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1
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Sabeel Z, Wang J, Dong J, Liu Y, Yu C, Yang Z. The duality of GSK-3β in urinary bladder cancer: Tumor suppressor and promoter roles through multiple signaling pathways. Biochim Biophys Acta Rev Cancer 2025; 1880:189324. [PMID: 40258445 DOI: 10.1016/j.bbcan.2025.189324] [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: 11/28/2024] [Revised: 04/11/2025] [Accepted: 04/12/2025] [Indexed: 04/23/2025]
Abstract
Urinary bladder cancer (UBC), the tenth most common cancer globally, is primarily categorized into non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) types. NMIBC has a low risk of metastasis but tends to recur frequently after transurethral resection, whereas MIBC is associated with a higher likelihood of metastasis and poorer prognosis. At diagnosis, roughly 75 % of UBC patients have NMIBC, while the remaining 25 % present with tumor invasion into the bladder's muscle layer. The molecular complexity of UBC has driven research toward identifying subtypes for more personalized treatment approaches. Glycogen synthase kinase-3β (GSK-3β) has emerged as a pivotal regulator in UBC through its dual roles across six key pathways: (1) Wnt/β-catenin regulation (tumor suppression vs oncogenic activation), (2) ER stress responses (apoptosis induction vs cytoprotection), (3) Akt/GSK-3β/β-catenin/c-Myc signaling, (4) PI3K/Akt/mTOR interactions, (5) NF-κB-mediated immune modulation, and (6) Snail1/β-catenin-driven epithelial mesenchymal transition (EMT). Our analysis reveals that GSK-3β's context-dependent functions create both therapeutic opportunities and challenges - while inhibition suppresses tumor growth via β-catenin degradation, it may simultaneously activate NF-κB-mediated oncogenic processes. These paradoxical effects are particularly evident in the tumor microenvironment, where GSK-3β modulation differentially regulates CD8+ T cell function and macrophage polarization. Understanding these complex pathway interactions is crucial for developing precision therapies that exploit GSK-3β's tumor-suppressive roles while mitigating its oncogenic potential.
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Affiliation(s)
- Zufa Sabeel
- College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing, China
| | - Jianfeng Wang
- Department of Urology, China-Japan Friendship Hospital, Beijing, China
| | - Jian Dong
- College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing, China
| | - Yan Liu
- College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing, China
| | - Changyuan Yu
- College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing, China.
| | - Zhao Yang
- College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing, China.
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2
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Saadh MJ, Hussein WS, Al-Hussainy AF, Bishoyi AK, Rekha MM, Kundlas M, Kavitha V, Aminov Z, Taher SG, Alwan M, Jawad M, Mushtaq H. Circular RNAs: driving forces behind chemoresistance and immune evasion in bladder cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04032-y. [PMID: 40131386 DOI: 10.1007/s00210-025-04032-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Accepted: 03/06/2025] [Indexed: 03/27/2025]
Abstract
Bladder cancer (BCa) is characterized by recurring relapses and the emergence of chemoresistance, especially against standard treatments like cisplatin and gemcitabine. Despite its significance, the molecular mechanisms underlying chemoresistance in BCa remain elusive. Recent studies have revealed that circular RNAs (circRNAs) are pivotal regulators of cancer progression and chemoresistance. Through their function as miRNA sponges and protein sequesters, circRNAs modulate the expression of key genes, ultimately driving either drug resistance or sensitivity in BCa. The complex interplay between circRNAs and chemoresistance suggests that they may represent promising therapeutic targets for overcoming treatment resistance in patients with BCa. This review aims to summarize the current understanding of circRNAs' regulatory roles in chemoresistance and provide insights into their potential as therapeutic targets, particularly in the context of cisplatin and gemcitabine resistance. Furthermore, we explore how chemoresistance can also impact tumor immune evasion, thereby affecting the tumor microenvironment. Our findings may pave the way for the advancement of innovative treatment approaches for bladder cancer.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | - Wael Sheet Hussein
- Dental Prosthetics Techniques Department, Health and Medical Techniques College, Alnoor University, Mosul, Iraq.
