cell–derived EVs (BMSC-EVs) in osteosarcoma. The expression of circNRIP1 was examined in the clinical tissue samples of osteosarcoma patients, after which the downstream genes of circNRIP1 were bioinformatically predicted. Gain- and loss-of function assays were then performed in osteosarcoma cells with manipulation of circNRIP1 and miR-532-3p expression. EVs isolated from BMSCs were characterized and co-cultured with osteosarcoma cells to examine their effects on cell phenotypes, as reflected by CCK-8 and Transwell assays. Further, a mouse model of tumor xenografts was established for in vivo substantiation. circNRIP1 was upregulated in osteosarcoma tissues and cells. Overexpression of circNRIP1 promoted the proliferative, migratory, and invasive potential of osteosarcoma cells. Co-culture data showed that BMSC-EVs could transfer circNRIP1 into osteosarcoma cells where it competitively bound to miR-532-3p and weakened miR-532-3p’s binding ability to AKT3. By this mechanism, the PI3K/AKT signaling pathway was activated and the malignant characteristics of osteosarcoma cells were stimulated. In vivo experimental results unveiled that circNRIP1-overexpressing BMSC-EVs in nude mice resulted in enhanced tumor growth. In conclusion, the BMSC-EV-enclosed circNRIP1 revealed a new molecular mechanism in the pathogenesis of osteosarcoma, which might provide a novel therapeutic target for osteosarcoma.
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Affiliation(s)
- Zuowei Shi
- Department of Orthopaedics, First Hospital of Harbin Medical University, Harbin, China
| | - Kaifu Wang
- Department of Orthopaedics, First Hospital of Harbin Medical University, Harbin, China
| | - Yufei Xing
- Department of Orthopaedics, First Hospital of Harbin Medical University, Harbin, China
| | - Xuefeng Yang
- Department of Orthopaedics, First Hospital of Harbin Medical University, Harbin, China
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Geng X, Wang J, Zhang C, Zhou X, Jing J, Pan W. Circular RNA circCOL6A3_030 is involved in the metastasis of gastric cancer by encoding polypeptide. Bioengineered 2021; 12:8202-8216. [PMID: 34595992 PMCID: PMC8806935 DOI: 10.1080/21655979.2021.1979915] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is a serious digestive tract disease that threatens human life worldwide, and the prognosis of gastric cancer accompanied by distant lymph node or the distant metastasis organs is worse. The purpose of this study was to investigate the role of circular RNA COL6A3_030 (circBase ID: hsa_circ_0006401; circRNADb ID: hsa_circ_28198; circBank ID: hsa_circCOL6A3_030) in GC metastasis. qRT-PCR analysis using back-splicing primers and Sanger sequencing of PCR products were performed to identify circCOL6A3_030 in GC tissues and cell lines; RNA-FISH assay was performed to validate the subcellular localization of circCOL6A3_030. Transwell and wound-healing assays were carried out to evaluate the migration ability of GC cells. Western blot was conducted to detect the polypeptide encoded by circCOL6A3_030 in cells. circCOL6A3_030 was down-regulated in GC tissues and cell lines, while circCOL6A3_030 was up-regulated in GC with distant lymph node metastasis. The migration of circCOL6A3_030 silenced GC cells was significantly inhibited in both SGC-7901 and BGC-823 cell lines. Importantly, in vivo assay, silencing circCOL6A3_030 could reduce liver metastases from gastric cancer cells. Meanwhile, further studies suggested that circCOL6A3_030 encoded a small peptide that had a function as a tumor-promoting metastasis factor and immunohistochemistry confirmed the presence of this polypeptide. To sum up, our study showed that circCOL6A3_030 promoted GC cell migration by encoding a small peptide called circCOL6A3_030_198aa. Therefore, our results highlight the potential role of circCOL6A3_030 for clinical diagnosis and treatment of GC with distant lymph node metastasis.
