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Ying W, Zhao Y, He Y, Deng Y, Gan X, Li P, Chen X, Ding Z. Exosomal miR-184 facilitates bladder cancer progression by targeting AKR1C3 and inducing immune escape via IRF2-CXCL10 axis. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167627. [PMID: 39689761 DOI: 10.1016/j.bbadis.2024.167627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/27/2024] [Accepted: 12/11/2024] [Indexed: 12/19/2024]
Abstract
Currently, the molecular mechanisms underlying bladder cancer progression remain unclear. Immune checkpoint inhibitors (ICIs) have been used to treat bladder cancer, but their efficacy is limited. Exosomes, which play a critical role in cell communication, can alter the tumor microenvironment. Therefore, it is essential to investigate the impact of bladder cancer exosomes on the tumor microenvironment. Our research demonstrates a significant up-regulation of miR-184 in exosomes derived from bladder cancer cells. miR-184 promotes bladder cancer cell proliferation in vitro and facilitates tumor growth in mice by targeting the 3' UTR of AKR1C3 mRNA. Additionally, miR-184 targets IRF2 mRNA, reducing its transcriptional inhibition on CXCL10. This process induces the expression of CXCL10, which promotes the infiltration of CD8+ T cells into the tumor. However, these infiltrating T cells become exhausted. In summary, our study reveals that bladder cancer-derived exosomes deliver miR-184, which targets AKR1C3, contributing to bladder carcinogenesis and development. We also investigate how the IRF2-CXCL10 pathway induces T cell exhaustion and leads to immune escape. This research provides new insights into the immunotherapy of bladder cancer, highlighting potential molecular targets for more effective treatment strategies.
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Affiliation(s)
- Wenwei Ying
- Department of Urology, Peking University First Hospital, Beijing 100034, China; Department of Urology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Ying Zhao
- Department of Urology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yuhui He
- Department of Urology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yisen Deng
- Department of Urology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xiaoming Gan
- Department of Urology, China-Japan Friendship Hospital, Beijing 100029, China; Beijing Engineering Research Center of Advanced Elastomers, Beijing University of Chemical Technology, Beijing 100029, China
| | - Peizhe Li
- Department of Urology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xing Chen
- Department of Urology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Zhenshan Ding
- Department of Urology, China-Japan Friendship Hospital, Beijing 100029, China.
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Wei D, Zhang F, Li M, Fan Z, Ma J, Ji J, Qiao S, Huang P, Zhang W, Fan K, Li L, Zheng W, Li X, Ren L. CircDUSP16 mediates the effect of triple-negative breast cancer in pirarubicin via the miR-1224-3p/TFDP2 axis. Biochem Pharmacol 2025; 232:116719. [PMID: 39710273 DOI: 10.1016/j.bcp.2024.116719] [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: 08/20/2024] [Revised: 12/02/2024] [Accepted: 12/12/2024] [Indexed: 12/24/2024]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive molecular subtype of breast cancer characterized by a high recurrence rate, poor prognosis, and elevated mortality. Identifying novel molecular targets is crucial for developing more effective therapeutic strategies against TNBC. Recent studies have highlighted the role of circular RNAs (circRNAs) in the progression of TNBC. In this study, we identified and validated that circDUSP16 (hsa_circ_0003855) is significantly upregulated in TNBC cells, tissues, and plasma exosomes. Functional assays in vitro demonstrated that overexpression of circDUSP16 promoted the proliferation, migration and invasion of TNBC cells, weathers circDUSP16 knockdown exerted the opposite effect. In vivo studies confirmed that circDUSP16 knockdown can inhibit tumor growth. Using bioinformatics analysis, circDUSP16/miR-1224-3p/TFDP2 pathway was predicted and cascaded. Mechanistically, circDUSP16 was shown to promote the progression of TNBC via the miR-1224-3p/TFDP2 axis. Additionally, THP, a commonly used anthracycline chemotherapy drug, was found to downregulate circDUSP16, suggesting that its therapeutic effects on TNBC may be mediated through circDUSP16/miR-1224-3p/TFDP2 pathway. Our findings suggest that circDUSP16 is a promising biomarker and potential therapeutic target for TNBC.
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Affiliation(s)
- Dexian Wei
- Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, China
| | - Fan Zhang
- Qingdao Municipal Hospital Qingdao, Shandong 266000, China
| | - Min Li
- Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, China
| | - Zhimin Fan
- General Surgery Center, Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Jiulong Ma
- School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, Shandong 266000, China
| | - Jiahua Ji
- Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, China
| | - Sennan Qiao
- Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, China
| | - Peng Huang
- School of Agroforestry and Medicine, The Open University of China, Beijing 100000, China
| | - Wenqing Zhang
- Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, China
| | - Kaiqi Fan
- Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, China
| | - Lu Li
- Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, China
| | - Wentao Zheng
- Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, China
| | - Xiangjun Li
- Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, China.
| | - Liqun Ren
- Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, China.
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Karimi R, Javandoost E, Asadmasjedi N, Atashi A, Soleimani A, Behzadifard M. Circular RNAs: history, metabolism, mechanisms of function, and regulatory roles at a glance. Ann Med Surg (Lond) 2025; 87:141-150. [PMID: 40109602 PMCID: PMC11918698 DOI: 10.1097/ms9.0000000000002761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 11/05/2024] [Indexed: 03/22/2025] Open
Abstract
Circular RNAs (circRNAs) are non-coding RNA (ncRNA) molecules that, due to their covalent ring structure and lack of free ends, have a very high intracellular stability compared to their linear counterparts. In general, circRNAs are expressed in mammalian cells and exhibit tissue/cell-specific expression patterns. Mounting evidence is indicative that circRNAs regulate a variety of cellular processes by acting as miRNA sponges, transcriptional regulators, protein sponges, molecular scaffolds, and protein/peptide translators. The emergence of the biological functions of circRNAs has brought a novel outlook to our better understanding of cellular physiology and disease pathogenesis. CircRNAs have also been shown to play a critical role in the occurrence, development and progression of cancers. Their participation in the pathophysiology of various diseases including cardiovascular diseases, diabetes and neurological disorders is very important. Such characteristics have led to more studies investigating circRNAs as promising tools in molecular medicine and targeted therapy.
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Affiliation(s)
- Roqaye Karimi
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ehsan Javandoost
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Nooshin Asadmasjedi
- Department of Laboratory Sciences, School of Allied Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran
| | - Amir Atashi
- Stem cell and Tissue Engineering Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Alireza Soleimani
- Student Research Committee Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mahin Behzadifard
- Department of Laboratory Sciences, School of Allied Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran
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Fang L, Zhu Z, Han M, Li S, Kong X, Yang L. Unlocking the potential of extracellular vesicle circRNAs in breast cancer: From molecular mechanisms to therapeutic horizons. Biomed Pharmacother 2024; 180:117480. [PMID: 39357330 DOI: 10.1016/j.biopha.2024.117480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 10/04/2024] Open
Abstract
Breast cancer remains the leading cause of cancer-related morbidity and mortality among women worldwide, underscoring the urgent need for novel diagnostic and therapeutic strategies. This review explores the emerging roles of circular RNAs (circRNAs) within extracellular vesicles (exosomes) in breast cancer. circRNAs, known for their stability and tissue-specific expression, are aberrantly expressed in breast cancer and regulate critical cellular processes such as proliferation, migration, and apoptosis, positioning them as promising biomarkers. Exosomes facilitate intercellular communication by delivering circRNAs, reflecting the physiological and pathological state of their source cells. This review highlights the multifaceted roles of exosomal circRNAs in promoting tumor growth, metastasis, and drug resistance through their modulation of tumor metabolism, the tumor microenvironment, and immune responses. In particular, we emphasize their contributions to chemotherapy resistance and their potential as both diagnostic markers and therapeutic targets. By synthesizing current research, this review provides novel insights into the clinical applications of exosomal circRNAs, offering a foundation for future studies aimed at improving breast cancer management through non-invasive diagnostics and targeted therapies.
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Affiliation(s)
- Lijuan Fang
- Department of Laboratory Medicine, Hangzhou Ninth People's Hospital, Hangzhou, Zhejaing Province 311200, China
| | - Zehua Zhu
- Department of Laboratory Medicine, Hangzhou Ninth People's Hospital, Hangzhou, Zhejaing Province 311200, China
| | - Mingyue Han
- Department of Laboratory Medicine, Hangzhou Ninth People's Hospital, Hangzhou, Zhejaing Province 311200, China
| | - Shaojie Li
- Department of Laboratory Medicine, Hangzhou Ninth People's Hospital, Hangzhou, Zhejaing Province 311200, China
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lusen Yang
- Department of Laboratory Medicine, Hangzhou Ninth People's Hospital, Hangzhou, Zhejaing Province 311200, China.
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Figueroa-Angulo EE, Puente-Rivera J, Perez-Navarro YF, Condado EM, Álvarez-Sánchez ME. Epigenetic alteration in cervical cancer induced by human papillomavirus. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 390:25-66. [PMID: 39864896 DOI: 10.1016/bs.ircmb.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The critical role of a subset of Human Papillomavirus in cervical cancer has been widely acknowledged and studied. Despite progress in our understanding of the viral molecular mechanisms of pathogenesis, knowledge of how infection with HPV oncogenic variants progresses from latent infection to incurable cancer has not been completely elucidated. In this paper we reviewed the relationship between HPV infection and epigenetic mechanisms such as histone acetylation and deacetylation, DNA methylation and non-coding RNAs associated with this infection and the carcinogenic process.
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Affiliation(s)
- Elisa-Elvira Figueroa-Angulo
- Licenciatura en Ciencias Genómicas, Laboratorio de Patogénesis Celular y Molecular Humana y Veterinaria, Universidad Autónoma de la Ciudad de la México, Ciudad de México, México
| | - Jonathan Puente-Rivera
- División de Investigación, Hospital Juárez De México, Ciudad de México, México; Posgrado en Ciencias Genómicas, Laboratorio de Patogenesis Celular y Molecular Humana y Veterinaria, Universidad Autónoma de la Ciudad de México, Ciudad de México, México
| | - Yussel Fernando Perez-Navarro
- Posgrado en Ciencias Genómicas, Laboratorio de Patogenesis Celular y Molecular Humana y Veterinaria, Universidad Autónoma de la Ciudad de México, Ciudad de México, México
| | - Edgar Mendieta Condado
- Laboratorio Estatal de Salud Pública, Secretaría de Salud de Jalisco, Guadalajara, Jalisco, México
| | - María-Elizbeth Álvarez-Sánchez
- Posgrado en Ciencias Genómicas, Laboratorio de Patogenesis Celular y Molecular Humana y Veterinaria, Universidad Autónoma de la Ciudad de México, Ciudad de México, México.
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Wang Y, Zhang J, Yang Y, Liu Z, Sun S, Li R, Zhu H, Li T, Zheng J, Li J, Ma L. Circular RNAs in human diseases. MedComm (Beijing) 2024; 5:e699. [PMID: 39239069 PMCID: PMC11374765 DOI: 10.1002/mco2.699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/25/2024] [Accepted: 07/30/2024] [Indexed: 09/07/2024] Open
Abstract
Circular RNAs (circRNAs) are a unique class of RNA molecules formed through back-splicing rather than linear splicing. As an emerging field in molecular biology, circRNAs have garnered significant attention due to their distinct structure and potential functional implications. A comprehensive understanding of circRNAs' functions and potential clinical applications remains elusive despite accumulating evidence of their involvement in disease pathogenesis. Recent research highlights their significant roles in various human diseases, but comprehensive reviews on their functions and applications remain scarce. This review provides an in-depth examination of circRNAs, focusing first on their involvement in non-neoplastic diseases such as respiratory, endocrine, metabolic, musculoskeletal, cardiovascular, and renal disorders. We then explore their roles in tumors, with particular emphasis on exosomal circular RNAs, which are crucial for cancer initiation, progression, and resistance to treatment. By detailing their biogenesis, functions, and impact on disease mechanisms, this review underscores the potential of circRNAs as diagnostic biomarkers and therapeutic targets. The review not only enhances our understanding of circRNAs' roles in specific diseases and tumor types but also highlights their potential as novel diagnostic and therapeutic tools, thereby paving the way for future clinical investigations and potential therapeutic interventions.