| | | | - Ashok Kumar Bishoyi
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, 360003, Gujarat, India
| | - M M Rekha
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Mayank Kundlas
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - V Kavitha
- Department of Chemistry, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Zafar Aminov
- Department of Public Health and Healthcare Management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | - Sada Ghalib Taher
- College of Health and Medical Technology, National University of Science and Technology, Nasiriyah, Dhi Qar, 64001, Iraq
| | - Mariem Alwan
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
| | - Mahmood Jawad
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
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3
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Zhang Z, Gao Z, Fang H, Zhao Y, Xing R. Therapeutic importance and diagnostic function of circRNAs in urological cancers: from metastasis to drug resistance. Cancer Metastasis Rev 2024; 43:867-888. [PMID: 38252399 DOI: 10.1007/s10555-023-10152-9] [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: 06/10/2023] [Accepted: 10/31/2023] [Indexed: 01/23/2024]
Abstract
Circular RNAs (circRNAs) are a member of non-coding RNAs with no ability in encoding proteins and their aberrant dysregulation is observed in cancers. Their closed-loop structure has increased their stability, and they are reliable biomarkers for cancer diagnosis. Urological cancers have been responsible for high mortality and morbidity worldwide, and developing new strategies in their treatment, especially based on gene therapy, is of importance since these malignant diseases do not respond to conventional therapies. In the current review, three important aims are followed. At the first step, the role of circRNAs in increasing or decreasing the progression of urological cancers is discussed, and the double-edged sword function of them is also highlighted. At the second step, the interaction of circRNAs with molecular targets responsible for urological cancer progression is discussed, and their impact on molecular processes such as apoptosis, autophagy, EMT, and MMPs is highlighted. Finally, the use of circRNAs as biomarkers in the diagnosis and prognosis of urological cancer patients is discussed to translate current findings in the clinic for better treatment of patients. Furthermore, since circRNAs can be transferred to tumor via exosomes and the interactions in tumor microenvironment provided by exosomes such as between macrophages and cancer cells is of importance in cancer progression, a separate section has been devoted to the role of exosomal circRNAs in urological tumors.
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Affiliation(s)
- Zhibin Zhang
- College of Traditional Chinese Medicine, Chengde Medical College, Chengde, 067000, Hebei, China.
| | - Zhixu Gao
- Chengde Medical College, Chengde, 067000, Hebei, China
| | - Huimin Fang
- Chengde Medical College, Chengde, 067000, Hebei, China
| | - Yutang Zhao
- Chengde Medical College, Chengde, 067000, Hebei, China
| | - Rong Xing
- Chengde Medical College, Chengde, 067000, Hebei, China
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4
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Zhao J, Ma Y, Zheng X, Sun Z, Lin H, Du C, Cao J. Bladder cancer: non-coding RNAs and exosomal non-coding RNAs. Funct Integr Genomics 2024; 24:147. [PMID: 39217254 DOI: 10.1007/s10142-024-01433-9] [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: 07/28/2024] [Revised: 08/15/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024]
Abstract
Bladder cancer (BCa) is a highly prevalent type of cancer worldwide, and it is responsible for numerous deaths and cases of disease. Due to the diverse nature of this disease, it is necessary to conduct significant research that delves deeper into the molecular aspects, to potentially discover novel diagnostic and therapeutic approaches. Lately, there has been a significant increase in the focus on non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), due to their growing recognition for their involvement in the progression and manifestation of BCa. The interest in exosomes has greatly grown due to their potential for transporting a diverse array of active substances, including proteins, nucleic acids, carbohydrates, and lipids. The combination of these components differs based on the specific cell and its condition. Research indicates that using exosomes could have considerable advantages in identifying and forecasting BCa, offering a less invasive alternative. The distinctive arrangement of the lipid bilayer membrane found in exosomes is what makes them particularly effective for administering treatments aimed at managing cancer. In this review, we have tried to summarize different ncRNAs that are involved in BCa pathogenesis. Moreover, we highlighted the role of exosomal ncRNAs in BCa.
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Affiliation(s)
- Jingang Zhao
- Department of Urology, Hangzhou Mingzhou Hospital, Hangzhou, 311215, Zhe'jiang, China
| | - Yangyang Ma
- Department of Urology, Hangzhou Mingzhou Hospital, Hangzhou, 311215, Zhe'jiang, China
| | - Xiaodong Zheng
- Department of the First Surgery, Zhejiang Provincial Corps Hospital of Chinese People's Armed Police Force, Hangzhou, 310051, Zhe'jiang, China
| | - Zhen Sun
- Department of the First Surgery, Zhejiang Provincial Corps Hospital of Chinese People's Armed Police Force, Hangzhou, 310051, Zhe'jiang, China
| | - Hongxiang Lin
- Department of Urology, Ganzhou Donghe Hospital, Ganzhou, 341000, Jiang'xi, China
| | - Chuanjun Du
- Department of Urology, Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, 310009, Zhe'jiang, China
| | - Jing Cao
- Department of Urology, Hangzhou Mingzhou Hospital, Hangzhou, 311215, Zhe'jiang, China.
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Liu K, Chen H, Li Y, Wang B, Li Q, Zhang L, Liu X, Wang C, Ertas YN, Shi H. Autophagy flux in bladder cancer: Cell death crosstalk, drug and nanotherapeutics. Cancer Lett 2024; 591:216867. [PMID: 38593919 DOI: 10.1016/j.canlet.2024.216867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/20/2024] [Accepted: 04/03/2024] [Indexed: 04/11/2024]
Abstract
Autophagy, a self-digestion mechanism, has emerged as a promising target in the realm of cancer therapy, particularly in bladder cancer (BCa), a urological malignancy characterized by dysregulated biological processes contributing to its progression. This highly conserved catabolic mechanism exhibits aberrant activation in pathological events, prominently featured in human cancers. The nuanced role of autophagy in cancer has been unveiled as a double-edged sword, capable of functioning as both a pro-survival and pro-death mechanism in a context-dependent manner. In BCa, dysregulation of autophagy intertwines with cell death mechanisms, wherein pro-survival autophagy impedes apoptosis and ferroptosis, while pro-death autophagy diminishes tumor cell survival. The impact of autophagy on BCa progression is multifaceted, influencing metastasis rates and engaging with the epithelial-mesenchymal transition (EMT) mechanism. Pharmacological modulation of autophagy emerges as a viable strategy to impede BCa progression and augment cell death. Notably, the introduction of nanoparticles for targeted autophagy regulation holds promise as an innovative approach in BCa suppression. This review underscores the intricate interplay of autophagy with cell death pathways and its therapeutic implications in the nuanced landscape of bladder cancer.