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Affiliation(s)
- Xiaoge Geng
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jingya Wang
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Chenjing Zhang
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Xiaolu Zhou
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jiyong Jing
- Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Wensheng Pan
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
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Xu J, Pan HW, Wang XQ, Chen KP. Status of diagnosis and treatment of esophageal cancer and non-coding RNA correlation research: a narrative review. Transl Cancer Res 2021; 10:4532-4552. [PMID: 35116309 PMCID: PMC8798506 DOI: 10.21037/tcr-21-687] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 08/20/2021] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To describe and discuss the progression of the non-coding RNA as biomarkers in early esophageal cancer. BACKGROUND Esophageal cancer without obvious symptoms during early stages is one of the most common cancers, the current clinical treatments offer possibilities of a cure, but the survival rates and the prognoses remain poor, it is a serious threat to human life and health. Most patients are usually diagnosed during terminal stages due to low sensitivity of esophageal cancer's early detection techniques. With the development of molecular biology, an increasing number of non-coding RNAs are found to be associated with the occurrence, development, and prognosis of esophageal cancer. Some of these have begun to be used in clinics and laboratories for diagnosis, treatment, and prognosis, with the goal of reducing mortality. METHODS The information for this paper was collected from a variety of sources, including a search of the keynote's references, a search for texts in college libraries, and discussions with experts in the field of esophageal cancer clinical treatment. CONCLUSIONS Non-coding RNA does play a regulatory role in the development of esophageal cancer, which can predict the occurrence or prognosis of tumors, and become a new class of tumor markers and therapeutic targets in clinical applications. In this review, we survey the recent developments in the incidence, diagnosis, and treatment of esophageal cancer, especially with new research progresses on non-coding RNA biomarkers in detail, and discuss its potential clinical applications.
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Affiliation(s)
- Jia Xu
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Hui-Wen Pan
- Department of Cardiothoracic Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
| | - Xue-Qi Wang
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Ke-Ping Chen
- School of Life Sciences, Jiangsu University, Zhenjiang, China
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CircAGFG1 acts as a sponge of miR-4306 to stimulate esophageal cancer progression by modulating MAPRE2 expression. Acta Histochem 2021; 123:151776. [PMID: 34461454 DOI: 10.1016/j.acthis.2021.151776] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 08/13/2021] [Accepted: 08/19/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVE This work aims to determine the role of circular RNA (circRNA) AGFG1 and related molecular mechanism in esophageal squamous cell carcinoma (ESCC) cells. METHODS CircAGFG1 expression in ESCC cell lines was probed with qRT-PCR. ESCC cells were transfected/cotransfected with si-circAGFG1, pcDNA3.1-circAGFG1, si-Microtubule Associated Protein RP/EB Family Member 2 (MAPRE2), pcDNA3.1-circAGFG1 + miR-4306 mimic or pcDNA3.1-circAGFG1 + si-MAPRE2. The interactions between circAGFG1 and miR-4306 as well as miR-4306 and MAPRE2 were confirmed by dual-luciferase reporter assay. Cell proliferation, migration and invasion were detected by CCK-8, cell scratch and Transwell assays, respectively. Relative RNA expression levels of circAGFG1, miR-4306 and MAPRE2 in ESCC cells were measured by qRT-PCR. The protein level of MAPRE2 in ESCC cells was monitored by Western blot. RESULTS CircAGFG1 was observably upregulated in ESCC cell lines. Besides, circAGFG1 silencing hindered ESCC cell development in vitro, and these effects were enhanced by miR-4306 overexpression or MAPRE2 silencing. Mechanistic analysis evidenced that circAGFG1 might act as a competitive endogenous RNA of miR-4306 to relieve the repressive effect of miR-4306 on its target MAPRE2. CONCLUSION CircAGFG1 facilitates ESCC progression via the miR-4306/MAPRE2 axis, and it may act as a possible biomarker for therapy and diagnosis in ESCC treatment.
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Zhou Q, Ju LL, Ji X, Cao YL, Shao JG, Chen L. Plasma circRNAs as Biomarkers in Cancer. Cancer Manag Res 2021; 13:7325-7337. [PMID: 34584458 PMCID: PMC8464305 DOI: 10.2147/cmar.s330228] [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: 07/20/2021] [Accepted: 08/26/2021] [Indexed: 12/20/2022] Open
Abstract
The incidence and mortality of cancer are increasing each year. At present, the sensitivity and specificity of the blood biomarkers that were used in clinical practice are low, which make the detection rate of cancer decrease. With advances in bioinformatics and technology, some non-coding RNA as biomarkers can be easily detected through some traditional and new technologies. Circular RNAs (circRNAs) are non-coding RNAs, that is, they do not encode proteins, and have important regulatory functions. CircRNAs can remain stable in bodily fluids, such as in saliva, blood, urine, and especially plasma. The difference in the expression of plasma circRNAs between cancer patients and normal people may suggest that plasma circRNAs may play an important role in the occurrence and development of cancer. In this review, we summarized the clinical effect of plasma circRNAs in several high-incidence cancers. CircRNAs may be effective biomarkers for tumour diagnosis, treatment selection and prognosis evaluation.