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Affiliation(s)
- Yuanyong Wang
- Department of Thoracic Surgery Tangdu Hospital Air Force Medical University Xi'an China
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) The First Department of Thoracic Surgery Peking University Cancer Hospital and Institute Peking University School of Oncology Beijing China
| | - Jin Zhang
- Department of Traditional Chinese Medicine Tangdu Hospital Air Force Medical University Xi'an China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine Tumor Diagnosis and Treatment in Shaanxi Province Xi'an China
| | - Yuchen Yang
- Department of Traditional Chinese Medicine Tangdu Hospital Air Force Medical University Xi'an China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine Tumor Diagnosis and Treatment in Shaanxi Province Xi'an China
| | - Zhuofeng Liu
- Department of Traditional Chinese Medicine The Third Affiliated Hospital of Xi'an Medical University Xi'an China
| | - Sijia Sun
- Department of Traditional Chinese Medicine Tangdu Hospital Air Force Medical University Xi'an China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine Tumor Diagnosis and Treatment in Shaanxi Province Xi'an China
| | - Rui Li
- Department of Epidemiology School of Public Health Air Force Medical University Xi'an China
| | - Hui Zhu
- Department of Anatomy Medical College of Yan'an University Yan'an China
- Institute of Medical Research Northwestern Polytechnical University Xi'an China
| | - Tian Li
- School of Basic Medicine Fourth Military Medical University Xi'an China
| | - Jin Zheng
- Department of Traditional Chinese Medicine Tangdu Hospital Air Force Medical University Xi'an China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine Tumor Diagnosis and Treatment in Shaanxi Province Xi'an China
| | - Jie Li
- Department of Endocrine Xijing 986 Hospital Air Force Medical University Xi'an China
| | - Litian Ma
- Department of Thoracic Surgery Tangdu Hospital Air Force Medical University Xi'an China
- Department of Traditional Chinese Medicine Tangdu Hospital Air Force Medical University Xi'an China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine Tumor Diagnosis and Treatment in Shaanxi Province Xi'an China
- Department of Gastroenterology Tangdu Hospital Air Force Medical University Xi'an China
- School of Medicine Northwest University Xi'an China
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Liu W, Sun Y, Huo Y, Zhang L, Zhang N, Yang M. Circular RNAs in lung cancer: implications for preventing therapeutic resistance. EBioMedicine 2024; 107:105309. [PMID: 39191172 PMCID: PMC11445705 DOI: 10.1016/j.ebiom.2024.105309] [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: 05/19/2024] [Revised: 08/11/2024] [Accepted: 08/12/2024] [Indexed: 08/29/2024] Open
Abstract
LC is one of the most common malignant tumours that often presents with no distinct symptoms in the early stages, leading to late diagnoses when patients are at an advanced stage and no longer suitable for surgical treatment. Although adjuvant treatments are available, patients frequently develop tolerance to these treatments over time, resulting in poor prognoses for patients with advanced LC. Recently, circular RNAs (circRNAs), a type of non-coding RNA, have gained significant attention in LC research. Owing to their unique circular structure, circRNAs are highly stable within cells. This review systematically summarises the expression, characteristics, biological functions, and molecular regulatory mechanisms of circRNAs involved in therapy resistance as well as the potential applications in early diagnosis and gene targeting therapy in LC.
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Affiliation(s)
- Wenjuan Liu
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China; School of Life Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, 271021, Shandong Province, China
| | - Yawen Sun
- Department of Scientific Research and Education, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Yanfei Huo
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Long Zhang
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Ming Yang
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China; School of Life Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, 271021, Shandong Province, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
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Weidle UH, Nopora A. CircRNAs in Pancreatic Cancer: New Tools for Target Identification and Therapeutic Intervention. Cancer Genomics Proteomics 2024; 21:327-349. [PMID: 38944427 PMCID: PMC11215428 DOI: 10.21873/cgp.20451] [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: 05/07/2024] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 07/01/2024] Open
Abstract
We have reviewed the literature for circular RNAs (circRNAs) with efficacy in preclinical pancreatic-cancer related in vivo models. The identified circRNAs target chemoresistance mechanisms (n=5), secreted proteins and transmembrane receptors (n=15), transcription factors (n=9), components of the signaling- (n=11), ubiquitination- (n=2), autophagy-system (n=2), and others (n=9). In addition to identifying targets for therapeutic intervention, circRNAs are potential new entities for treatment of pancreatic cancer. Up-regulated circRNAs can be inhibited by antisense oligonucleotides (ASO), small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs) or clustered regularly interspaced short-palindromic repeats-CRISPR associated protein (CRISPR-CAS)-based intervention. The function of down-regulated circRNAs can be reconstituted by replacement therapy using plasmids or virus-based vector systems. Target validation experiments and the development of improved delivery systems for corresponding agents were examined.
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Affiliation(s)
- Ulrich H Weidle
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Adam Nopora
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
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Li Z, Yin S, Yang K, Zhang B, Wu X, Zhang M, Gao D. CircRNA Regulation of T Cells in Cancer: Unraveling Potential Targets. Int J Mol Sci 2024; 25:6383. [PMID: 38928088 PMCID: PMC11204142 DOI: 10.3390/ijms25126383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/06/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
T lymphocytes play a critical role in antitumor immunity, but their exhaustion poses a significant challenge for immune evasion by malignant cells. Circular RNAs (circRNAs), characterized by their covalently closed looped structure, have emerged as pivotal regulators within the neoplastic landscape. Recent studies have highlighted their multifaceted roles in cellular processes, including gene expression modulation and protein function regulation, which are often disrupted in cancer. In this review, we systematically explore the intricate interplay between circRNAs and T cell modulation within the tumor microenvironment. By dissecting the regulatory mechanisms through which circRNAs impact T cell exhaustion, we aim to uncover pathways crucial for immune evasion and T cell dysfunction. These insights can inform innovative immunotherapeutic strategies targeting circRNA-mediated molecular pathways. Additionally, we discuss the translational potential of circRNAs as biomarkers for therapeutic response prediction and as intervention targets. Our comprehensive analysis aims to enhance the understanding of immune evasion dynamics in the tumor microenvironment by facilitating the development of precision immunotherapy.
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Affiliation(s)
- Zelin Li
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330047, China; (Z.L.); (B.Z.)
- The First Clinical Medical College, Nanchang University, Nanchang 330047, China; (S.Y.); (X.W.)
| | - Shuanshuan Yin
- The First Clinical Medical College, Nanchang University, Nanchang 330047, China; (S.Y.); (X.W.)
| | - Kangping Yang
- The Second Clinical Medical College, Nanchang University, Nanchang 330047, China;
| | - Baojie Zhang
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330047, China; (Z.L.); (B.Z.)
| | - Xuanhuang Wu
- The First Clinical Medical College, Nanchang University, Nanchang 330047, China; (S.Y.); (X.W.)
| | - Meng Zhang
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330047, China; (Z.L.); (B.Z.)
| | - Dian Gao
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330047, China; (Z.L.); (B.Z.)
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10
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Wu Z, Wang B, Chen S, Zuo T, Zhang W, Cheng Z, Fu J, Gong J. Hsa_circ_0009096/miR-370-3p modulates hepatic stellate cell proliferation and fibrosis during biliary atresia pathogenesis. PeerJ 2024; 12:e17356. [PMID: 38766485 PMCID: PMC11100479 DOI: 10.7717/peerj.17356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 04/18/2024] [Indexed: 05/22/2024] Open
Abstract
Background Hepatic stellate cell (HSC) activation and hepatic fibrosis mediated biliary atresia (BA) development, but the underlying molecular mechanisms are poorly understood. This study aimed to investigate the roles of circRNA hsa_circ_0009096 in the regulation of HSC proliferation and hepatic fibrosis. Methods A cellular hepatic fibrosis model was established by treating LX-2 cells with transforming growth factor β (TGF-β1). RNaseR and actinomycin D assays were performed to detect hsa_circ_0009096 stability. Expression of hsa_circ_0009096, miR-370-3p, and target genes was detected using reverse transcription-qPCR. Direct binding of hsa_circ_0009096 to miR-370-3p was validated using dual luciferase reporter assay. Cell cycle progression and apoptosis of LX-2 cells were assessed using flow cytometry. The alpha-smooth muscle actin (α-SMA), collagen 1A1 (COL1A1), and TGF beta receptor 2 (TGFBR2) protein levels in LX-2 cells were analyzed using immunocytochemistry and western blotting. Results Hsa_circ_0009096 exhibited more resistance to RNase R and actinomycinD digestion than UTRN mRNA. Hsa_circ_0009096 expression increased significantly in LX-2 cells treated with TGF-β1, accompanied by elevated α-SMA and COL1A1 expression. Hsa_circ_0009096 siRNAs effectively promoted miR-370-3p and suppressed TGFBR2 expression in LX-2 cells, mediated by direct association of hsa_circ_0009096 with miR-370-3p. Hsa_circ_0009096 siRNA interfered with the cell cycle progression, promoted apoptosis, and reduced α-SMA and COL1A1 expression in LX-2 cells treated with TGF-β1. MiR-370-3p inhibitors mitigated the alterations in cell cycle progression, apoptosis, and α-SMA, COL1A1, and TGFBR2 expression in LX-2 cells caused by hsa_circ_0009096 siRNA. In conclusion, hsa_circ_0009096 promoted HSC proliferation and hepatic fibrosis during BA pathogenesis by accelerating TGFBR2 expression by sponging miR-370-3p.
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Affiliation(s)
- Zhouguang Wu
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, China
| | - Bin Wang
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, China
| | - Siqi Chen
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, China
| | - Taoyan Zuo
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, China
| | - Wenjie Zhang
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, China
| | - Zhen Cheng
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, China
| | - Jingru Fu
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, China
| | - Jiafeng Gong
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, China
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Liu X, Xiong H, Lu M, Liu B, Hu C, Liu P. Trans-3, 5, 4'-trimethoxystilbene restrains non-small-cell lung carcinoma progression via suppressing M2 polarization through inhibition of m6A modified circPACRGL-mediated Hippo signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 126:155436. [PMID: 38394728 DOI: 10.1016/j.phymed.2024.155436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/17/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024]
Abstract
BACKGROUND Non-small-cell lung carcinoma (NSCLC) accounts for ∼85% of all lung carcinomas. Trans-3,5,4'-trimethoxystilbene (TMS) shows strong anti-tumor activity and induces tumor cell apoptosis. However, its function and mechanism in NSCLC still require investigation. METHODS PMA was used to treated THP-1 cells for macrophage differentiation. The abundance and m6A modification of circPACRGL were examined with qRT-PCR and MeRIP. Colony forming, transwell, wound healing, and Western blotting assays were applied to analyze proliferation, invasion, migration, and EMT. Macrophage polarization was determined through flow cytometry analysis of M1 and M2 markers. The interplay between circPACRGL, IGF2BP2 and YAP1 was validated by RNA pull-down and RIP assays. Mice received subcutaneous injection of NSCLC cells as a mouse model of subcutaneous tumor. RESULTS CircPACRGL was upregulated in NSCLC cells, but it was reduced by TMS treatment. CircPACRGL depletion blocked proliferation, migration, and invasion in H1299 and H1975 cells. TMS suppressed these malignant behaviors, but it was abolished by circPACRGL overexpression. In addition, NSCLC-derived exosomes delivered circPACRGL into THP-1 cells to promote its M2 polarization, but TMS inhibited these effects by downregulating exosomal circPACRGL. Mechanically, exosomal circPACRGL bound to IGF2BP2 to improve the stability of YAP1 mRNA and regulate Hippo signaling in polarized THP-1 cells. TMS inhibited NSCLC growth via suppressing Hippo signaling and M2 polarization in vivo. CONCLUSION TMS restrains M2 polarization and NSCLC progression by reducing circPACRGL and inhibiting exosomal circPACRGL-mediated Hippo signaling. Thus, these findings provide a novel mechanism underlying NSCLC progression and potential therapeutic targets.
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Affiliation(s)
- Xiaoyu Liu
- Department of Oncology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, PR China
| | - Hui Xiong
- Department of Oncology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, PR China
| | - Min Lu
- Department of Oncology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, PR China
| | - Bin Liu
- Department of Oncology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, PR China
| | - Chunhong Hu
- Department of Oncology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, PR China
| | - Ping Liu
- Department of Oncology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, PR China.
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Heydarnia E, Dorostgou Z, Hedayati N, Mousavi V, Yahyazadeh S, Alimohammadi M, Gheibi M, Heidari P, Igder S, Mafi A, Vakili O. Circular RNAs and cervical cancer: friends or foes? A landscape on circRNA-mediated regulation of key signaling pathways involved in the onset and progression of HPV-related cervical neoplasms. Cell Commun Signal 2024; 22:107. [PMID: 38341592 PMCID: PMC10859032 DOI: 10.1186/s12964-024-01494-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 01/20/2024] [Indexed: 02/12/2024] Open
Abstract
Cervical cancer (CC) is a common gynecologic malignancy, accounting for a significant proportion of women death worldwide. Human papillomavirus (HPV) infection is one of the major etiological causes leading to CC onset; however, genetic, and epigenetic factors are also responsible for disease expansion. Circular RNAs (circRNAs), which are known as a particular subset of non-coding RNA (ncRNA) superfamily, with covalently closed loop structures, have been reported to be involved in the progression of diverse diseases, especially neoplasms. In this framework, abnormally expressed circRNAs are in strong correlation with CC pathogenesis through regulating substantial signaling pathways. Also, these RNA molecules can be considered as promising biomarkers and therapeutic targets for CC diagnosis/prognosis and treatment, respectively. Herein, we first review key molecular mechanisms, including Wnt/β-catenin, MAPK, and PI3K/Akt/mTOR signaling pathways, as well as angiogenesis and metastasis, by which circRNAs interfere with CC development. Then, diagnostic, prognostic, and therapeutic potentials of these ncRNA molecules will be highlighted in depth.