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Affiliation(s)
- Kuan Liu
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Huijing Chen
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Yanhong Li
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Bei Wang
- Department of Gynecology, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Qian Li
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Lu Zhang
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Xiaohui Liu
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China.
| | - Ce Wang
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China.
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri, 38039, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, 38039, Turkey; UNAM-National Nanotechnology Research Center, Bilkent University, Ankara, 06800, Turkey.
| | - Hongyun Shi
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China.
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Cheng S, Li C, Liu L, Liu X, Li M, Zhuo J, Wang J, Zheng W, Wang Z. Dysregulation and antimetastatic function of circLRIG1 modulated by miR-214-3p/LRIG1 axis in bladder carcinoma. Biol Direct 2024; 19:20. [PMID: 38454507 PMCID: PMC10918934 DOI: 10.1186/s13062-023-00446-x] [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: 09/12/2023] [Accepted: 12/19/2023] [Indexed: 03/09/2024] Open
Abstract
CircLRIG1, a newly discovered circRNA, has yet to have its potential function and biological processes reported. This study explored the role of circLRIG1 in the development and progression of bladder carcinoma and its potential molecular mechanisms. Techniques such as qRT-PCR, Western blot, various cellular assays, and in vivo models were used to investigate mRNA and protein levels, cell behavior, molecular interactions, and tumor growth. The results showed that both circLRIG1 and LRIG1 were significantly reduced in bladder carcinoma tissues and cell lines. Low circLRIG1 expression was associated with poor patient prognosis. Overexpressing circLRIG1 inhibited bladder carcinoma cell growth, migration, and invasion, promoted apoptosis, and decreased tumor growth and metastasis in vivo. Importantly, circLRIG1 was found to sponge miR-214-3p, enhancing LRIG1 expression, and its overexpression also modulated protein levels of E-cadherin, N-cadherin, Vimentin, and LRIG1. Similar effects were observed with LRIG1 overexpression. Notably, a positive correlation was found between circLRIG1 and LRIG1 expression in bladder carcinoma tissues. Additionally, the tumor-suppressing effect of circLRIG1 was reversed by overexpressing miR-214-3p or silencing LRIG1. The study concludes that circLRIG1 suppresses bladder carcinoma progression by enhancing LRIG1 expression via sponging miR-214-3p, providing a potential strategy for early diagnosis and treatment of bladder carcinoma.
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Affiliation(s)
- Shiliang Cheng
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan Xingqi Medical Laboratory Co., Ltd., 12 Wuyingshan Middle Road, Jinan, 250000, Shandong, China.
| | - Chunguang Li
- Department of Digestive Oncology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, ShenyangLiaoning, 110042, China
| | - Lu Liu
- Department of Digestive Oncology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, ShenyangLiaoning, 110042, China
| | - Xinli Liu
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, 12 Wuyingshan Middle Road, Jinan, 250000, Shandong, China
| | - Meng Li
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, 12 Wuyingshan Middle Road, Jinan, 250000, Shandong, China
| | - Jinhua Zhuo
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, 12 Wuyingshan Middle Road, Jinan, 250000, Shandong, China
| | - Jue Wang
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, 12 Wuyingshan Middle Road, Jinan, 250000, Shandong, China
| | - Wen Zheng
- Department of Emergency, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, 12 Wuyingshan Middle Road, Jinan, 250000, Shandong, China.
| | - Zhongmin Wang
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Military Medical University, 225 Changhai Road, Shanghai, 200000, China.