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Affiliation(s)
- Qian Zhou
- Medical School of Nantong University, Nantong Third People's Hospital, Nantong, Jiangsu, People's Republic of China
| | - Lin-Ling Ju
- Nantong Institute of Liver Disease, Nantong Third People's Hospital, Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Xiang Ji
- Medical School of Nantong University, Nantong Third People's Hospital, Nantong, Jiangsu, People's Republic of China
| | - Ya-Li Cao
- Nantong Institute of Liver Disease, Nantong Third People's Hospital, Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Jian-Guo Shao
- Nantong Institute of Liver Disease, Nantong Third People's Hospital, Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Lin Chen
- Nantong Institute of Liver Disease, Nantong Third People's Hospital, Nantong University, Nantong, Jiangsu, People's Republic of China
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Zhou S, Guo Z, Zhou C, Zhang Y, Wang S. circ_NRIP1 is oncogenic in malignant development of esophageal squamous cell carcinoma (ESCC) via miR-595/SEMA4D axis and PI3K/AKT pathway. Cancer Cell Int 2021; 21:250. [PMID: 33957921 PMCID: PMC8101145 DOI: 10.1186/s12935-021-01907-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 04/07/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The hsa_circ_0004771 derived from NRIP1 (called circ_NRIP1) is a recently identified oncogenic circRNA. Here, we intended to investigate the role and mechanism of circ_NRIP1 in esophageal squamous cell carcinoma (ESCC), a prevalent and aggressive type of esophageal cancer. METHODS Expression of circ_NRIP1, miRNA-595-5p (miR-595) and semaphorin 4D (SEMA4D) was detected by RT-qPCR and western blotting. Cell growth was assessed by colony formation assay, MTS assay, flow cytometry, and xenograft experiment; migration and invasion were evaluated by transwell assay and western blotting. Dual-luciferase reporter assay identified the relationship among circ_NRIP1, miR-595 and SEMA4D. Western blotting measured phosphatidylinositol-3-hydroxykinase (PI3K)/AKT pathway-related proteins. RESULTS Expression of circ_NRIP1 was upregulated in ESCC tissues and cells. Knockdown of circ_NRIP1 could enhance apoptosis rate and E-cadherin expression, but suppress colony formation, cell viability, migration, invasion, and snail expression in KYSE30 and KYSE450 cells, as well as retarded tumor growth in mice. The suppressive role of circ_NRIP1 knockdown in cell growth, migration and invasion in vitro was abated by blocking miR-595; meanwhile, miR-595 overexpression elicited similar anti-tumor role in KYSE30 and KYSE450 cells, which was abrogated by restoring SEMA4D. Notably, circ_NRIP1 was a sponge for miR-595, and SEMA4D was a target of miR-595. Besides, PI3K/AKT signal was inhibited by circ_NRIP1 knockdown and/or miR-595 overexpression via indirectly or directly regulating SEMA4D. CONCLUSION circ_NRIP1 functioned as an oncogene in ESCC, and modulated ESCC cell growth, migration and invasion both in vitro and in vivo via targeting miR-595/SEMA4D axis and inhibiting PI3K/AKT signaling pathway.
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Affiliation(s)
- Shifan Zhou
- Henan University of Chinese Medicine, No.156 Jinshui East Road, Zhengzhou, 450046, Henan, China. .,Department of Oncology, The Second Affiliated Hospital of Henan University of Chinese Medicine, No.6 Dongfeng Road, Jinshui District, Zhengzhou, 450002, Henan, China.
| | - Zhizhong Guo
- Department of Oncology, The Second Affiliated Hospital of Henan University of Chinese Medicine, No.6 Dongfeng Road, Jinshui District, Zhengzhou, 450002, Henan, China
| | - Chaofeng Zhou
- Department of Oncology, The Second Affiliated Hospital of Henan University of Chinese Medicine, No.6 Dongfeng Road, Jinshui District, Zhengzhou, 450002, Henan, China
| | - Yu Zhang
- Department of Oncology, The Second Affiliated Hospital of Henan University of Chinese Medicine, No.6 Dongfeng Road, Jinshui District, Zhengzhou, 450002, Henan, China
| | - Sai Wang
- Department of Oncology, The Second Affiliated Hospital of Henan University of Chinese Medicine, No.6 Dongfeng Road, Jinshui District, Zhengzhou, 450002, Henan, China
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Wang M, Xie F, Lin J, Zhao Y, Zhang Q, Liao Z, Wei P. Diagnostic and Prognostic Value of Circulating CircRNAs in Cancer. Front Med (Lausanne) 2021; 8:649383. [PMID: 33816529 PMCID: PMC8012499 DOI: 10.3389/fmed.2021.649383] [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: 01/04/2021] [Accepted: 02/15/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer has been regarded as one of the leading causes of mortality worldwide. Diagnostic and prognostic biomarkers with high sensitivity and specificity for cancer play a crucial role in preventing or treating cancer. Circular RNAs (circRNAs), which hold great potential for the management of cancer patients due to their abundance, stable property, and high specificity in serum, plasma, and other body fluids, can be used as non-invasive and blood-based biomarkers in cancer diagnosis and prognosis. There are four types of circRNAs including exonic circRNAs (ecircRNA), intronic circRNAs, exon-intron circRNAs (EIciRNA), and intergenic circRNAs. CircRNAs can act as miRNA sponges, affect protein translation, interplay with RNA binding proteins, regulate protein recruitment, and modulate protein scaffolding and assembly. Therefore, the multifunctionalities of circRNAs make them ideal for detecting and predicting cancer. Indeed, circRNAs manifest high sensitivity and specificity in more than ten types of cancer. This review aims to consolidate the types and functions of circRNAs, as well as discuss the diagnostic and prognostic value of circulating circRNAs in cancer.