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Affiliation(s)
- Emad Heydarnia
- Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Dorostgou
- Department of Biochemistry, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
| | - Neda Hedayati
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Vahide Mousavi
- School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Sheida Yahyazadeh
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mina Alimohammadi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mobina Gheibi
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Parasta Heidari
- School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran.
| | - Somayeh Igder
- Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
- Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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13
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Shen HY, Xu JL, Zhang W, Chen QN, Zhu Z, Mao Y. Exosomal circRHCG promotes breast cancer metastasis via facilitating M2 polarization through TFEB ubiquitination and degradation. NPJ Precis Oncol 2024; 8:22. [PMID: 38287113 PMCID: PMC10825185 DOI: 10.1038/s41698-024-00507-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 12/06/2023] [Indexed: 01/31/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive cancer with distant metastasis. Accumulated evidence has demonstrated that exosomes are involved in TNBC metastasis. Elucidating the mechanism underlying TNBC metastasis has important clinical significance. In the present study, exosomes were isolated from clinical specimens and TNBC cell lines. Colony formation, EdU incorporation, wound healing, and transwell assays were performed to examine TNBC cell proliferation, migration, and metastasis. Macrophage polarization was evaluated by flow cytometry and RT-qPCR analysis of polarization markers. A mouse model of subcutaneous tumor was established for assessment of tumor growth and metastasis. RNA pull-down, RIP and Co-IP assays were used for analyzing molecular interactions. Here, we proved that high abundance of circRHCG was observed in exosomes derived from TNBC patients, and increased exosomal circRHCG indicated poor prognosis. Silencing of circRHCG suppressed TNBC cell proliferation, migration, and metastasis. TNBC cell-derived exosomes promoted M2 polarization via delivering circRHCG. Exosomal circRHCG stabilized BTRC mRNA via binding FUS and naturally enhanced BTRC expression, thus promoting the ubiquitination and degradation of TFEB in THP-1 cells. In addition, knockdown of BTRC or overexpression of TFEB counteracted exosomal circRHCG-mediated facilitation of M2 polarization. Furthermore, exosomal circRHCG promoted TNBC cell proliferation and metastasis by facilitating M2 polarization. Knockdown of circRHCG reduced tumor growth, metastasis, and M2 polarization through the BTRC/TFEB axis in vivo. In summary, exosomal circRHCG promotes M2 polarization by stabilizing BTRC and promoting TFEB degradation, thereby accelerating TNBC metastasis and growth. Our study provides promising therapeutic strategies against TNBC.
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Affiliation(s)
- Hong-Yu Shen
- Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhou, China
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jia-Lin Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Zhang
- Division of Gastrointestinal Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
| | - Qin-Nan Chen
- Department of Clinical Medicine, Jiangsu Health Vocational College, Nanjing, China.
| | - Zhen Zhu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Yuan Mao
- Department of Oncology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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14
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Wang Y, Xie Y, Wang X, Yang N, Wu Z, Zhang X. Tumor cells-derived extracellular vesicles carry circ_0064516 competitively inhibit microRNA-6805-3p and promote cervical cancer angiogenesis and tumor growth. Expert Opin Ther Targets 2024; 28:97-112. [PMID: 38270096 DOI: 10.1080/14728222.2024.2306353] [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: 03/19/2023] [Accepted: 01/12/2024] [Indexed: 01/26/2024]
Abstract
BACKGROUND The current study tried to elucidate the regulatory role of tumor cell-derived exosomes (Exos)-circ_0064516 in angiogenesis and growth of cervical cancer. RESEARCH DESIGN AND METHODS Related cirRNAs and downstream target genes were identified through bioinformatics analysis. Exos were isolated from cervical cancer cell line CaSki, followed by co-cultured with human umbilical vein endothelial cells (HUVECs). Then, the roles of circ_0064516, miR-6805-3p, and MAPK1 in migration and angiogenesis of HUVECs were assayed. Furthermore, xenografted tumors were transplanted into nude mice for in vivo validation. RESULTS In vitro assay validated highly expressed circ_0064516 in cervical cancer cells. Tumor cell-derived Exos carried circ_0064516 to HUVECs. circ_0064516 increased MAPK1 expression by binding to miR-6805-3p, thus enhancing migration and angiogenesis. Exos containing circ_0064516 also promoted tumorigenesis of cervical cancer cells in nude mice. CONCLUSIONS We confirmed the oncogenic role of tumor cell-derived Exos carrying circ_0064516 in cervical cancer progression through miR-6805-3p/MAPK1.
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Affiliation(s)
- Yujue Wang
- Department of Obstetrics and Gynecology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yao Xie
- Department of Obstetrics and Gynecology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xue Wang
- Department of Obstetrics and Gynecology, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu, Sichuan, China
| | - Nian Yang
- Department of Obstetrics and Gynecology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhao Wu
- Department of Obstetrics and Gynecology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xun Zhang
- Department of Obstetrics and Gynecology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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15
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Guo Z, Wang G, Yun Z, Li Y, Huang B, Jin Q, Chen Y, Xu L, Lv W. Global research trends in tumor stem cell-derived exosomes and tumor microenvironment: visualization biology analysis. J Cancer Res Clin Oncol 2023; 149:17581-17595. [PMID: 37914951 PMCID: PMC10657319 DOI: 10.1007/s00432-023-05450-2] [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: 07/25/2023] [Accepted: 09/29/2023] [Indexed: 11/03/2023]
Abstract
BANKGROUND The tumor microenvironment (TME) is an internal environment composed of various cells and an extracellular matrix. Cancer stem cell-derived exosomes (CSC-Exos), as essential messengers involved in various tumor processes, are important carriers for bidirectional communication between the tumor microenvironment and tumor cells and play an important role in the tumor microenvironment. Nevertheless, few bibliometric analyses have been systematically studied in this field. METHODS Therefore, we aimed to visualize the research hotspots and trends in this field through bibliometrics to comprehend the future evolution of fundamental and clinical research, as well as to offer insightful information and fresh viewpoints. The Scopus database was used to search the research literature related to exosomes and tumor microenvironments after the establishment of this repository. CiteSpace (version 5.8.R3) and VOSviewer (version 1.6.16) were used for visualization and analysis. RESULTS In this study, a total of 2077 articles and reviews were included, with the number of articles on exosomes and tumor microenvironments significantly increasing yearly. Recent trends showed that the potential value of exosomes as "tumor diagnostics" and "the application prospect of exosomes as therapeutic agents and drug delivery carriers" will receive more attention in the future. CONCLUSIONS We revealed the current status and hotspots of tumor stem cell-derived exosomes and tumor microenvironments globally through bibliometrics. The prospect of the regulatory role of CSC-Exos in TME, the potential value of diagnosis, and the application of drug delivery vectors will all remain cutting-edge research areas in the field of tumor therapy. Meanwhile, this study provided a functional literature analysis for related researchers.
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Affiliation(s)
- Ziwei Guo
- Department of Infection, China Academy of Chinese Medical Sciences, Guang' anmen Hospital, Beijing, China
| | - Gang Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Zhangjun Yun
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yanbo Li
- Department of Infection, China Academy of Chinese Medical Sciences, Guang' anmen Hospital, Beijing, China
| | - Bohao Huang
- Guang' anmen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Qian Jin
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yue Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Luchun Xu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Wenliang Lv
- Department of Infection, China Academy of Chinese Medical Sciences, Guang' anmen Hospital, Beijing, China.
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16
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Ruiz Esparza Garrido R, Velázquez Flores MÁ. Circular RNAs: the next level of gene regulation. Am J Transl Res 2023; 15:6122-6135. [PMID: 37969203 PMCID: PMC10641363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/07/2023] [Indexed: 11/17/2023]
Abstract
Gene regulation is a highly complex process involving the presence and participation of many molecules and complexes that regulate gene expression in the genome, which occurs in a precise and coordinated way. Among all these regulatory molecules, the circular RNAs (circRNAs) are the most novel and peculiar family of noncoding RNAs (ncRNAs) as they have a circular structure, are very specific on their expression, highly conserved, and highly resistant to degradation. These molecules have been described in recent years as excellent disease markers and as potential therapeutic targets. In this review, we focused on general characteristics and on the evolution of the circRNAs, as well as on their biological functions, emphasizing on their participation in the formation of brain tumors.
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Affiliation(s)
- Ruth Ruiz Esparza Garrido
- Investigadora por México, Laboratorio de RNAs No Codificantes de la Unidad de Investigación Médica en Genética Humana, Hospital de Pediatría CMNSXXI, Instituto Mexicano del Seguro Social (IMSS)CDMX, México
| | - Miguel Ángel Velázquez Flores
- Laboratorio de RNAs No Codificantes de la Unidad de Investigación Médica en Genética Humana, Hospital de Pediatría CMNSXXI, Instituto Mexicano del Seguro Social (IMSS)CDMX, México
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17
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Liu X, Zheng M, Han R, Yu Z, Yuan W, Xie B, Zhang Y, Zhong J, Wang L, Wang L, Liu X. Circulating Exosomal CircRNAs as Diagnostic Biomarkers for Chronic Coronary Syndrome. Metabolites 2023; 13:1066. [PMID: 37887391 PMCID: PMC10608616 DOI: 10.3390/metabo13101066] [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: 07/28/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/28/2023] Open
Abstract
Circular RNA (circRNA) has been reported to be involved in the pathogenesis of cardiovascular disease; however, it is unclear whether circRNA carried by exosomes (exos) can be used as biomarkers for chronic coronary syndrome (CCS). High-throughput sequencing was carried out in the plasma exosomal RNA of 15 CCS patients and 15 non-cardiac chest pain patients (NCCP, control group) to screen for differentially expressed circRNAs. Selected differentially expressed exo-circRNAs were further verified by real-time polymerase chain reaction in a small-sample cohort and a large-sample cohort. A total of 276 circRNAs were differentially expressed in the plasma exosomes of CCS patients, with 103 up-regulated and 173 down-regulated. Among the 103 up-regulated circRNAs, 5 circRNAs with high expression levels were selected for validation. Real time quantitative PCR of the first and second validation cohort demonstrated that exo-hsa_circ_0075269 and exo-hsa_circ_0000284 were significantly up-regulated in patients with CCS. Circulating exo-hsa_circ_0075269 and exo-hsa_circ_0000284 yielded the area under the curve values of 0.761 (p < 0.001, 95%CI = 0.669, 0.852) and 0.623 (p = 0.015, 95%CI = 0.522, 0.724) for CCS, respectively, by ROC curve analysis. In conclusion, the expression profile of circRNA in plasma exosomes of patients with CCS was significantly different from that of the control group. Plasma exo-hsa_circ_0075269 and exo-hsa_circ_0000284 have the potential to be new biomarkers for CCS.
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Affiliation(s)
- Xiaoyan Liu
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; (X.L.); (M.Z.); (B.X.); (Y.Z.); (J.Z.); (L.W.)
- Department of Cardiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China;
| | - Meili Zheng
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; (X.L.); (M.Z.); (B.X.); (Y.Z.); (J.Z.); (L.W.)
- Department of Cardiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Ruijuan Han
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen 518172, China;
| | - Ziyang Yu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100105, China;
| | - Wen Yuan
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China;
| | - Boqia Xie
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; (X.L.); (M.Z.); (B.X.); (Y.Z.); (J.Z.); (L.W.)
- Department of Cardiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Yeping Zhang
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; (X.L.); (M.Z.); (B.X.); (Y.Z.); (J.Z.); (L.W.)
| | - Jiuchang Zhong
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; (X.L.); (M.Z.); (B.X.); (Y.Z.); (J.Z.); (L.W.)
- Department of Cardiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Lefeng Wang
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; (X.L.); (M.Z.); (B.X.); (Y.Z.); (J.Z.); (L.W.)
- Department of Cardiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Lixia Wang
- Department of Cardiology, Sinopharm Tongmei General Hospital, Datong 037003, China
| | - Xinming Liu
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; (X.L.); (M.Z.); (B.X.); (Y.Z.); (J.Z.); (L.W.)