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Jóźwicka TM, Erdmańska PM, Stachowicz-Karpińska A, Olkiewicz M, Jóźwicki W. Exosomes-Promising Carriers for Regulatory Therapy in Oncology. Cancers (Basel) 2024; 16:923. [PMID: 38473285 DOI: 10.3390/cancers16050923] [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: 12/31/2023] [Revised: 01/29/2024] [Accepted: 02/15/2024] [Indexed: 03/14/2024] Open
Abstract
Extracellular vesicles (EVs), including exosomes and microvesicles, together with apoptotic bodies form a diverse group of nanoparticles that play a crucial role in intercellular communication, participate in numerous physiological and pathological processes. In the context of cancer, they can allow the transfer of bioactive molecules and genetic material between cancer cells and the surrounding stromal cells, thus promoting such processes as angiogenesis, metastasis, and immune evasion. In this article, we review recent advances in understanding how EVs, especially exosomes, influence tumor progression and modulation of the microenvironment. The key mechanisms include exosomes inducing the epithelial-mesenchymal transition, polarizing macrophages toward protumoral phenotypes, and suppressing antitumor immunity. The therapeutic potential of engineered exosomes is highlighted, including their loading with drugs, RNA therapeutics, or tumor antigens to alter the tumor microenvironment. Current techniques for their isolation, characterization, and engineering are discussed. Ongoing challenges include improving exosome loading efficiency, optimizing biodistribution, and enhancing selective cell targeting. Overall, exosomes present promising opportunities to understand tumorigenesis and develop more targeted diagnostic and therapeutic strategies by exploiting the natural intercellular communication networks in tumors. In the context of oncology, regulatory therapy provides the possibility of reproducing the original conditions that are unfavorable for the existence of the cancer process and may thus be a feasible alternative to population treatments. We also review current access to the technology enabling regulatory intervention in the cancer process using exosomes.
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Affiliation(s)
- Teresa Maria Jóźwicka
- Department of Oncology, Faculty of Health Sciences, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 87-100 Torun, Poland
| | - Patrycja Maria Erdmańska
- Department of Oncology, Faculty of Health Sciences, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 87-100 Torun, Poland
| | - Agnieszka Stachowicz-Karpińska
- Department of Lung Diseases, Tuberculosis and Sarcoidosis, Kuyavian-Pomeranian Pulmonology Center, 85-326 Bydgoszcz, Poland
| | - Magdalena Olkiewicz
- Eurecat, Centre Tecnològic de Catalunya, Unitat de Tecnologia Química, Marcel·lí Domingo 2, 43007 Tarragona, Spain
| | - Wojciech Jóźwicki
- Department of Oncology, Faculty of Health Sciences, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 87-100 Torun, Poland
- Department of Pathology, Kuyavian-Pomeranian Pulmonology Center, 85-326 Bydgoszcz, Poland
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Zhang Z, Huang Y, Guo AY, Yang L. Research progress of circular RNA molecules in aging and age-related diseases. Ageing Res Rev 2023; 87:101913. [PMID: 36934850 DOI: 10.1016/j.arr.2023.101913] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/05/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023]
Abstract
Circular RNAs (circRNAs) are a class of single-chain endogenous closed circular RNAs that do not have a poly(A) tail at the 3' end and a cap structure at the 5' end and are connected end-to-end by covalent bonds. CircRNAs, which are pervasive, diverse, stable, and conversed, have functions in transcriptional control and protein translation and play vital roles in modulating cell senescence, individual aging, as well as the occurrence and development of age-related diseases. Studies in recent years were reviewed from aspects including the biosynthesis mechanisms, classification, expression, biomedical functions, associations with aging and age-related diseases, and potential clinical applications of circRNAs. It will provide the theoretic basis for exploring the molecular biological mechanisms of aging, using circRNA as the therapeutic target to delay aging, and finding therapeutic strategies to prevent and treat age-related diseases.
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Affiliation(s)
- Zhidan Zhang
- Departments of Infectious Disease, The First Hospital of China Medical University, Shenyang, PR China
| | - Yuling Huang
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, PR China
| | - AYao Guo
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, PR China.
| | - Lina Yang
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, PR China.
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9
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Crosstalk of miRNAs with signaling networks in bladder cancer progression: Therapeutic, diagnostic and prognostic functions. Pharmacol Res 2022; 185:106475. [DOI: 10.1016/j.phrs.2022.106475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/17/2022] [Accepted: 09/27/2022] [Indexed: 12/24/2022]
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Ren YZ, Ding SS, Jiang YP, Wen H, Li T. Application of exosome-derived noncoding RNAs in bone regeneration: Opportunities and challenges. World J Stem Cells 2022; 14:473-489. [PMID: 36157529 PMCID: PMC9350624 DOI: 10.4252/wjsc.v14.i7.473] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 05/15/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
With advances in the fields of regenerative medicine, cell-free therapy has received increased attention. Exosomes have a variety of endogenous properties that provide stability for molecular transport across biological barriers to cells, as a form of cell-to-cell communication that regulates function and phenotype. In addition, exosomes are an important component of paracrine signaling in stem-cell-based therapy and can be used as a stand-alone therapy or as a drug delivery system. The remarkable potential of exosomes has paved the pathway for cell-free treatment in bone regeneration. Exosomes are enriched in distinct noncoding RNAs (ncRNAs), including microRNAs, long ncRNAs and circular RNAs. Different ncRNAs have multiple functions. Altered expression of ncRNA in exosomes is associated with the regenerative potential and development of various diseases, such as femoral head osteonecrosis, myocardial infarction, and cancer. Although there is increasing evidence that exosome-derived ncRNAs (exo-ncRNAs) have the potential for bone regeneration, the detailed mechanisms are not fully understood. Here, we review the biogenesis of exo-ncRNA and the effects of ncRNAs on angiogenesis and osteoblast- and osteoclast-related pathways in different diseases. However, there are still many unsolved problems and challenges in the clinical application of ncRNA; for instance, production, storage, targeted delivery and therapeutic potency assessment. Advancements in exo-ncRNA methods and design will promote the development of therapeutics, revolutionizing the present landscape.