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Affiliation(s)
- Mina Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.,Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing, China
| | - Feiyu Xie
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.,Oncology Department, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiaran Lin
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.,Department of Nephrology and Endocrinology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yihan Zhao
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qian Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Zehuan Liao
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.,Department of Microbiology, Tumor, and Cell Biology (MTC), Karolinska Institutet, Biomedicum, Solnavägen, Sweden
| | - Peng Wei
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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Tao X, Shao Y, Yan J, Yang L, Ye Q, Wang Q, Lu R, Guo J. Biological roles and potential clinical values of circular RNAs in gastrointestinal malignancies. Cancer Biol Med 2021; 18:j.issn.2095-3941.2020.0348. [PMID: 33710802 PMCID: PMC8185857 DOI: 10.20892/j.issn.2095-3941.2020.0348] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 11/19/2020] [Indexed: 01/17/2023] Open
Abstract
Circular RNAs (circRNAs), a class of endogenous RNA molecules, are produced by alternative splicing of precursor RNA and are covalently linked at the 5' and 3' ends. Recent studies have revealed that dysregulated circRNAs are closely related to the occurrence and progression of gastrointestinal malignancies. Accumulating evidence indicates that circRNAs, including circPVT1, circLARP4, circ-SFMBT2, cir-ITCH, circRNA_100782, circ_100395, circ-DONSON, hsa_circ_0001368, circNRIP1, circFAT1(e2), circCCDC66, circSMARCA5, circ-ZNF652, and circ_0030235 play important roles in the proliferation, differentiation, invasion, and metastasis of cancer cells through a variety of mechanisms, such as acting as microRNA sponges, interacting with RNA-binding proteins, regulating gene transcription and alternative splicing, and being translated into proteins. With the characteristics of high abundance, high stability, extensive functions, and certain tissue-, time- and disease-specific expressions, circRNAs are expected to provide novel perspectives for the diagnoses and treatments of gastrointestinal malignancies.
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Affiliation(s)
- Xueping Tao
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo 315211, China
- Department of Gastroenterology, the Affiliated Hospital of Medical School of Ningbo University, Ningbo 315020, China
| | - Yongfu Shao
- Department of Gastroenterology, the Affiliated Hospital of Medical School of Ningbo University, Ningbo 315020, China
| | - Jianing Yan
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo 315211, China
- Department of Gastroenterology, the Affiliated Hospital of Medical School of Ningbo University, Ningbo 315020, China
| | - Liyang Yang
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo 315211, China
- Department of Gastroenterology, the Affiliated Hospital of Medical School of Ningbo University, Ningbo 315020, China
| | - Qihua Ye
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo 315211, China
- Department of Gastroenterology, the Affiliated Hospital of Medical School of Ningbo University, Ningbo 315020, China
| | - Qingling Wang
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo 315211, China
- Department of Gastroenterology, the Affiliated Hospital of Medical School of Ningbo University, Ningbo 315020, China
| | - Rongdan Lu
- Department of Gastroenterology, the Affiliated Hospital of Medical School of Ningbo University, Ningbo 315020, China
| | - Junming Guo
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo 315211, China
- Department of Gastroenterology, the Affiliated Hospital of Medical School of Ningbo University, Ningbo 315020, China
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Zhou S, Fang J, Hu M, Pan S, Liu D, Xing G, Liu Z. Determining the influence of high glucose on exosomal lncRNAs, mRNAs, circRNAs and miRNAs derived from human renal tubular epithelial cells. Aging (Albany NY) 2021; 13:8467-8480. [PMID: 33714195 PMCID: PMC8034913 DOI: 10.18632/aging.202656] [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: 08/10/2020] [Accepted: 01/13/2021] [Indexed: 02/06/2023]
Abstract
Diabetic nephropathy is a lethal disease that can lead to chronic kidney disease and end-stage kidney disease. Exosomes, which are nanosized extracellular vesicles, are closely involved in intercellular communication. Most importantly, exosomes play critical roles in disease occurrence and development. However, the function of exosomes in diabetic nephropathy progression has not been fully elucidated. In the present study, we determined the expression profiles and differences of lncRNAs, mRNAs, circRNAs and miRNAs in exosomes derived from human renal tubular epithelial cells with or without high glucose (HG) treatment. A total of 169 lncRNAs, 885 mRNAs, 3 circRNAs and 152 miRNAs were differentially expressed in exosomes secreted by HG-challenged HK-2 cells (HG group) compared with controls (NC group). The functions of differentially expressed mRNAs, mRNAs colocalized or coexpressed with differentially expressed lncRNAs (DElncRNAs), potential target genes of miRNAs and source genes of circRNAs were investigated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. According to these differentially expressed RNAs, we established an integrated circRNA-lncRNA-miRNA-mRNA regulatory network. In conclusion, our study suggested that exosomal lncRNAs, mRNAs, circRNAs and miRNAs participate in the progression of diabetic nephropathy and may be possible biomarkers and therapeutic targets in diabetic nephropathy.