- Department of Cardiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
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Zhu M, Chen D, Ruan C, Yang P, Zhu J, Zhang R, Li Y. CircRNAs: A Promising Star for Treatment and Prognosis in Oral Squamous Cell Carcinoma. Int J Mol Sci 2023; 24:14194. [PMID: 37762497 PMCID: PMC10532269 DOI: 10.3390/ijms241814194] [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: 08/15/2023] [Revised: 09/11/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
CircRNAs are a class of endogenous long non-coding RNAs with a single-stranded circular structure. Most circRNAs are relatively stable, highly conserved, and specifically expressed in tissue during the cell and developmental stages. Many circRNAs have been discovered in OSCC. OSCC is one of the most severe and frequent forms of head and neck cancer today, with a poor prognosis and low overall survival rate. Due to its prevalence, OSCC is a global health concern, characterized by genetic and epigenomic changes. However, the mechanism remains vague. With the advancement of biotechnology, a large number of circRNAs have been discovered in mammalian cells. CircRNAs are dysregulated in OSCC tissues and thus associated with the clinicopathological characteristics and prognosis of OSCC patients. Research studies have demonstrated that circRNAs can serve as biomarkers for OSCC diagnosis and treatment. Here, we summarized the properties, functions, and biogenesis of circRNAs, focusing on the progress of current research on circRNAs in OSCC.
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Affiliation(s)
| | | | | | | | | | - Rongxin Zhang
- Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China; (M.Z.); (D.C.); (C.R.); (J.Z.)
| | - Yan Li
- Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China; (M.Z.); (D.C.); (C.R.); (J.Z.)
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Yang X, Xia J, Peng C, Cai W. Expression of plasma exosomal circLPAR1 in patients with gastric cancer and its clinical application value. Am J Cancer Res 2023; 13:4269-4276. [PMID: 37818058 PMCID: PMC10560946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 08/13/2023] [Indexed: 10/12/2023] Open
Abstract
OBJECTIVE To determine plasma exosomal circular RNA LPAR1 (circLPAR1) expression in gastric cancer (GC) and analyze its clinical value in GC diagnosis and prognosis evaluation. METHODS The research subjects were 64 GC patients, 30 chronic gastritis (CG) patients (disease control group) and 30 healthy controls (HCs; healthy control group). RT-PCR quantified circLPAR1 expression in GC tissues and adjacent counterparts of GC patients as well as plasma exosomal circLPAR1 in each group. The correlation of differentially expressed circLPAR1 with clinicopathological indexes was analyzed, and receiver operating characteristics (ROC) and Kaplan-Meier curves were drawn to evaluate the value of plasma exosomal circLPAR1 in GC diagnosis and prognosis assessment. RESULTS GC patients exhibited lower plasma exosomal circLPAR1 levels than CG patients and HCs (P<0.05). Lower circLPAR1 expression was determined in GC tissues than in adjacent counterparts (P<0.05), and a positive connection between GC tissue circLPAR1 and plasma exosomal circLPAR1 was identified in GC patients (P<0.05). Evidently elevated plasma exosomal circLPAR1 was observed in post-surgical GC patients (P<0.05). ROC curves showed that the areas under the curve (AUCs) of plasma exosomal circLPAR1, serum carcinoembryonic antigen (CEA), and serum carbohydrate antigen 19-9 (CA19-9) for the diagnosis of GC were 0.836, 0.767 and 0.746, respectively, and the AUC of their combined diagnosis was 0.914. Low plasma exosomal circLPAR1 was strongly linked to tumor size, differentiation degree, tumor-node-metastasis (TNM) staging, vascular invasion, lymphatic metastasis, and HER2 expression of GC patients (P<0.05). GC patients with high plasma exosomal circLPAR1 expression had significantly longer prognostic survival time than those with low expression (P<0.05). According to univariate and multivariate Cox regression analyses, tissue differentiation degree (HR=1.415), TNM stage (HR=1.637), HER2 expression (HR=1.831), and low plasma exosomal circLPAR1 expression (HR=2.042) were risk factors for adverse prognosis in GC patients. CONCLUSIONS circLPAR1 expression is related to GC progression, and the detection of plasma exosomal circLPAR1 has promising clinical application value in assisting the diagnosis and prognosis evaluation of GC.
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Affiliation(s)
- Xiaobin Yang
- Day Clinic Area, The Sixth Medical Center of PLA General HospitalBeijing, China
| | - Jing Xia
- Day Clinic Area, The Sixth Medical Center of PLA General HospitalBeijing, China
| | - Chaosheng Peng
- Day Clinic Area, The Sixth Medical Center of PLA General HospitalBeijing, China
| | - Weiping Cai
- Department of Geriatric Medicine, The Sixth Medical Center of PLA General HospitalBeijing, China
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20
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Xu HZ, Lin XY, Xu YX, Xue HB, Lin S, Xu TW. An emerging research: the role of hepatocellular carcinoma-derived exosomal circRNAs in the immune microenvironment. Front Immunol 2023; 14:1227150. [PMID: 37753074 PMCID: PMC10518420 DOI: 10.3389/fimmu.2023.1227150] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/28/2023] [Indexed: 09/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common primary malignancy of the liver, is one of the leading causes of cancer-related death and is associated with a poor prognosis. The tumor microenvironment (TME) of HCC comprises immune, immunosuppressive, and interstitial cells with hypoxic, angiogenic, metabolic reprogramming, inflammatory, and immunosuppressive features. Exosomes are nanoscale extracellular vesicles that secrete biologically active signaling molecules such as deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA), microribonucleic acid (miRNA), proteins, and lipids. These signaling molecules act as messengers in the tumor microenvironment, especially the tumor immunosuppressive microenvironment. Exosomal circRNAs reshape the tumor microenvironment by prompting hypoxic stress response, stimulating angiogenesis, contributing to metabolic reprogramming, facilitating inflammatory changes in the HCC cells and inducing tumor immunosuppression. The exosomes secreted by HCC cells carry circRNA into immune cells, which intervene in the activation of immune cells and promote the overexpression of immune checkpoints to regulate immune response, leading tumor cells to acquire immunosuppressive properties. Furthermore, immunosuppression is the final result of a combination of TME-related factors, including hypoxia, angiogenesis, metabolic reprogramming, and inflammation changes. In conclusion, exosomal circRNA accelerates the tumor progression by adjusting the phenotype of the tumor microenvironment and ultimately forming an immunosuppressive microenvironment. HCC-derived exosomal circRNA can affect HCC cell proliferation, invasion, metastasis, and induction of chemoresistance. Therefore, this review aimed to summarize the composition and function of these exosomes, the role that HCC-derived exosomal circRNAs play in microenvironment formation, and the interactions between exosomes and immune cells. This review outlines the role of exosomal circRNAs in the malignant phenotype of HCC and provides a preliminary exploration of the clinical utility of exosomal circRNAs.
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Affiliation(s)
- Huang-Zhen Xu
- Department of Digestive Tumor, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Xin-Yi Lin
- Department of Digestive Tumor, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yun-Xian Xu
- Department of Digestive Tumor, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Hui-Bin Xue
- Department of Digestive Tumor, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Tian-Wen Xu
- Department of Digestive Tumor, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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21
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Li J, Song Y, Cai H, Zhou B, Ma J. Roles of circRNA dysregulation in esophageal squamous cell carcinoma tumor microenvironment. Front Oncol 2023; 13:1153207. [PMID: 37384299 PMCID: PMC10299836 DOI: 10.3389/fonc.2023.1153207] [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: 01/29/2023] [Accepted: 05/30/2023] [Indexed: 06/30/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the most prevalent histological esophageal cancer characterized by advanced diagnosis, metastasis, resistance to treatment, and frequent recurrence. In recent years, numerous human disorders such as ESCC, have been linked to abnormal expression of circular RNAs (circRNAs), suggesting that they are fundamental to the intricate system of gene regulation that governs ESCC formation. The tumor microenvironment (TME), referring to the area surrounding the tumor cells, is composed of multiple components, including stromal cells, immune cells, the vascular system, extracellular matrix (ECM), and numerous signaling molecules. In this review, we briefly described the biological purposes and mechanisms of aberrant circRNA expression in the TME of ESCC, including the immune microenvironment, angiogenesis, epithelial-to-mesenchymal transition, hypoxia, metabolism, and radiotherapy resistance. As in-depth research into the processes of circRNAs in the TME of ESCC continues, circRNAs are promising therapeutic targets or delivery systems for cancer therapy and diagnostic and prognostic indicators for ESCC.
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Affiliation(s)
- Jingyi Li
- Department of Clinical Laboratory, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuxia Song
- Department of Reproductive Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Huihong Cai
- Department of Clinical Laboratory, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Bo Zhou
- Medical Research Center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jun Ma
- Department of Clinical Laboratory, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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22
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Chen C, Yang C, Tian X, Liang Y, Wang S, Wang X, Shou Y, Li H, Xiao Q, Shu J, Sun M, Chen K. Downregulation of miR-100-5p in cancer-associated fibroblast-derived exosomes facilitates lymphangiogenesis in esophageal squamous cell carcinoma. Cancer Med 2023. [PMID: 37184125 DOI: 10.1002/cam4.6078] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 04/27/2023] [Accepted: 05/03/2023] [Indexed: 05/16/2023] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC), an aggressive gastrointestinal tumor, often has high early lymphatic metastatic potential. Cancer-associated fibroblasts (CAFs) are primary components in tumor microenvironment (TME), and the impact of CAFs and its derived exosomes on lymphangiogenesis remains elusive. MATERIALS AND METHODS CAFs and the microlymphatic vessel density (MLVD) in ESCC was examined. Exosomes were extracted from primary normal fibroblast (NFs) and CAFs. Subsequently, tumor-associated lymphatic endothelial cells (TLECs) were treated with these exosomes, and the effect on their biological behavior was examined. miR-100-5p was selected as the target miRNA, and its effect on TLECs was examined. The target of miR-100-5p was predicted and confirmed. Subsequently, IGF1R, PI3K, AKT, and p-AKT expression in TLECs and tumors treated with exosomes and miR-100-5p were examined. RESULTS A large number of CAFs and microlymphatic vessels were present in ESCC, leading to a poor prognosis. CAF-derived exosomes promoted proliferation, migration, invasion, and tube formation in TLECs. Further, they also enhanced lymphangiogenesis in ESCC xenografts. miR-100-5p levels were significantly lower in CAF-derived exosomes than in NF-derived exosomes. miR-100-5p inhibited proliferation, migration, invasion, and tube formation in TLECs. Further, miR-100-5p inhibited lymphangiogenesis in ESCC xenografts. Mechanistic studies revealed that this inhibition was mediated by the miR-100-5p-induced inhibition of IGF1R/PI3K/AKT axis. CONCLUSION Taken together, our study demonstrates that CAF-derived exosomes with decreased miR-100-5p levels exhibit pro-lymphangiogenesis capacity, suggesting a possibility of targeting IGF1R/PI3K/AKT axis as a strategy to inhibit lymphatic metastasis in ESCC.
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Affiliation(s)
- Chao Chen
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chenbo Yang
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiangyu Tian
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Osteology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yinghao Liang
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Shuaiyuan Wang
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoqian Wang
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yuwei Shou
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hui Li
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
| | - Qiankun Xiao
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
| | - Jiao Shu
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Miaomiao Sun
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Kuisheng Chen
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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23
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J Saadh M, Abedi Kiasari B, Shahrtash SA, Arias-Gonzáles JL, Chaitanya M, Cotrina-Aliaga JC, Kadham MJ, Sârbu I, Akhavan-Sigari R. Exosomal non-coding RNAs' role in immune regulation and potential therapeutic applications. Pathol Res Pract 2023; 247:154522. [PMID: 37201467 DOI: 10.1016/j.prp.2023.154522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 05/07/2023] [Accepted: 05/08/2023] [Indexed: 05/20/2023]
Abstract
Exosomes are now significant players in both healthy and unhealthy cell-to-cell communication. Exosomes can mediate immune activation or immunosuppression, which can influence the growth of tumors. Exosomes affect the immune responses to malignancies in various ways by interacting with tumor cells and the environment around them. Exosomes made by immune cells can control the growth, metastasis, and even chemosensitivity of tumor cells. In contrast, exosomes produced by cancer cells can encourage immune responses that support the tumor. Exosomes carry circular RNAs, long non-coding RNAs, and microRNAs (miRNAs), all involved in cell-to-cell communication. In this review, we focus on the most recent findings concerning the role of exosomal miRNAs, lncRNAs, and circRNAs in immune modulation and the potential therapeutic implications of these discoveries.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan; Applied Science Research Center. Applied Science Private University, Amman, Jordan
| | - Bahman Abedi Kiasari
- Virology Department, Faculty of Veterinary Medicine, The University of Tehran, Tehran, Iran
| | - Seyed Abbas Shahrtash
- Department of Pharmaceutical Engineering, Alborz Campus, University of Tehran, Tehran, Iran
| | | | - Mvnl Chaitanya
- Department of Pharmacognosy, School of Pharmacy, Lovely professional university Phagwara, Punjab 144001, India
| | | | | | - Ioan Sârbu
- 2nd Department of Surgery - Pediatric Surgery and Orthopedics, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania.