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Affiliation(s)
- Yuan-Zhong Ren
- Department of Emergency Trauma Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang 471000, Henan Province, China
| | - Shan-Shan Ding
- Department of Geriatrics, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang 471000, Henan Province, China
| | - Ya-Ping Jiang
- Department of Oral Implantology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Hui Wen
- Department of Emergency Trauma Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang 471000, Henan Province, China
| | - Tao Li
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
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11
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Wei X, Zhang QM, Liu C, Wu S, Nong WX, Ge YY, Lin LN, Li F, Xie XX, Luo B. Microrna-1224-5p Is a Potential Prognostic and Therapeutic Biomarker in Glioblastoma: Integrating Bioinformatics and Clinical Analyses. Curr Med Sci 2022; 42:584-596. [PMID: 35678909 DOI: 10.1007/s11596-022-2593-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 03/22/2022] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Glioblastoma (GBM) is the most common, invasive, and malignant primary brain tumor with a poor prognosis and high recurrence rate. It's known that some microRNAs (miRNAs) which are associated with tumorigenesis and progression can be considered as prognostic and therapeutic targets in tumors including GBM. This study aims to highlight the potential role of the core miRNAs in GBM and their potential use as a prognostic and therapeutic biomarker. METHODS Differentially expressed miRNAs (DEmiRNAs) were identified in GBM by integrating miRNA-sequencing results and a GBM microarray dataset from the Gene Expression Omnibus (GEO) database through bioinformatics tools. The dysregulated miRNAs were identified by survival analysis through Chinese Glioma Genome Atlas (CGGA). Target genes of the dysregulated miRNAs were predicted on MiRWalk and miRTarBase database. TAM2.0 database, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis were used to analyze the function of the dysregulated miRNAs. Subsequently, protein-protein interaction (PPI) network analysis was used to identify the top 20 hub targets of the up-regulated and down-regulated miRNAs, respectively. Then, core miRNAs in GBM were identified by constructing dysregulated miRNA-differentially expressed hub gene networks. Validation of the core miRNAs expression was detected in 41 GBM tissues compared to 8 normal brain tissues. Furthermore, the potential biomarkers were identified by clinical correlation analysis and survival analysis. RESULTS Totally, 68 intersecting DEmiRNAs were identified, 40 of which were upregulated and the other 28 miRNAs were downregulated. Two upregulated and 4 downregulated miRNAs showed prognostic significance. Most differentially expressed hub genes were regulated by the miR-28-5p and miR-1224-5p, which were respectively upregulated and downregulated in GBM. The correlation between miR-1224-5p level and recurrence was statistically significant (P=0.011). Survival analysis showed that high miR-28-5p level and high miR-1224-5p level were both associated with better prognosis. Moreover, high miR-1224-5p level was an independent prognosis factor for GBM patients according to the cox regression analysis. CONCLUSION MiRNA-1224-5p could be a potential target for the prognosis and treatment in GBM.
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Affiliation(s)
- Xing Wei
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, 530021, China
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
| | - Qing-Mei Zhang
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, 530021, China
- Central Laboratory of Pre-Clinical Medicine (Key Laboratory of Guangxi Colleges and Universities), Guangxi Medical University, Nanning, 530021, China
| | - Chang Liu
- Department of Neurosurgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
| | - Song Wu
- Department of Neurosurgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
| | - Wei-Xia Nong
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, 530021, China
| | - Ying-Ying Ge
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, 530021, China
| | - Li-Na Lin
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, 530021, China
| | - Feng Li
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, 530021, China
| | - Xiao-Xun Xie
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, 530021, China.
- Key Laboratory of Early Prevention and Treatment of Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, 530021, China.
| | - Bin Luo
- Department of Histology and Embryology, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, 530021, China.
- Central Laboratory of Pre-Clinical Medicine (Key Laboratory of Guangxi Colleges and Universities), Guangxi Medical University, Nanning, 530021, China.
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12
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Ma M, Li J, Zhang Z, Sun J, Liu Z, Zeng Z, Ouyang S, Kang W. The Role and Mechanism of microRNA-1224 in Human Cancer. Front Oncol 2022; 12:858892. [PMID: 35494023 PMCID: PMC9046935 DOI: 10.3389/fonc.2022.858892] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/22/2022] [Indexed: 11/24/2022] Open
Abstract
microRNAs (miRNAs) are a type of small endogenous non-coding RNAs composed of 20-22 nucleotides, which can regulate the expression of a gene by targeting 3’ untranslated region (3’-UTR) of mRNA. Many studies have reported that miRNAs are involved in the occurrence and progression of human diseases, including malignant tumors. miR-1224 plays significant roles in different tumors, including tumor proliferation, metastasis, invasion, angiogenesis, biological metabolism, and drug resistance. Mostly, it serves as a tumor suppressor. With accumulating proofs of miR-1224, it can act as a potential bio-indicator in the diagnosis and prognosis of patients with cancer. In this article, we review the characteristics and research progress of miR-1224 and emphasize the regulation and function of miR-1224 in different cancer. Furthermore, we conclude the clinical implications of miR-1224. This review may provide new horizons for deeply understanding the role of miR-1224 as biomarkers and therapeutic targets in human cancer.