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Affiliation(s)
- Sijie Zhou
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, P. R. China.,Research Center for Kidney Disease, Henan Province, Zhengzhou 450052, P. R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, P. R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, P. R. China
| | - Jiuyuan Fang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
| | - Mingyang Hu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, P. R. China.,Research Center for Kidney Disease, Henan Province, Zhengzhou 450052, P. R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, P. R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, P. R. China
| | - Shaokang Pan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, P. R. China.,Research Center for Kidney Disease, Henan Province, Zhengzhou 450052, P. R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, P. R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, P. R. China
| | - Dongwei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, P. R. China.,Research Center for Kidney Disease, Henan Province, Zhengzhou 450052, P. R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, P. R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, P. R. China
| | - Guolan Xing
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, P. R. China.,Research Center for Kidney Disease, Henan Province, Zhengzhou 450052, P. R. China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, P. R. China.,Research Center for Kidney Disease, Henan Province, Zhengzhou 450052, P. R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, P. R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, P. R. China
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Wang W, Zhu D, Zhao Z, Sun M, Wang F, Li W, Zhang J, Jiang G. RNA sequencing reveals the expression profiles of circRNA and identifies a four-circRNA signature acts as a prognostic marker in esophageal squamous cell carcinoma. Cancer Cell Int 2021; 21:151. [PMID: 33663506 PMCID: PMC7934454 DOI: 10.1186/s12935-021-01852-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 02/24/2021] [Indexed: 12/13/2022] Open
Abstract
Background CircRNAs with tissue-specific expression and stable structure may be good tumor prognostic markers. However, the expression of circRNAs in esophageal squamous cell carcinoma (ESCC) remain unknown. We aim to identify prognostic circRNAs and construct a circRNA-related signature in ESCC. Methods RNA sequencing was used to test the circRNA expression profiles of 73 paired ESCC tumor and normal tissues after RNase R enrichment. Bioinformatics methods, such as principal component analysis (PCA), t-distributed Stochastic Neighbor Embedding (t-SNE) algorithm, unsupervised clustering and hierarchical clustering were performed to analyze the circRNA expression characteristics. Univariate cox regression analysis, random survival forests-variable hunting (RSFVH), Kaplan–Meier analysis, multivariable Cox regression and ROC (receiver operating characteristic) curve analysis were used to screen the prognostic circRNA signature. Real-time quantitative PCR (qPCR) and fluorescence in situ hybridization(FISH) in 125 ESCC tissues were performed. Results Compared with normal tissues, there were 11651 differentially expressed circRNAs in cancer tissues. A total of 1202 circRNAs associated with ESCC prognosis (P < 0.05) were identified. Through bioinformatics analysis, we screened a circRNA signature including four circRNAs (hsa_circ_0000005, hsa_circ_0007541, hsa_circ_0008199, hsa_circ_0077536) which can classify the ESCC patients into two groups with significantly different survival (log rank P < 0.001), and found its predictive performance was better than that of the TNM stage(0.84 vs. 0.66; 0.65 vs. 0.62). Through qPCR and FISH experiment, we validated the existence of the screened circRNAs and the predictive power of the circRNA signature. Conclusion The prognostic four-circRNA signature could be a new prognostic biomarker for ESCC, which has high clinical application value.