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University Warsaw, Poland
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24
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Li S, Xin K, Pan S, Wang Y, Zheng J, Li Z, Liu X, Liu B, Xu Z, Chen X. Blood-based liquid biopsy: insights into early detection, prediction, and treatment monitoring of bladder cancer. Cell Mol Biol Lett 2023; 28:28. [PMID: 37016296 PMCID: PMC10074703 DOI: 10.1186/s11658-023-00442-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 03/21/2023] [Indexed: 04/06/2023] Open
Abstract
Bladder cancer (BC) is a clinical challenge worldwide with late clinical presentation, poor prognosis, and low survival rates. Traditional cystoscopy and tissue biopsy are routine methods for the diagnosis, prognosis, and monitoring of BC. However, due to the heterogeneity and limitations of tumors, such as aggressiveness, high cost, and limited applicability of longitudinal surveillance, the identification of tumor markers has attracted significant attention in BC. Over the past decade, liquid biopsies (e.g., blood) have proven to be highly efficient methods for the discovery of BC biomarkers. This noninvasive sampling method is used to analyze unique tumor components released into the peripheral circulation and allows serial sampling and longitudinal monitoring of tumor progression. Several liquid biopsy biomarkers are being extensively studied and have shown promising results in clinical applications of BC, including early detection, detection of microscopic residual disease, prediction of recurrence, and response to therapy. Therefore, in this review, we aim to provide an update on various novel blood-based liquid biopsy markers and review the advantages and current limitations of liquid biopsy in BC therapy. The role of blood-based circulating tumor cells, circulating tumor DNA, cell-free RNA, exosomes, metabolomics, and proteomics in diagnosis, prognosis, and treatment monitoring, and their applicability to the personalized management of BC, are highlighted.
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Affiliation(s)
- Shijie Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China
| | - Kerong Xin
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China
| | - Shen Pan
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China
| | - Yang Wang
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, Liaoning, People's Republic of China
| | - Jianyi Zheng
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China
| | - Zeyu Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China
| | - Xuefeng Liu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China
| | - Bitian Liu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China.
| | - Zhenqun Xu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China.
| | - Xiaonan Chen
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China.
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25
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Tsutsumi K, Otsuka M. Clinical application of pancreatic juice‐derived small extracellular vesicles of pancreatic ductal adenocarcinoma. CLINICAL AND TRANSLATIONAL DISCOVERY 2023; 3. [DOI: 10.1002/ctd2.177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 02/08/2023] [Indexed: 02/07/2025]
Abstract
AbstractBackgroundRecent imaging modalities have helped inthe early detection of pancreatic ductal adenocarcinoma (PDAC), resulting inimproved survival rates for patients with early‐stage PDAC. However, preoperative pathological diagnosis of early‐stage PDAC remains a challenge, particularly for small PDAC that is difficult to diagnose through standardendoscopic ultrasound‐guided fine‐needle biopsy. In this context, pancreaticjuice cytology has been re‐evaluated as an important tool for the preoperativediagnosis of early‐stage PDAC.MainPancreatic juice (PJ) comes in directcontact with PDAC lesions in the pancreatic duct and thus may contain a fewHG‐PanIN/PDAC cells and specific molecules. Additionally, the PJ may containconcentrated small extracellular vesicles (sEVs) that are released from cancerlesions. sEVs are double‐layered lipid‐bound particles that contain cargoassociated with the cell‐of‐origin, including proteins, microRNA, and RNA. sEVsreleased from cancer lesions found in body fluids, such as blood, urine, andsaliva, have already been studied as potential sources of diagnostic biomarkersfor cancer. PJ‐derived sEVs could serve as a “liquid biopsy” for theearly diagnosis of PDAC. However, little is known about the existence,physiological status, and function of PJ‐derived sEVs and their potentialutility as biomarkers for diagnostic, surveillance, and monitoring purposes oras therapeutic targets.ConclusionPJ‐derived sEVs represent a promisingavenue for the early diagnosis of PDAC. The utility of these particles as biomarkersfor diagnostic, surveillance, and monitoring purposes, or as therapeutictargets, warrants further research. Understanding the existence, physiologicalstatus, and function of PJ‐derived sEVs is crucial to unlocking their potentialas a valuable tool for overcoming PDAC.
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Affiliation(s)
- Koichiro Tsutsumi
- Department of Gastroenterology Okayama University Hospital Okayama Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology Okayama University Hospital Okayama Japan
- Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Science Okayama Japan
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26
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Circular RNAs and Untranslated Regions in Acute Myeloid Leukemia. Int J Mol Sci 2023; 24:ijms24043215. [PMID: 36834627 PMCID: PMC9967498 DOI: 10.3390/ijms24043215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/05/2023] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
Before the advent of next-generation sequencing, research on acute myeloid leukemia (AML) mostly centered on protein-coding genes. In recent years, breakthroughs in RNA sequencing technologies and whole transcriptome analysis have led to the discovery that approximately 97.5% of the human genome is transcribed into non-coding RNAs (ncRNAs). This paradigm shift has led to an explosion of research interest in different classes of non-coding RNAs, such as circular RNAs (circRNAs) as well as non-coding untranslated regions (UTRs) of protein-coding messenger RNAs. The critical roles of circRNAs and UTRs in AML pathogenesis have become increasingly apparent. In this review, we discuss the cellular mechanisms of circRNAs and summarize recent studies that reveal their biological roles in AML. Furthermore, we also review the contribution of 3'UTRs to disease progression. Finally, we discuss the potential of circRNAs and 3'UTRs as new biomarkers for disease stratification and/or the prediction of treatment response and targets for the development of RNA-directed therapeutic applications.
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27
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Yang J, Yang C, Li P. circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway. Open Med (Wars) 2023; 18:20220613. [PMID: 36694627 PMCID: PMC9835196 DOI: 10.1515/med-2022-0613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 10/26/2022] [Accepted: 11/03/2022] [Indexed: 01/13/2023] Open
Abstract
This study aims to explore the role and mechanism of circ-IARS in non-small-cell lung cancer (NSCLC) progression. Expression of circ-IARS, microRNA (miR)-1252-5p, and hepatoma-derived growth factor (HDGF) was measured by real-time quantitative PCR and western blotting. The interactions among circ-IARS, miR-1252-5p, and HDGF were determined by dual-luciferase reporter assay and RNA immunoprecipitation. Cell behaviors were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry, scratch wound assay, and transwell assay, and validated in in vivo xenograft model. Exosomes were isolated using commercial kit, and the expression and functions of exosomal circ-IARS (exo-circ-IARS) were analyzed as described above. Results showed that the expression of circ-IARS was upregulated in NSCLC cells, NSCLC tissues, and serum exosomes from NSCLC patients. circ-IARS exhaustion antagonized cell proliferation, cell cycle progression, migration, and invasion and promoted apoptosis in NSCLC. Molecularly, circ-IARS could sponge miR-1252-5p to modulate the expression of the downstream gene HDGF. In addition, miR-1252-5p downregulation attenuated circ-IARS exhaustion-mediated effects in H1299 and A549 cells. MiR-1252-5p mimic-induced effects were relieved by increasing HDGF expression in H1299 and A549 cells. Exo-circ-IARS promoted H460 cell proliferation, migration, and invasion and inhibited cell apoptosis. Silencing circ-IARS retarded tumor growth of NSCLC cells in vivo. Thus, circ-IARS, secreted by exosomes, was a novel oncogene in NSCLC and regulated the malignant development of NSCLC cells via circ-IARS/miR-1252-5p/HDGF competing endogenous RNA regulatory axis.
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Affiliation(s)
- Jinhua Yang
- Department of Thoracic and Cardiovascular Surgery, Zigong First People’s Hospital, No. 178, Tongda South Street, Ziliujing District, Zigong, Sichuan, China
| | - Chunping Yang
- Department of Thoracic and Cardiovascular Surgery, Zigong First People’s Hospital, Zigong, Sichuan, China
| | - Ping Li
- Department of Thoracic and Cardiovascular Surgery, Zigong First People’s Hospital, Zigong, Sichuan, China
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28
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Hussen BM, Mohamadtahr S, Abdullah SR, Hidayat HJ, Rasul MF, Hama Faraj GS, Ghafouri-Fard S, Taheri M, Khayamzadeh M, Jamali E. Exosomal circular RNAs: New player in breast cancer progression and therapeutic targets. Front Genet 2023; 14:1126944. [PMID: 36926585 PMCID: PMC10011470 DOI: 10.3389/fgene.2023.1126944] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 02/20/2023] [Indexed: 03/08/2023] Open
Abstract
Breast cancer is the most prevalent type of malignancy among women. Exosomes are extracellular vesicles of cell membrane origin that are released via exocytosis. Their cargo contains lipids, proteins, DNA, and different forms of RNA, including circular RNAs. Circular RNAs are new class of non-coding RNAs with a closed-loop shape involved in several types of cancer, including breast cancer. Exosomes contained a lot of circRNAs which are called exosomal circRNAs. By interfering with several biological pathways, exosomal circRNAs can have either a proliferative or suppressive role in cancer. The involvement of exosomal circRNAs in breast cancer has been studied with consideration to tumor development and progression as well as its effects on therapeutic resistance. However, its exact mechanism is still unclear, and there have not been available clinical implications of exo-circRNAs in breast cancer. Here, we highlight the role of exosomal circRNAs in breast cancer progression and to highlight the most recent development and potential of circRNAas therapeutic targets and diagnostics for breast cancer.
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Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Medical Analysis, College of Pharmacy, Hawler Medical University, Erbil, Iraq.,Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Sayran Mohamadtahr
- Department of Medical Analysis, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | | | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University-Erbil, Erbil, Iraq
| | - Mohammad Fatih Rasul
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Tishk International University, Erbil, Iraq
| | - Goran Sedeeq Hama Faraj
- Department of Medical Laboratory Science, Komar University of Science and Technology, Sulaimany, Iraq
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany.,Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Khayamzadeh
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Academy of Medical Sciences, Tehran, Iran
| | - Elena Jamali
- Department of Pathology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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29
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Zhang XP, Pei JP, Zhang CD, Yusupu M, Han MH, Dai DQ. Exosomal circRNAs: A key factor of tumor angiogenesis and therapeutic intervention. Biomed Pharmacother 2022; 156:113921. [DOI: 10.1016/j.biopha.2022.113921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 10/16/2022] [Accepted: 10/24/2022] [Indexed: 11/02/2022] Open
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30
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Zhang P, Dai M. CircRNA: a rising star in plant biology. J Genet Genomics 2022; 49:1081-1092. [PMID: 35644325 DOI: 10.1016/j.jgg.2022.05.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 01/14/2023]
Abstract
Circular RNAs (circRNAs) are covalently closed single-stranded RNA molecules, which are widespread in eukaryotic cells. As regulatory molecules, circRNAs have various functions, such as regulating gene expression, binding miRNAs or proteins, and being translated into proteins, which are important for cell proliferation and cell differentiation, individual growth and development, as well as many other biological processes. However, compared with that in animal models, studies of circRNAs in plants lags behind and, particularly, the regulatory mechanisms of biogenesis and molecular functions of plant circRNAs remain elusive. Recent studies have shown that circRNAs are wide spread in plants with tissue- or development-specific expression patterns and are responsive to a variety of environmental stresses. In this review, we summarize these advances, focusing on the regulatory mechanisms of biogenesis, molecular and biological functions of circRNAs, and the methods for investigating circRNAs. We also discuss the challenges and the prospects of plant circRNA studies.
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Affiliation(s)
- Pei Zhang
- National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Mingqiu Dai
- National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
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31
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Seimiya T, Otsuka M, Fujishiro M. Roles of circular RNAs in the pathogenesis and treatment of pancreatic cancer. Front Cell Dev Biol 2022; 10:1023332. [PMID: 36467402 PMCID: PMC9712786 DOI: 10.3389/fcell.2022.1023332] [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: 08/22/2022] [Accepted: 11/07/2022] [Indexed: 08/29/2023] Open
Abstract
Circular RNAs are single-stranded RNAs with a covalently closed structure formed by the process of back-splicing. Aberrant expression of circular RNAs contributes to the pathogenesis of a wide range of cancers. Pancreatic cancer is one of the most lethal cancers due to diagnostic difficulties and limited therapeutic options. Circular RNAs are emerging as novel diagnostic biomarkers and therapeutic targets for pancreatic cancer. Moreover, recent advances in the therapeutic application of engineered circular RNAs have provided a promising approach to overcoming pancreatic cancer. This review discusses the roles of circular RNAs in the pathogenesis of pancreatic cancer and in potential treatment applications and their usefulness as diagnostic biomarkers.