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Affiliation(s)
- Mingwei Ma
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Jie Li
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Zimu Zhang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Juan Sun
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Zhen Liu
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Ziyang Zeng
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Siwen Ouyang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Weiming Kang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
- *Correspondence: Weiming Kang,
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13
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Ghafouri-Fard S, Najafi S, Hussen BM, Basiri A, Hidayat HJ, Taheri M, Rashnoo F. The Role of Circular RNAs in the Carcinogenesis of Bladder Cancer. Front Oncol 2022; 12:801842. [PMID: 35296022 PMCID: PMC8918517 DOI: 10.3389/fonc.2022.801842] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 01/28/2022] [Indexed: 12/15/2022] Open
Abstract
Circular RNAs (circRNAs) are a group of transcripts with enclosed configurations which can regulate gene expression. These transcripts have important roles in normal development and in the pathogenesis of disorders. Recent evidence has supported involvement of circRNAs in the development of bladder cancer. Several circRNAs such as circ_0058063, hsa-circRNA-403658, circPDSS1, circCASC15, circRNA-MYLK, and circRNA_103809 have been upregulated in bladder cancer samples. On the other hand, hsa_circ_0137606, BCRC-3, circFUT8, hsa_circ_001598, circSLC8A1, hsa_circ_0077837, hsa_circ_0004826, and circACVR2A are among downregulated circRNAs in bladder cancer. Numerous circRNAs have diagnostic or prognostic value in bladder cancer. In this review, we aim to outline the latest findings about the role of circRNAs in bladder cancer and introduce circRNAs for further investigations as therapeutic targets.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajad Najafi
- Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Abbas Basiri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University-Erbil, Erbil, Iraq
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
- *Correspondence: Mohammad Taheri, ; Fariborz Rashnoo,
| | - Fariborz Rashnoo
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Mohammad Taheri, ; Fariborz Rashnoo,
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14
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Liu YP, Wu X, Meng JH, Xing JX, Xuan JF, Xia X, Yao J, Wang BJ. The effect of human GRIN1 gene 5' functional region on gene expression regulation in vitro. Gene 2022; 808:145973. [PMID: 34592350 DOI: 10.1016/j.gene.2021.145973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 08/31/2021] [Accepted: 09/24/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Abnormal expression of ionotropic glutamate receptor NMDA type subunit 1, the key subunit of the NMDA receptor, may be related to many neuropsychiatric disorders. In this study, we explored the functional sequence of the 5' regulatory region of the human GRIN1 gene and discussed the transcription factors that may regulate gene expression. MATERIALS AND METHODS Twelve recombinant pGL3 vectors with gradually truncated fragment lengths were constructed, transfected into HEK-293, U87, and SK-N-SH cell lines, and analyzed through the luciferase reporter gene assay. JASPAR database is used to predict transcription factors. RESULTS In SK-N-SH and U87 cell lines, regions from -337 to -159 bp, -704 to -556 bp inhibited gene expression, while -556 to -337 bp upregulated gene expression. In HEK-293 and U87 cell lines, the expression of fragment -1703 to + 188 bp was significantly increased compared to adjacent fragments -1539 to + 188 bp and -1843 to + 188 bp. The protein expressions of fragments -2162 to + 188 bp and -2025 to + 188 bp, -1539 to + 188 bp and -1215 to + 188 bp, -1215 to + 188 bp and -1066 to + 188 bp were significantly different in HEK-293 and SK-N-SH cells. According to the predictions of the JASPAR database, the transcription factors REST, EGR1, and CREB1/HIC2 may bind the DNA sequences of GRIN1 gene from the -337 to -159, -556 to -337, and -704 to -556, respectively. In addition, zinc finger transcription factors may regulate the expression of other differentially expressed fragments. CONCLUSIONS Abnormal transcription regulation in the proximal promoter region of GRIN1 (-704 to + 188 bp) may be involved in the course of neuropsychiatric diseases.
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Affiliation(s)
- Yong-Ping Liu
- School of Forensic Medicine, China Medical University, Shenyang 110122, China; Department of Clinic Pathology, Weifang Medical University, Weifang 261053, China.
| | - Xue Wu
- School of Forensic Medicine, China Medical University, Shenyang 110122, China.
| | - Jing-Hua Meng
- School of Forensic Medicine, China Medical University, Shenyang 110122, China.
| | - Jia-Xin Xing
- School of Forensic Medicine, China Medical University, Shenyang 110122, China.
| | - Jin-Feng Xuan
- School of Forensic Medicine, China Medical University, Shenyang 110122, China.
| | - Xi Xia
- School of Forensic Medicine, China Medical University, Shenyang 110122, China.
| | - Jun Yao
- School of Forensic Medicine, China Medical University, Shenyang 110122, China.
| | - Bao-Jie Wang
- School of Forensic Medicine, China Medical University, Shenyang 110122, China.