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Affiliation(s)
- Weiwei Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Jian she Dong Road 1, Zhengzhou, 450052, Henan, China.,Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, 450002, China.,Henan Key Laboratory for Tumor Pathology, Zhengzhou University, Zhengzhou, 450052, China
| | - Di Zhu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Jian she Dong Road 1, Zhengzhou, 450052, Henan, China.,Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, 450002, China.,Henan Key Laboratory for Tumor Pathology, Zhengzhou University, Zhengzhou, 450052, China
| | - Zhihua Zhao
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Jian she Dong Road 1, Zhengzhou, 450052, Henan, China.,Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, 450002, China.,Henan Key Laboratory for Tumor Pathology, Zhengzhou University, Zhengzhou, 450052, China
| | - Miaomiao Sun
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Jian she Dong Road 1, Zhengzhou, 450052, Henan, China.,Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, 450002, China.,Henan Key Laboratory for Tumor Pathology, Zhengzhou University, Zhengzhou, 450052, China
| | - Feng Wang
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China
| | - Wencai Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Jian she Dong Road 1, Zhengzhou, 450052, Henan, China.,Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, 450002, China.,Henan Key Laboratory for Tumor Pathology, Zhengzhou University, Zhengzhou, 450052, China
| | - Jianying Zhang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Guozhong Jiang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Jian she Dong Road 1, Zhengzhou, 450052, Henan, China. .,Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, 450002, China. .,Henan Key Laboratory for Tumor Pathology, Zhengzhou University, Zhengzhou, 450052, China.
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CircRNAs: a new target for the diagnosis and treatment of digestive system neoplasms. Cell Death Dis 2021; 12:205. [PMID: 33627631 PMCID: PMC7904779 DOI: 10.1038/s41419-021-03495-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/27/2021] [Accepted: 02/01/2021] [Indexed: 02/06/2023]
Abstract
A circRNA is a type of endogenous noncoding RNA that consists of a closed circular RNA molecule formed by reverse splicing; these RNAs are widely distributed in a variety of biological cells. In contrast to linear RNAs, circRNAs have no 5′ cap or 3′ poly(A) tail. They have a stable structure, a high degree of conservation, and high stability, and they are richly and specifically expressed in certain tissues and developmental stages. CircRNAs play a very important role in the occurrence and progression of malignant tumors. According to their origins, circRNAs can be divided into four types: exon-derived circRNAs (ecRNAs), intron-derived circRNAs (ciRNAs), circRNAs containing both exons and introns (EIciRNAs) and intergenic circRNAs. A large number of studies have shown that circRNAs have a variety of biological functions, participate in the regulation of gene expression and play an important role in the occurrence and progression of tumors. In this paper, the structure and function of circRNAs are reviewed, along with their biological role in malignant tumors of the digestive tract, in order to provide a reference for the diagnosis and treatment of digestive system neoplasms.
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Wang S, Zhang K, Tan S, Xin J, Yuan Q, Xu H, Xu X, Liang Q, Christiani DC, Wang M, Liu L, Du M. Circular RNAs in body fluids as cancer biomarkers: the new frontier of liquid biopsies. Mol Cancer 2021; 20:13. [PMID: 33430880 PMCID: PMC7798340 DOI: 10.1186/s12943-020-01298-z] [Citation(s) in RCA: 195] [Impact Index Per Article: 48.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 12/21/2020] [Indexed: 02/08/2023] Open
Abstract
Cancer is a leading cause of death worldwide, particularly because of its high mortality rate in patients who are diagnosed at late stages. Conventional biomarkers originating from blood are widely used for cancer diagnosis, but their low sensitivity and specificity limit their widespread application in cancer screening among the general population. Currently, emerging studies are exploiting novel, highly-accurate biomarkers in human body fluids that are obtainable through minimally invasive techniques, which is defined as liquid biopsy. Circular RNAs (circRNAs) are a newly discovered class of noncoding RNAs generated mainly by pre-mRNA splicing. Following the rapid development of high-throughput transcriptome analysis techniques, numerous circRNAs have been recognized to exist stably and at high levels in body fluids, including plasma, serum, exosomes, and urine. CircRNA expression patterns exhibit distinctly differences between patients with cancer and healthy controls, suggesting that circRNAs in body fluids potentially represent novel biomarkers for monitoring cancer development and progression. In this study, we summarized the expression of circRNAs in body fluids in a pan-cancer dataset and characterized their clinical applications in liquid biopsy for cancer diagnosis and prognosis. In addition, a user-friendly web interface was developed to visualize each circRNA in fluids (https://mulongdu.shinyapps.io/circrnas_in_fluids/).
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Affiliation(s)
- Sumeng Wang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Ke Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Shanyue Tan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Junyi Xin
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Centre for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, People's Republic of China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Centre for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Qianyu Yuan
- Departments of Environmental Health, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA
| | - Huanhuan Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Xian Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Qi Liang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - David C Christiani
- Departments of Environmental Health, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA.,Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA
| | - Meilin Wang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Centre for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, People's Republic of China. .,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Centre for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, People's Republic of China.
| | - Lingxiang Liu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.
| | - Mulong Du
- Department of Biostatistics, Centre for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, People's Republic of China.