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Affiliation(s)
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Aili Y, Maimaitiming N, Qin H, Ji W, Fan G, Wang Z, Wang Y. Tumor microenvironment and exosomes in brain metastasis: Molecular mechanisms and clinical application. Front Oncol 2022; 12:983878. [PMID: 36338717 PMCID: PMC9631487 DOI: 10.3389/fonc.2022.983878] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 09/28/2022] [Indexed: 12/03/2022] Open
Abstract
Metastasis is one of the important biological features of malignant tumors and one of the main factors responsible for poor prognosis. Although the widespread application of newer clinical technologies and their continuous development have significantly improved survival in patients with brain metastases, there is no uniform standard of care. More effective therapeutic measures are therefore needed to improve prognosis. Understanding the mechanisms of tumor cell colonization, growth, and invasion in the central nervous system is of particular importance for the prevention and treatment of brain metastases. This process can be plausibly explained by the “seed and soil” hypothesis, which essentially states that tumor cells can interact with various components of the central nervous system microenvironment to produce adaptive changes; it is this interaction that determines the development of brain metastases. As a novel form of intercellular communication, exosomes play a key role in the brain metastasis microenvironment and carry various bioactive molecules that regulate receptor cell activity. In this paper, we review the roles and prospects of brain metastatic tumor cells, the brain metastatic tumor microenvironment, and exosomes in the development and clinical management of brain metastases.
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Affiliation(s)
- Yirizhati Aili
- Department of Neurosurgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Nuersimanguli Maimaitiming
- Department of Four Comprehensive Internal Medicine, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Hu Qin
- Department of Neurosurgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Wenyu Ji
- Department of Neurosurgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Guofeng Fan
- Department of Neurosurgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Zengliang Wang
- Department of Neurosurgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- School of Health Management, Xinjiang Medical University, Urumqi, China
- Department of Neurosurgery, Xinjiang Bazhou People’s Hospital, Xinjiang, China
- *Correspondence: Zengliang Wang, ; Yongxin Wang,
| | - Yongxin Wang
- Department of Neurosurgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- *Correspondence: Zengliang Wang, ; Yongxin Wang,
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Du Z, Yuan J, Wu Z, Chen Q, Liu X, Jia J. Circulating Exosomal circRNA_0063476 Impairs Expression of Markers of Bone Growth Via the miR-518c-3p/DDX6 Axis in ISS. Endocrinology 2022; 163:6668858. [PMID: 35974445 DOI: 10.1210/endocr/bqac138] [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: 05/21/2022] [Indexed: 11/19/2022]
Abstract
OBJECTIVES Idiopathic short stature (ISS), a disorder of unknown cause, accounts for approximately 80% of the clinical diagnoses of children with short stature. Exosomal circular RNA in plasma has been implicated in various disease processes. However, the role of exosome-derived circRNA in ISS has not been elucidated yet. METHODS Plasma exosomes of ISS and normal children were cocultured with human chondrocytes. Microarray analysis and RT-PCR identified the differential expression of circRNA in exosomes between ISS and normal children. Hsa_circ_0063476 was upregulated or downregulated in human chondrocytes. Subsequently, overexpression rats of hsa_circ_0063476 was constructed via adenoviral vector to further validate the role of hsa_circ_0063476 on longitudinal bone growth via in vivo experiment. RESULTS The plasma exosome of ISS children suppressed the expression of markers of chondrocyte hypertrophy and endochondral ossification. Subsequently, upregulation of hsa_circ_0063476 in ISS exosome was identified. In vitro experiments demonstrated that chondrocyte proliferation, cell cycle and endochondral ossification were suppressed, and apoptosis was increased following hsa_circ_0063476 overexpression in human chondrocytes. Conversely, silencing hsa_circ_0063476 in human chondrocytes can show opposite outcomes. Our study further revealed hsa_circ_0063476 overexpression in vitro can enhance chondrocyte apoptosis and inhibit the expression of markers of chondrocyte proliferation and endochondral ossification via miR-518c-3p/DDX6 axis. Additionally, the rats with hsa_circ_0063476 overexpression showed a short stature phenotype. CONCLUSIONS The authors identified a novel pathogenesis in ISS that exosome-derived hsa_circ_0063476 retards the expression of markers of endochondral ossification and impairs longitudinal bone growth via miR-518c-3p/DDX6 axis, which may provide a unique therapeutic avenue for ISS.
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Affiliation(s)
- Zhi Du
- Departments of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, China
| | - Jinghong Yuan
- Departments of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, China
| | - Zhiwen Wu
- Departments of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, China
| | - Qi Chen
- Department of Obstetrics & Gynecology, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, China
| | - Xijuan Liu
- Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, China
| | - Jingyu Jia
- Departments of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, China
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Small Extracellular Vesicles and Their Involvement in Cancer Resistance: An Up-to-Date Review. Cells 2022; 11:cells11182913. [PMID: 36139487 PMCID: PMC9496799 DOI: 10.3390/cells11182913] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/25/2022] [Accepted: 09/15/2022] [Indexed: 12/11/2022] Open
Abstract
In recent years, tremendous progress has been made in understanding the roles of extracellular vesicles (EVs) in cancer. Thanks to advancements in molecular biology, it has been found that the fraction of EVs called exosomes or small EVs (sEVs) modulates the sensitivity of cancer cells to chemotherapeutic agents by delivering molecularly active non-coding RNAs (ncRNAs). An in-depth analysis shows that two main molecular mechanisms are involved in exosomal modified chemoresistance: (1) translational repression of anti-oncogenes by exosomal microRNAs (miRs) and (2) lack of translational repression of oncogenes by sponging of miRs through long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). At the cellular level, these processes increase the proliferation and survival of cancer cells and improve their ability to metastasize and resist apoptosis. In addition, studies in animal models have shown enhancing tumor size under the influence of exosomal ncRNAs. Ultimately, exosomal ncRNAs are responsible for clinically significant chemotherapy failures in patients with different types of cancer. Preliminary data have also revealed that exosomal ncRNAs can overcome chemotherapeutic agent resistance, but the results are thoroughly fragmented. This review presents how exosomes modulate the response of cancer cells to chemotherapeutic agents. Understanding how exosomes interfere with chemoresistance may become a milestone in developing new therapeutic options, but more data are still required.
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Palkina N, Aksenenko M, Zemtsov D, Lavrentev S, Zinchenko I, Belenyuk V, Kirichenko A, Savchenko A, Ruksha T. miR-204-5p in vivo inhibition cause diminished CD45RO cells rate in lungs of melanoma B16-bearing mice. Noncoding RNA Res 2022; 7:133-141. [PMID: 35756165 PMCID: PMC9188961 DOI: 10.1016/j.ncrna.2022.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/31/2022] [Accepted: 06/01/2022] [Indexed: 10/25/2022] Open
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Yao X, Zhang Q. Function and Clinical Significance of Circular RNAs in Thyroid Cancer. Front Mol Biosci 2022; 9:925389. [PMID: 35936780 PMCID: PMC9353217 DOI: 10.3389/fmolb.2022.925389] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 06/22/2022] [Indexed: 12/28/2022] Open
Abstract
Thyroid cancer (TC) is the leading cause and mortality of endocrine malignancies worldwide. Tumourigenesis involves multiple molecules including circular RNAs (circRNAs). circRNAs with covalently closed single-stranded structures have been identified as a type of regulatory RNA because of their high stability, abundance, and tissue/developmental stage-specific expression. Accumulating evidence has demonstrated that various circRNAs are aberrantly expressed in thyroid tissues, cells, exosomes, and body fluids in patients with TC. CircRNAs have been identified as either oncogenic or tumour suppressor roles in regulating tumourigenesis, tumour metabolism, metastasis, ferroptosis, and chemoradiation resistance in TC. Importantly, circRNAs exert pivotal effects on TC through various mechanisms, including acting as miRNA sponges or decoys, interacting with RNA-binding proteins, and translating functional peptides. Recent studies have suggested that many different circRNAs are associated with certain clinicopathological features, implying that the altered expression of circRNAs may be characteristic of TC. The purpose of this review is to provide an overview of recent advances on the dysregulation, functions, molecular mechanisms and potential clinical applications of circRNAs in TC. This review also aimes to improve our understanding of the functions of circRNAs in the initiation and progression of cancer, and to discuss the future perspectives on strategies targeting circRNAs in TC.
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Sun R, Zhou Y, Cai Y, Shui C, Wang X, Zhu J. circ_0000045 promotes proliferation, migration, and invasion of head and neck squamous cell carcinomas via regulating HSP70 and MAPK pathway. BMC Cancer 2022; 22:799. [PMID: 35854245 PMCID: PMC9297571 DOI: 10.1186/s12885-022-09880-y] [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: 09/01/2021] [Accepted: 07/05/2022] [Indexed: 02/08/2023] Open
Abstract
Objective Head and neck squamous cell carcinoma (HNSCC) is one severe malignancy driven by complex cellular and signaling mechanisms. However, the roles of circular RNAs (circRNAs) in HNSCC’s development remains poorly understood. Therefore, this study investigated the functions of differentially expressed circRNAs in regulating HNSCC cell functions. Methods Differentially expressed circRNAs were characterized through RNA sequencing in HNSCC tissues. CircRNA’s identity was then confirmed using RT-PCR and Sanger’s sequencing. Next, expression levels of circRNA and mRNA were detected by qRT-PCR, after which protein abundances were measured by Western blotting. Subsequently, the proliferation, migration, and invasion of HNSCC cells was assessed by MTS, wound healing, and Transwell system, respectively, followed by identification of circRNA-binding proteins in HNSCC cells by circRNA pull-down, coupled with mass spectrometry. Results Great alterations in circRNA profiles were detected in HNSCC tissues, including the elevated expression of circ_0000045. As observed, silencing of circ_0000045 effectively repressed the proliferation, migration, and invasion of HNSCC cell lines (FaDu and SCC-9). Contrarily, circ_0000045’s overexpression promoted the proliferation, migration, and invasion in FaDu and SCC-9 cells. Results also showed that circ_0000045 was associated with multiple RNA-binding proteins in HNSCC cells, such as HSP70. Moreover, circ_0000045 knockdown enhanced HSP70 expression and inhibited JNK2 and P38’s expression in HNSCC cells, which were oppositely regulated by circ_0000045’s overexpression. Conclusion The high expression of circ_0000045; therefore, promoted cell proliferation, migration, and invasion during HNSCC’s development through regulating HSP70 protein and mitogen-activated protein kinase signaling. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09880-y.
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Affiliation(s)
- Ronghao Sun
- Department of Head and Neck Surgery, Sichuan Cancer Hospital and Institute,University of Electronic Science and Technology of China, No.55, 4th section of Southern Renmin Road, Chengdu, Sichuan, 610041, China. .,Department of Thyroid and Parathyroid Surgery, West China Hospital, No. 37, Guoxue Alley, Chengdu, Sichuan, 610041, China.
| | - Yuqiu Zhou
- Department of Head and Neck Surgery, Sichuan Cancer Hospital and Institute,University of Electronic Science and Technology of China, No.55, 4th section of Southern Renmin Road, Chengdu, Sichuan, 610041, China
| | - Yongcong Cai
- Department of Head and Neck Surgery, Sichuan Cancer Hospital and Institute,University of Electronic Science and Technology of China, No.55, 4th section of Southern Renmin Road, Chengdu, Sichuan, 610041, China
| | - Chunyan Shui
- Department of Head and Neck Surgery, Sichuan Cancer Hospital and Institute,University of Electronic Science and Technology of China, No.55, 4th section of Southern Renmin Road, Chengdu, Sichuan, 610041, China
| | - Xu Wang
- Department of Head and Neck Surgery, Sichuan Cancer Hospital and Institute,University of Electronic Science and Technology of China, No.55, 4th section of Southern Renmin Road, Chengdu, Sichuan, 610041, China
| | - Jingqiang Zhu
- Department of Head and Neck Surgery, Sichuan Cancer Hospital and Institute,University of Electronic Science and Technology of China, No.55, 4th section of Southern Renmin Road, Chengdu, Sichuan, 610041, China. .,Department of Thyroid and Parathyroid Surgery, West China Hospital, No. 37, Guoxue Alley, Chengdu, Sichuan, 610041, China.