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15
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Liu Q, You B, Meng J, Huang CP, Dong G, Wang R, Chou F, Gao S, Chang C, Yeh S, Xu W. Targeting the androgen receptor to enhance NK cell killing efficacy in bladder cancer by modulating ADAR2/circ_0001005/PD-L1 signaling. Cancer Gene Ther 2022; 29:1988-2000. [PMID: 35915245 PMCID: PMC9750871 DOI: 10.1038/s41417-022-00506-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 06/18/2022] [Accepted: 07/06/2022] [Indexed: 01/25/2023]
Abstract
Although androgen receptor (AR) can influence bladder cancer (BCa) initiation and progression, its impact on tumor immune escape remains unclear. Here, we found that targeting AR could enhance natural killer (NK) cell tumor-killing efficacy by decreasing PD-L1 expression. Both antiandrogen treatment and AR knockdown effectively reduced membrane PD-LI expression to facilitate NK cell-mediated BCa cell killing by downregulating circ_0001005. Mechanistically, AR upregulated circRNA circ_0001005 expression via the RNA-editing gene ADAR2. circ_0001005 competitively sponged the miRNA miR-200a-3p to promote PD-L1 expression. A preclinical BCa xenograft mouse model further confirmed this newly identified signaling using the small molecule circ_0001005-shRNA to improve NK cell killing of BCa tumor cells. Collectively, these results suggest that targeting the newly identified ADAR2/circ_0001005/miR-200a-3p/PD-L1 pathway to impact antitumor immunity may suppress progression and boost immunotherapeutic efficacy in BCa.
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Affiliation(s)
- Qing Liu
- grid.412463.60000 0004 1762 6325Department of Radiation Oncology, Urology, and Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001 China ,grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Bosen You
- grid.412463.60000 0004 1762 6325Department of Radiation Oncology, Urology, and Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001 China ,grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Jialin Meng
- grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Chi-Ping Huang
- grid.411508.90000 0004 0572 9415Department of Urology, China Medical University/Hospital, Taichung, 404 Taiwan
| | - Guanglu Dong
- grid.412463.60000 0004 1762 6325Department of Radiation Oncology, Urology, and Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| | - Ronghao Wang
- grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Fuju Chou
- grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Shan Gao
- grid.412463.60000 0004 1762 6325Department of Radiation Oncology, Urology, and Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| | - Chawnshang Chang
- grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA ,grid.411508.90000 0004 0572 9415Department of Urology, China Medical University/Hospital, Taichung, 404 Taiwan
| | - Shuyuan Yeh
- grid.412750.50000 0004 1936 9166Departments of Urology, Pathology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Wanhai Xu
- grid.410736.70000 0001 2204 9268Department of Urology, The 4th Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
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16
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Yu K, Liu M, Huang Y, Yu Q, Ma D, Dai G, Chen Y. circMBOAT2 serves as the sponge of miR-433-3p to promote the progression of bladder cancer. Pathol Res Pract 2021; 227:153613. [PMID: 34563754 DOI: 10.1016/j.prp.2021.153613] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/06/2021] [Accepted: 09/08/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Bladder cancer (Bca) is the most common cancer in urinary system. Recent studies revealed that circular RNAs (circRNAs) play vital roles in the development and progression of cancers. circMBOAT2 serves as an oncogenic gene in various kinds of cancer, promoting cell growth and metastasis. Nevertheless, the biological function of circMBOAT2 in Bca has not been reported. METHODS qRT-PCR was used to measure the mRNA, circRNA and miRNA expression levels in Bca tissues and cells. Loss-of function experiments were carried to investigate the effect of circMBOAT2 on cell proliferation and migration. Nuclear mass separation, RNA pull-down and dual-luciferase reporter were performed to the molecular mechanisms underlying the functions of circMBOAT2. RESULTS In this research, we identified that circMBOAT2 expression was increased in Bca tissues and positively corelated with unfavorable prognosis. In vitro assay demonstrated that suppression of circMBOAT2 impaired the proliferation and migration of Bca cells. Mechanically, circMBOAT2 was predominantly spread in cytoplasm and it sponged miR-433-3p to strengthen CREB1 expression. CONCLUSION Hence, our study suggested that circMBOAT2 may serve as an oncogene in the development and progression of Bca and it will be the novel tumor biomarker and therapeutic target for Bca.
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Affiliation(s)
- Keqin Yu
- Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, 310007 Hangzhou, China
| | - Maomao Liu
- Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, 310007 Hangzhou, China
| | - Yasheng Huang
- Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, 310007 Hangzhou, China
| | - Qiqi Yu
- Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, 310007 Hangzhou, China
| | - Dechen Ma
- Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, 310007 Hangzhou, China
| | - Guangcheng Dai
- Department of Urology, The Second Affiliated Hospital of Soochow University, 215004 Suzhou, China.
| | - Yin Chen
- Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, 310007 Hangzhou, China.