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Ding X, Zheng J, Cao M. Circ_0004771 Accelerates Cell Carcinogenic Phenotypes via Suppressing miR-1253-Mediated DDAH1 Inhibition in Breast Cancer. Cancer Manag Res 2021; 13:1-11. [PMID: 33442289 PMCID: PMC7797298 DOI: 10.2147/cmar.s273783] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 12/04/2020] [Indexed: 12/20/2022] Open
Abstract
Background Circ_0004771 was demonstrated to mediate cell growth promotion and apoptosis suppression in breast cancer (BC). Herein, the precise functions and mechanism of circ_0004771 in the biological property of BC cells were investigated. Methods The expression of circ_0004771, microRNA (miR)-1253 and dimethylarginine dimethylaminohydrolase 1 (DDAH1) mRNA was analyzed using quantitative real-time polymerase chain reaction. The proliferation, apoptosis, migration, invasion, adhesion, Western blot and in vivo tumorigenesis assays were employed to evaluate the roles of circ_0004771 and DDAH1 in BC tumorigenesis. The interaction between miR-1253 and circ_0004771 or DDAH1 was validated by dual-luciferase reporter, pull-down and RNA immunoprecipitation (RIP) assay. Exosomes were isolated by Exoquick-TC® methods, and qualified using Nanosight™ technology and Western blot. Results Circ_0004771 or DDAH1 expression was elevated in BC, and silencing either of them suppressed cell malignant phenotypes, thus impeding BC progression. Importantly, circ_0004771 up-regulation attenuated the anticancer action of DDAH1-knockdown in BC. Additionally, we confirmed that circ_0004771 functioned as a sponge of miR-1253 to up-regulate DDAH1 expression. Moreover, xenograft assay exhibited that circ_0004771 knockdown also hindered tumor growth in vivo via regulating DDAH1 and miR-1253. Besides that, it was found that circ_0004771 was packaged into exosomes isolated from the serum of BC. Conclusion Circ_0004771 accelerated cell carcinogenic phenotypes via up-regulating DDAH1 expression through absorbing miR-1253 in BC. Besides, circ_0004771 was packaged into exosomes isolated from the serum of BC. All these findings suggested a promising molecular target for BC treatment.
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Affiliation(s)
- Xubei Ding
- Thyroid and Breast Surgery, Jingmen No.1 People's Hospital, Jingmen, Hubei, People's Republic of China
| | - Junjun Zheng
- Pharmacy Intravenous Admixture Services, Jingmen No.2 People's Hospital, Jingmen, Hubei, People's Republic of China
| | - Mingxiang Cao
- Department of Anesthesiology, Jingmen No.1 People's Hospital, Jingmen, Hubei, People's Republic of China
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Rajappa A, Banerjee S, Sharma V, Khandelia P. Circular RNAs: Emerging Role in Cancer Diagnostics and Therapeutics. Front Mol Biosci 2020; 7:577938. [PMID: 33195421 PMCID: PMC7655967 DOI: 10.3389/fmolb.2020.577938] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/26/2020] [Indexed: 12/17/2022] Open
Abstract
Circular RNAs (circRNAs) are rapidly coming to the fore as major regulators of gene expression and cellular functions. They elicit their influence via a plethora of diverse molecular mechanisms. It is not surprising that aberrant circRNA expression is common in cancers and they have been implicated in multiple aspects of cancer pathophysiology such as apoptosis, invasion, migration, and proliferation. We summarize the emerging role of circRNAs as biomarkers and therapeutic targets in cancer.
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Affiliation(s)
| | | | - Vivek Sharma
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Hyderabad, India
| | - Piyush Khandelia
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Hyderabad, India
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Zhao X, Wang Y, Yu Q, Yu P, Zheng Q, Yang X, Gao D. Circular RNAs in gastrointestinal cancer: Current knowledge, biomarkers and targeted therapy (Review). Int J Mol Med 2020; 46:1611-1632. [PMID: 33000182 PMCID: PMC7521476 DOI: 10.3892/ijmm.2020.4731] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 09/01/2020] [Indexed: 01/17/2023] Open
Abstract
Circular RNAs (circRNAs) are a type of endogenous non‑coding RNAs that are connected at the 3' and 5' ends by exon or intron cyclization, which forms a covalently closed loop. They are stable, well conserved, exhibit specific expression in mammalian cells and can function as microRNA (miRNA or miR) sponges to regulate the target genes of miRNAs, which influences biological processes. Such as tumor proliferation, invasion, metastasis, apoptosis and tumor stage. circRNAs represent promising candidates for clinical diagnosis and treatment. In the present review, the biogenesis, classification and functions of circRNAs in tumors are briefly summarized and discussed. In addition, the participation of circRNAs in signal transduction pathways regulating gastrointestinal cancer cellular functions is highlighted.