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Guo L, Jia L, Luo L, Xu X, Xiang Y, Ren Y, Ren D, Shen L, Liang T. Critical Roles of Circular RNA in Tumor Metastasis via Acting as a Sponge of miRNA/isomiR. Int J Mol Sci 2022; 23:ijms23137024. [PMID: 35806027 PMCID: PMC9267010 DOI: 10.3390/ijms23137024] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/20/2022] [Accepted: 06/23/2022] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs), a class of new endogenous non-coding RNAs (ncRNAs), are closely related to the carcinogenic process and play a critical role in tumor metastasis. CircRNAs can lay the foundation for tumor metastasis via promoting tumor angiogenesis, make tumor cells gain the ability of migration and invasion by regulating epithelial-mesenchymal transition (EMT), interact with immune cells, cytokines, chemokines, and other non-cellular components in the tumor microenvironment, damage the normal immune function or escape the immunosuppressive network, and further promote cell survival and metastasis. Herein, based on the characteristics and biological functions of circRNA, we elaborated on the effect of circRNA via circRNA-associated competing endogenous RNA (ceRNA) network by acting as miRNA/isomiR sponges on tumor angiogenesis, cancer cell migration and invasion, and interaction with the tumor microenvironment (TME), then explored the potential interactions across different RNAs, and finally discussed the potential clinical value and application as a promising biomarker. These results provide a theoretical basis for the further application of metastasis-related circRNAs in cancer treatment. In summary, we briefly summarize the diverse roles of a circRNA-associated ceRNA network in cancer metastasis and the potential clinical application, especially the interaction of circRNA and miRNA/isomiR, which may complicate the RNA regulatory network and which will contribute to a novel insight into circRNA in the future.
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Affiliation(s)
- Li Guo
- Smart Health Big Data Analysis and Location Services Engineering Laboratory of Jiangsu Province, Department of Bioinformatics, School of Geographic and Biologic Information, Nanjing University of Posts and Telecommunications, Nanjing 210023, China; (L.G.); (Y.X.); (Y.R.); (D.R.)
| | - Lin Jia
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China; (L.J.); (L.L.); (X.X.); (L.S.)
| | - Lulu Luo
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China; (L.J.); (L.L.); (X.X.); (L.S.)
| | - Xinru Xu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China; (L.J.); (L.L.); (X.X.); (L.S.)
| | - Yangyang Xiang
- Smart Health Big Data Analysis and Location Services Engineering Laboratory of Jiangsu Province, Department of Bioinformatics, School of Geographic and Biologic Information, Nanjing University of Posts and Telecommunications, Nanjing 210023, China; (L.G.); (Y.X.); (Y.R.); (D.R.)
| | - Yujie Ren
- Smart Health Big Data Analysis and Location Services Engineering Laboratory of Jiangsu Province, Department of Bioinformatics, School of Geographic and Biologic Information, Nanjing University of Posts and Telecommunications, Nanjing 210023, China; (L.G.); (Y.X.); (Y.R.); (D.R.)
| | - Dekang Ren
- Smart Health Big Data Analysis and Location Services Engineering Laboratory of Jiangsu Province, Department of Bioinformatics, School of Geographic and Biologic Information, Nanjing University of Posts and Telecommunications, Nanjing 210023, China; (L.G.); (Y.X.); (Y.R.); (D.R.)
| | - Lulu Shen
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China; (L.J.); (L.L.); (X.X.); (L.S.)
| | - Tingming Liang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China; (L.J.); (L.L.); (X.X.); (L.S.)
- Correspondence:
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Niu ZS, Wang WH. Circular RNAs in hepatocellular carcinoma: Recent advances. World J Gastrointest Oncol 2022; 14:1067-1085. [PMID: 35949213 PMCID: PMC9244981 DOI: 10.4251/wjgo.v14.i6.1067] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/22/2021] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) have covalently closed loop structures at both ends, exhibiting characteristics dissimilar to those of linear RNAs. Emerging evidence suggests that aberrantly expressed circRNAs play crucial roles in hepatocellular carcinoma (HCC) by affecting the proliferation, apoptosis and invasive capacity of HCC cells. Certain circRNAs may be used as biomarkers to diagnose and predict the prognosis of HCC. Therefore, circRNAs are expected to become novel biomarkers and therapeutic targets for HCC. Herein, we briefly review the characteristics and biological functions of circRNAs, focusing on their roles in HCC to provide new insights for the early diagnosis and targeted therapy of HCC.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
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Wang R, Liu H, Dong M, Huang D, Yi J. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis. Open Med (Wars) 2022; 17:826-840. [PMID: 35582196 PMCID: PMC9055259 DOI: 10.1515/med-2022-0428] [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: 09/12/2021] [Revised: 12/07/2021] [Accepted: 01/03/2022] [Indexed: 12/25/2022] Open
Abstract
This study aims to explore the function and mechanism of exosomal circ_0000519 in non-small cell lung cancer (NSCLC) development. Expression of circ_0000519, microRNA (miR)-1258, and Ras homolog gene family V (RHOV) in serum samples of NSCLC patients or cell lines were examined via quantitative reverse transcription-polymerase chain reaction and Western blotting. The function of circ_0000519 was evaluated through 5-ethynyl-2′-deoxyuridine (EdU) staining, colony formation, transwell, Western blotting, xenograft, and immunohistochemistry analyses. The binding relationship was evaluated by a dual-luciferase reporter assay and RNA pull-down assay. Results showed that circ_0000519 abundance was enhanced in the serum samples of NSCLC patients and cells. circ_0000519 knockdown suppressed the cell growth by decreasing the colony-formation ability and Cyclin D1 expression and inhibited cell metastasis via reducing migration, invasion, and levels of Vimentin and matrix metalloproteinase 9 (MMP9). circ_0000519 overexpression promoted cell growth and metastasis. circ_0000519 was carried by exosomes and knockdown of exosomal circ_0000519 suppressed the cell growth and metastasis. miR-1258 was downregulated in NSCLC cells and targeted by circ_0000519. RHOV was targeted by miR-1258 and upregulated in the NSCLC cells. miR-1258 knockdown or RHOV overexpression attenuated the influence of exosomal circ_0000519 knockdown on cell growth and metastasis. Exosomal circ_0000519 knockdown decreased xenograft tumor growth. Collectively, the knockdown of exosomal circ_0000519 repressed the cell growth and metastasis in NSCLC through the miR-1258/RHOV axis, which provided a new insight into NSCLC development and treatment.
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Affiliation(s)
- Rui Wang
- Department of Oncology, Jingmen No. 1 People's Hospital, Jingmen, Hubei, China
| | - Hongliu Liu
- Department of Oncology, Jingmen No. 1 People's Hospital, Jingmen, Hubei, China
| | - Mingqiang Dong
- Department of Oncology, Jingmen No. 1 People's Hospital, Jingmen, Hubei, China
| | - Dan Huang
- Department of Health Care for Cadres, Jingmen No. 1 People's Hospital, Jingmen, Hubei, China
| | - Jun Yi
- Department of Cardiothoracic Surgery, Jingmen No. 1 People's Hospital, Jingmen, Hubei, China
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Zand Karimi H, Baldrich P, Rutter BD, Borniego L, Zajt KK, Meyers BC, Innes RW. Arabidopsis apoplastic fluid contains sRNA- and circular RNA-protein complexes that are located outside extracellular vesicles. THE PLANT CELL 2022; 34:1863-1881. [PMID: 35171271 PMCID: PMC9048913 DOI: 10.1093/plcell/koac043] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 12/14/2021] [Indexed: 05/21/2023]
Abstract
Previously, we have shown that apoplastic wash fluid (AWF) purified from Arabidopsis leaves contains small RNAs (sRNAs). To investigate whether these sRNAs are encapsulated inside extracellular vesicles (EVs), we treated EVs isolated from Arabidopsis leaves with the protease trypsin and RNase A, which should degrade RNAs located outside EVs but not those located inside. These analyses revealed that apoplastic RNAs are mostly located outside and are associated with proteins. Further analyses of these extracellular RNAs (exRNAs) revealed that they include both sRNAs and long noncoding RNAs (lncRNAs), including circular RNAs (circRNAs). We also found that exRNAs are highly enriched in the posttranscriptional modification N6-methyladenine (m6A). Consistent with this, we identified a putative m6A-binding protein in AWF, GLYCINE-RICH RNA-BINDING PROTEIN 7 (GRP7), as well as the sRNA-binding protein ARGONAUTE2 (AGO2). These two proteins coimmunoprecipitated with lncRNAs, including circRNAs. Mutation of GRP7 or AGO2 caused changes in both the sRNA and lncRNA content of AWF, suggesting that these proteins contribute to the secretion and/or stabilization of exRNAs. We propose that exRNAs located outside of EVs mediate host-induced gene silencing, rather than RNA located inside EVs.
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Affiliation(s)
- Hana Zand Karimi
- Department of Biology, Indiana University, Bloomington 47405, Indiana, USA
| | | | - Brian D Rutter
- Department of Biology, Indiana University, Bloomington 47405, Indiana, USA
| | - Lucía Borniego
- Department of Biology, Indiana University, Bloomington 47405, Indiana, USA
| | - Kamil K Zajt
- Department of Biology, Indiana University, Bloomington 47405, Indiana, USA
| | - Blake C Meyers
- Donald Danforth Plant Science Center, St Louis 63132, Missouri, USA
- Division of Plant Sciences, University of Missouri-Columbia, Columbia 65211, Missouri, USA
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Wen C, Li B, Nie L, Mao L, Xia Y. Emerging Roles of Extracellular Vesicle-Delivered Circular RNAs in Atherosclerosis. Front Cell Dev Biol 2022; 10:804247. [PMID: 35445015 PMCID: PMC9014218 DOI: 10.3389/fcell.2022.804247] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 03/09/2022] [Indexed: 01/20/2023] Open
Abstract
Atherosclerosis (AS) is universally defined as chronic vascular inflammation induced by dyslipidaemia, obesity, hypertension, diabetes and other risk factors. Extracellular vesicles as information transmitters regulate intracellular interactions and their important cargo circular RNAs are involved in the pathological process of AS. In this review, we summarize the current data to elucidate the emerging roles of extracellular vesicle-derived circular RNAs (EV-circRNAs) in AS and the mechanism by which EV-circRNAs affect the development of AS. Additionally, we discuss their vital role in the progression from risk factors to AS and highlight their great potential for use as diagnostic biomarkers of and novel therapeutic strategies for AS.
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Affiliation(s)
- Cheng Wen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bowei Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Nie
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Mao
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanpeng Xia
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Liu K, Chen H, Wang Y, Jiang L, Li Y. Evolving Insights Into the Biological Function and Clinical Significance of Long Noncoding RNA in Glioblastoma. Front Cell Dev Biol 2022; 10:846864. [PMID: 35531099 PMCID: PMC9068894 DOI: 10.3389/fcell.2022.846864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 02/28/2022] [Indexed: 11/13/2022] Open
Abstract
Glioblastoma (GBM) is one of the most prevalent and aggressive cancers worldwide. The overall survival period of GBM patients is only 15 months even with standard combination therapy. The absence of validated biomarkers for early diagnosis mainly accounts for worse clinical outcomes of GBM patients. Thus, there is an urgent requirement to characterize more biomarkers for the early diagnosis of GBM patients. In addition, the detailed molecular basis during GBM pathogenesis and oncogenesis is not fully understood, highlighting that it is of great significance to elucidate the molecular mechanisms of GBM initiation and development. Recently, accumulated pieces of evidence have revealed the central roles of long noncoding RNAs (lncRNAs) in the tumorigenesis and progression of GBM by binding with DNA, RNA, or protein. Targeting those oncogenic lncRNAs in GBM may be promising to develop more effective therapeutics. Furthermore, a better understanding of the biological function and underlying molecular basis of dysregulated lncRNAs in GBM initiation and development will offer new insights into GBM early diagnosis and develop novel treatments for GBM patients. Herein, this review builds on previous studies to summarize the dysregulated lncRNAs in GBM and their unique biological functions during GBM tumorigenesis and progression. In addition, new insights and challenges of lncRNA-based diagnostic and therapeutic potentials for GBM patients were also introduced.