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Affiliation(s)
- Xiaorui Zhao
- Department of Pathogen Biology and Immunology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yue Wang
- Department of Pathogen Biology and Immunology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Qiongfang Yu
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Pei Yu
- Department of Pathogen Biology and Immunology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Qiaoyu Zheng
- Department of Pathogen Biology and Immunology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xue Yang
- Department of Pathogen Biology and Immunology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Dian Gao
- Department of Pathogen Biology and Immunology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Circ-CUX1 Accelerates the Progression of Neuroblastoma via miR-16-5p/DMRT2 Axis. Neurochem Res 2020; 45:2840-2855. [PMID: 33000435 DOI: 10.1007/s11064-020-03132-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 09/10/2020] [Accepted: 09/12/2020] [Indexed: 12/24/2022]
Abstract
Circular RNAs (circRNAs) played pivotal roles in the initiation and progression of cancers. CircRNA cut like homeobox 1 (circ-CUX1; hsa_circ_0132813) has been reported to contribute to neuroblastoma (NB) development by previous study. Furthermore, previous works reported that microRNA-16-5p (miR-16-5p) was down-regulated while doublesex and mab-3 related transcription factor 2 (DMRT2) was up-regulated in NB. The interaction and functional association between miR-16-5p and circ-CUX1 or DMRT2 were investigated in this study. Cell proliferation, cell cycle progression, colony formation, migration and invasion of NB cells were examined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, colony formation assay and transwell migration and invasion assays. The glycolysis was analyzed through measuring the consumption of glucose and the production of lactate and ATP. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA-pull down assay were utilized to confirm the interaction between miR-16-5p and circ-CUX1 or DMRT2. Tumor xenograft assay was performed to explore the function of circ-CUX1 in xenograft tumor growth in vivo. Circ-CUX1 promoted the proliferation, migration, invasion and glycolysis of NB cells. miR-16-5p was a direct target of circ-CUX1, and miR-16-5p overexpression-mediated effects in NB cells were partly alleviated by the introduction of circ-CUX1 overexpression plasmid. DMRT2 was a target of miR-16-5p in NB cells, and the introduction of anti-miR-16-5p overturned the influences of DMRT2 interference on the proliferation, migration and invasion and glycolysis of NB cells. Circ-CUX1 silencing restrained xenograft tumor growth in vivo. In conclusion, circ-CUX1 accelerated the proliferation, migration, invasion and glycolysis of NB cells through targeting miR-16-5p/DMRT2 signaling cascade.
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Zhu J, Ma C, Zhu L, Li J, Peng F, Huang L, Luan X. A role for the NLRC4 inflammasome in premature rupture of membrane. PLoS One 2020; 15:e0237847. [PMID: 32833985 PMCID: PMC7446792 DOI: 10.1371/journal.pone.0237847] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/04/2020] [Indexed: 11/19/2022] Open
Abstract
PROM is one of the common complications of perinatal period, which seriously threatens the mother and newborn. The purpose of this study was to identify the role of NLRC4 inflammasomes in this process and their underlying mechanisms. We performed high-throughput RNA sequencing of fetal membrane tissue from 3 normal pregnant women and 3 term-premature rupture of fetal membrane (TPROM) patients who met the inclusion criteria, and found that NLRC4 was significantly up-regulated in TPROM patients. An observational study of TPROM patients (PROM group, n = 30) and normal pregnant women (control group, n = 30) was performed at the Xuzhou Maternal and Child Health Hospital affiliated to Xuzhou Medical University from May 2018 to May 2019. The expression of genes involved in inflammasome complex including NLRC1, NLRC3, AIM2, NLRC4, ASC, caspase-1, IL-6, IL-18 and IL-1βwas determined via real-time PCR, immunohistochemistry and immunofluorescence. Measurement of NLRC4 level in serum was conducted by ELISA assay. The results showed that the NLRC4, ASC, caspase-1, IL-1β and IL-18 levels in fetal membrane, placental tissues and maternal serum were markedly higher in the PROM group than that in the control group. In conclusion, NLRC4 is a markedly up-regulated gene in TPROM fetal membrane tissue, suggesting that NLRC4 is involved in the occurrence and development of TPROM; NLRC4 levels in maternal blood serum are closely related to TPROM and have the potential to assist doctors in predicting and diagnosing PROM.
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Affiliation(s)
- Jinming Zhu
- Department of Obstetrics, Xuzhou Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, China
- * E-mail:
| | - Chunling Ma
- Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Lina Zhu
- Department of Obstetrics and Gynecology, Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Juan Li
- Department of Obstetrics, Xuzhou Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fengyun Peng
- Department of Obstetrics, Xuzhou Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Lei Huang
- Department of Obstetrics, Xuzhou Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiaomei Luan
- Department of Obstetrics, Xuzhou Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, China
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