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Affiliation(s)
- Kun Liu
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Hong Chen
- Department of Oncology, 920th Hospital of Joint Logistics Support Force, Teaching Hospital of Kunming Medical University, Kunming, China
| | - Yuanyuan Wang
- Department of Pathology, 920th Hospital of Joint Logistics Support Force, Teaching Hospital of Kunming Medical University, Kunming, China
| | - Liping Jiang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, China
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, United States
- *Correspondence: Yi Li, ; Liping Jiang,
| | - Yi Li
- Department of Oncology, 920th Hospital of Joint Logistics Support Force, Teaching Hospital of Kunming Medical University, Kunming, China
- *Correspondence: Yi Li, ; Liping Jiang,
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Wang L, Li B, Yi X, Xiao X, Zheng Q, Ma L. Circ_0036412 affects the proliferation and cell cycle of hepatocellular carcinoma via hedgehog signaling pathway. J Transl Med 2022; 20:154. [PMID: 35382824 PMCID: PMC8981839 DOI: 10.1186/s12967-022-03305-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 02/12/2022] [Indexed: 12/27/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC), as the most common type of liver cancer, is characterized by high recurrence and metastasis. Circular RNA (circRNA) circ_0036412 was selected for studying the underlying mechanisms of HCC. Methods Quantitative real time-polymerase chain reaction (qRT-PCR) and western blot analyzed gene and protein expression. Functional experiments evaluated HCC cell proliferation, apoptosis and cell cycle in vitro. In vivo experiments detected HCC carcinogenesis in vivo. Fluorescence in situ hybridization (FISH) assays evaluated the subcellular distribution. Luciferase reporter, Chromatin immunoprecipitation (ChIP), DNA pulldown, RNA-binding protein immunoprecipitation (RIP), and RNA pulldown assays detected the underlying mechanisms. Results Circ_0036412 is overexpressed in HCC cells and features circular structure. PRDM1 activates circ_0036412 transcription to regulate the proliferation and cell cycle of HCC cells in vitro. Circ_0036412 modulates Hedgehog pathway. GLI2 propels HCC growth in vivo. Circ_0036412 up-regulates GLI2 expression by competitively binding to miR-579-3p, thus promoting the proliferation and inhibiting cell cycle arrest of HCC cells. Circ_0036412 stabilizes GLI2 expression by recruiting ELAVL1. Circ_0036412 propels the proliferation and inhibits cell cycle arrest of HCC cells in vitro through Hedgehog pathway. Conclusions Circ_0036412 affects the proliferation and cell cycle of HCC via Hedgehog signaling pathway. It offers an insight into the targeted therapies of HCC. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03305-x.
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Affiliation(s)
- Liyan Wang
- Department of Gastroenterology, Affiliated Hospital of Guilin Medical College, No. 15 Lequn Road, Xiufeng District, Guilin, 541001, Guangxi, China
| | - Bin Li
- Department of Gastroenterology, Affiliated Hospital of Guilin Medical College, No. 15 Lequn Road, Xiufeng District, Guilin, 541001, Guangxi, China.
| | - Xiaoyuan Yi
- Department of Gastroenterology, Affiliated Hospital of Guilin Medical College, No. 15 Lequn Road, Xiufeng District, Guilin, 541001, Guangxi, China
| | - Xuhua Xiao
- Department of Gastroenterology, Affiliated Hospital of Guilin Medical College, No. 15 Lequn Road, Xiufeng District, Guilin, 541001, Guangxi, China
| | - Qinghua Zheng
- Department of Gastroenterology, Affiliated Hospital of Guilin Medical College, No. 15 Lequn Road, Xiufeng District, Guilin, 541001, Guangxi, China
| | - Lei Ma
- Department of Gastroenterology, Affiliated Hospital of Guilin Medical College, No. 15 Lequn Road, Xiufeng District, Guilin, 541001, Guangxi, China
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Fan Q, Yu Y, Zhou Y, Zhang S, Wu C. An emerging role of radiation‑induced exosomes in hepatocellular carcinoma progression and radioresistance (Review). Int J Oncol 2022; 60:46. [PMID: 35266016 PMCID: PMC8923655 DOI: 10.3892/ijo.2022.5336] [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: 12/23/2021] [Accepted: 03/01/2022] [Indexed: 11/20/2022] Open
Abstract
The incidence rates of hepatocellular carcinoma (HCC) worldwide are increasing, and the role of radiotherapy is currently under discussion. Radioresistance is one of the most important challenges in the therapy of HCC compared with other local advanced, recurrent and metastatic cancers. The mechanisms of radioresistance are complex and remain to be fully understood; however, extracellular vesicles have been investigated in recent studies. Exosomes, which are 40- to 150-nm extracellular vesicles released by cancer cells, contain multiple pathogenic components, including proteins, nucleic acids and lipids, and play critical functions in cancer progression. Emerging data indicate a diagnosis potential for exosomes in HCC, since radiation-derived exosomes promote radioresistance. Radiation-based therapy alters the contents and components of exosomes, suggesting that exosomes and their components may serve as prognostic and predictive biomarkers to monitor radiation response. Therefore, understanding the roles and mechanisms of exosomes in HCC progression and radiation response during HCC therapy may increase our knowledge concerning the roles of exosomes in radioresistance, and may lead to novel approaches for HCC prognosis and treatment. The current review summarizes recent studies on exosome involvement in HCC and the molecular changes in exosome components during HCC progression. It also discusses the functions of exosomes in HCC therapy, and highlights the importance of exosomes in HCC progression and resistance for the development of novel therapies.
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Affiliation(s)
- Qing Fan
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Yue Yu
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Yueling Zhou
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Sheng Zhang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Chunli Wu
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
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Carlos-Reyes Á, Romero-Garcia S, Contreras-Sanzón E, Ruiz V, Prado-Garcia H. Role of Circular RNAs in the Regulation of Immune Cells in Response to Cancer Therapies. Front Genet 2022; 13:823238. [PMID: 35186039 PMCID: PMC8847670 DOI: 10.3389/fgene.2022.823238] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/11/2022] [Indexed: 12/25/2022] Open
Abstract
Circular RNAs (CircRNAs) are a class of small endogenous noncoding RNA that are formed by means of either the spliceosome or lariat-type splicing. CircRNAs have multiple regulatory functions and have been detected in different cell types, like normal, tumor and immune cells. CircRNAs have been suggested to regulate T cell functions in response to cancer. CircRNAs can enter into T cells and promote the expression of molecules that either trigger antitumoral responses or promote suppression and the consequent evasion to the immune response. Additionally, circRNAs may promote tumor progression and resistance to anticancer treatment in different types of neoplasias. In this minireview we discuss the impact of circRNAs and its function in the regulation of the T-cells in immune response caused by cancer therapies.
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Affiliation(s)
- Ángeles Carlos-Reyes
- Laboratorio de Onco-Inmunobiologia, Departamento de Enfermedades Crónico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias, Mexico, Mexico
| | | | | | - Víctor Ruiz
- Laboratorio de Biología Molecular, Instituto Nacional de Enfermedades Respiratorias, Mexico, Mexico
| | - Heriberto Prado-Garcia
- Laboratorio de Onco-Inmunobiologia, Departamento de Enfermedades Crónico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias, Mexico, Mexico
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PLA2G10 incorporated in exosomes could be diagnostic and prognostic biomarker for non-small cell lung cancer. Clin Chim Acta 2022; 530:55-65. [DOI: 10.1016/j.cca.2022.02.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 12/13/2022]
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Lampropoulou DI, Pliakou E, Aravantinos G, Filippou D, Gazouli M. The Role of Exosomal Non-Coding RNAs in Colorectal Cancer Drug Resistance. Int J Mol Sci 2022; 23:ijms23031473. [PMID: 35163397 PMCID: PMC8835818 DOI: 10.3390/ijms23031473] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
Background: Colorectal cancer (CRC) is one of the most common types of cancer diagnosed worldwide with high morbidity; drug resistance is often responsible for treatment failure in CRC. Non-coding RNAs (ncRNAs) play distinct regulatory roles in tumorigenesis, cancer progression and chemoresistance. Methods: A literature search was conducted in PubMed database in order to sum up and discuss the role of exosomal ncRNAs (ex-ncRNAs) in CRC drug resistance/response and their possible mechanisms. Results: Thirty-six (36) original research articles were identified; these included exosome or extracellular vesicle (EV)-containing microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and small-interfering (siRNAs). No studies were found for piwi-interacting RNAs. Conclusions: Exosomal transfer of ncRNAs has been documented as a new mechanism of CRC drug resistance. Despite being in its infancy, it has emerged as a promising field for research in order to (i) discover novel biomarkers for therapy monitoring and/or (ii) reverse drug desensitization.
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Affiliation(s)
- Dimitra Ioanna Lampropoulou
- Second Department of Medical Oncology, General Oncology Hospital of Kifissia “Agioi Anargiroi”, 14564 Athens, Greece; (D.I.L.); (E.P.); (G.A.)
| | - Evangelia Pliakou
- Second Department of Medical Oncology, General Oncology Hospital of Kifissia “Agioi Anargiroi”, 14564 Athens, Greece; (D.I.L.); (E.P.); (G.A.)
| | - Gerasimos Aravantinos
- Second Department of Medical Oncology, General Oncology Hospital of Kifissia “Agioi Anargiroi”, 14564 Athens, Greece; (D.I.L.); (E.P.); (G.A.)
| | - Dimitrios Filippou
- Department of Anatomy and Surgical Anatomy, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Maria Gazouli
- Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Correspondence:
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Li J, Zhang G, Liu CG, Xiang X, Le MT, Sethi G, Wang L, Goh BC, Ma Z. The potential role of exosomal circRNAs in the tumor microenvironment: insights into cancer diagnosis and therapy. Am J Cancer Res 2022; 12:87-104. [PMID: 34987636 PMCID: PMC8690929 DOI: 10.7150/thno.64096] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 10/21/2021] [Indexed: 12/11/2022] Open
Abstract
Exosomes are multifunctional regulators of intercellular communication by carrying various messages under both physiological and pathological status of cancer patients. Accumulating studies have identified the presence of circular RNAs (circRNAs) in exosomes with crucial regulatory roles in diverse pathophysiological processes. Exosomal circRNAs derived from donor cells can modulate crosstalk with recipient cells locally or remotely to enhance cancer development and propagation, and play crucial roles in the tumor microenvironment (TME), leading to significant enhancement of tumor immunity, metabolism, angiogenesis, drug resistance, epithelial mesenchymal transition (EMT), invasion and metastasis. In this review, we describe the advances of exosomal circRNAs and their roles in modulating cancer hallmarks, especially those in the TME. Moreover, clinical application potential of exosomal circRNAs in cancer diagnosis and therapy are highlighted, bridging the gap between basic knowledge and clinical practice.
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Eng GWL, Zheng Y, Yap DWT, Teo AYT, Cheong JK. Autophagy and ncRNAs: Dangerous Liaisons in the Crosstalk between the Tumor and Its Microenvironment. Cancers (Basel) 2021; 14:cancers14010020. [PMID: 35008183 PMCID: PMC8750064 DOI: 10.3390/cancers14010020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/14/2021] [Accepted: 12/18/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Tumor cells communicate with the stromal cells within the tumor microenvironment (TME) to create a conducive environment for tumor growth. One major avenue for mediating crosstalk between various cell types in the TME involves exchanges of molecular payloads in the form of extracellular vesicles/exosomes. Autophagy is a fundamental mechanism to maintain intracellular homeostasis but recent reports suggest that secretory autophagy plays an important role in promoting secretion of exosomes that are packaged with non-coding RNAs (ncRNAs) and other biomolecules from the donor cell. Uptake of exosomal autophagy-modulating ncRNAs by recipient cells may further perpetuate tumor progression. Abstract Autophagy is a fundamental cellular homeostasis mechanism known to play multifaceted roles in the natural history of cancers over time. It has recently been shown that autophagy also mediates the crosstalk between the tumor and its microenvironment by promoting the export of molecular payloads such as non-coding RNA (ncRNAs) via LC3-dependent Extracellular Vesicle loading and secretion (LDELS). In turn, the dynamic exchange of exosomal ncRNAs regulate autophagic responses in the recipient cells within the tumor microenvironment (TME), for both tumor and stromal cells. Autophagy-dependent phenotypic changes in the recipient cells further enhance tumor growth and metastasis, through diverse biological processes, including nutrient supplementation, immune evasion, angiogenesis, and therapeutic resistance. In this review, we discuss how the feedforward autophagy-ncRNA axis orchestrates vital communications between various cell types within the TME ecosystem to promote cancer progression.
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Affiliation(s)
- Gracie Wee Ling Eng
- Precision Medicine Programme, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 11, Singapore 119228, Singapore; (G.W.L.E.); (Y.Z.); (D.W.T.Y.); (A.Y.T.T.)
| | - Yilong Zheng
- Precision Medicine Programme, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 11, Singapore 119228, Singapore; (G.W.L.E.); (Y.Z.); (D.W.T.Y.); (A.Y.T.T.)
| | - Dominic Wei Ting Yap
- Precision Medicine Programme, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 11, Singapore 119228, Singapore; (G.W.L.E.); (Y.Z.); (D.W.T.Y.); (A.Y.T.T.)
| | - Andrea York Tiang Teo
- Precision Medicine Programme, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 11, Singapore 119228, Singapore; (G.W.L.E.); (Y.Z.); (D.W.T.Y.); (A.Y.T.T.)
| | - Jit Kong Cheong
- Precision Medicine Programme, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 11, Singapore 119228, Singapore; (G.W.L.E.); (Y.Z.); (D.W.T.Y.); (A.Y.T.T.)
- NUS Centre for Cancer Research, National University of Singapore, 14 Medical Dr, Centre for Translational Medicine #12-01, Singapore 117599, Singapore
- Department of Biochemistry, YLLSoM, National University of Singapore, 8 Medical Drive, MD7 #03-09, Singapore 117597, Singapore
- Correspondence: ; Tel.: +65-66016388
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