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17
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Feng L, Fu D, Gao L, Cheng H, Zhu C, Zhang G. Circular RNA_0001495 increases Robo1 expression by sponging microRNA-527 to promote the proliferation, migration and invasion of bladder cancer cells. Carcinogenesis 2021; 42:1046-1055. [PMID: 34021307 DOI: 10.1093/carcin/bgab040] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/26/2021] [Accepted: 05/20/2021] [Indexed: 01/03/2023] Open
Abstract
Bladder cancer (BCa) is a heterogeneous disease that poses great threats on public health. Increasing studies have identified the vital functions of circular RNAs (circRNAs) in BCa treatment. Hence, this current study set out to explore the modulatory role of circ_0001495 in BCa development. First, the expression of circ_0001495 was determined by reverse transcription quantitative polymerase chain reaction. Cell biological processes were then analyzed after altering the circ_0001495 expression in T24 cells. Next, interactions among circ_0001495, microRNA-527 (miR-527) and roundabout guidance receptor 1 (Robo1) were investigated by dual luciferase reporter gene assay, RNA pull down assay and FISH assay. Lastly, xenograft tumors in nude mice were established to explore the effect of circ_0001495 in vivo. It was found that circ_0001495 was highly expressed in BCa tissues and cells, and was further correlated with poor prognosis in BCa patients. In addition, circ_0001495 inhibited the activity of miR-527 by acting as a sponge to sponge miR-527, which further elevated the Robo1 expression. Lastly, circ_0001495 was found to promote the proliferation, migration and invasion of BCa cells in vitro through the miR-527/Robo1 axis and promote the growth and metastasis of BCa tumors in vivo. Altogether, findings in our study highlight the promoting role of circ_0001495 in the progression of BCa by increasing Robo1 via sponging miR-527, representing a promising target for BCa management.
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Affiliation(s)
- Liuwei Feng
- Department of Urology Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, P.R. China
| | - Dongmei Fu
- Color Doppler Ultrasound Room, Huaihe Hospital of Henan University, Kaifeng 475000, P.R. China
| | - Lei Gao
- Department of Urology Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, P.R. China
| | - Hepeng Cheng
- Department of Urology Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, P.R. China
| | - Chaoyang Zhu
- Department of Urology Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, P.R. China
| | - Guangwei Zhang
- Department of Urology Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, P.R. China
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18
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Zhang Z, Mou Z, Xu C, Wu S, Dai X, Chen X, Ou Y, Chen Y, Yang C, Jiang H. Autophagy-associated circular RNA hsa_circ_0007813 modulates human bladder cancer progression via hsa-miR-361-3p/IGF2R regulation. Cell Death Dis 2021; 12:778. [PMID: 34365465 PMCID: PMC8349354 DOI: 10.1038/s41419-021-04053-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 01/07/2023]
Abstract
Circular RNAs (circRNAs) drive several cellular processes including proliferation, survival, and differentiation. Here, we identified a circRNA hsa_circ_0007813, whose expression was upregulated in bladder cancer. High hsa_circ_0007813 expression was associated with larger tumor size, higher primary tumor T stage, and higher pathologic grade. Survival analysis showed that patients with high hsa_circ_0007813 expression levels had a poorer prognosis. Based on these findings from clinical tissue samples and cell lines, we assumed that hsa_circ_0007813 functioned a vital role in bladder cancer progression. Next, functional experiments revealed that knockdown of hsa_circ_0007813 inhibited proliferation, migration, and invasiveness of bladder cancer cells both in vitro and in vivo. Through extensive bioinformatic prediction and RNA pull-down assays, we identified hsa-miR-361-3p as a competing endogenous RNA of hsa_circ_0007813. Further bioinformatic studies narrowed targets to 35 possible downstream genes. We then found that knockdown of hsa_circ_0007813 led to altered cell autophagy, bringing our attention to IGF2R, one of the possible downstream genes. IGF2R was also known as cation-independent mannose-6-phosphate receptor (CI-M6PR), was discovered to participate in both autophagy and tumor biology. Regarding autophagy has a dominant role in the survival of tumor cells overcoming cellular stress and correlates with tumor progression, investigations were made to prove that hsa_circ_0007813 could regulate IGF2R expression via hsa-miR-361-3p sponging. The potential of hsa_circ_0007813 in regulating IGF2R expression explained its influence on cell behavior and clinical outcomes. Collectively, our data could offer new insight into the biology of circRNA in bladder cancer.
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Affiliation(s)
- Zheyu Zhang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Zezhong Mou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chenyang Xu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Siqi Wu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiyu Dai
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xinan Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxi Ou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yiling Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chen Yang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China.
| | - Haowen Jiang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China.
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19
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GATCDA: Predicting circRNA-Disease Associations Based on Graph Attention Network. Cancers (Basel) 2021; 13:cancers13112595. [PMID: 34070678 PMCID: PMC8198988 DOI: 10.3390/cancers13112595] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/19/2021] [Accepted: 05/22/2021] [Indexed: 12/11/2022] Open
Abstract
CircRNAs (circular RNAs) are a class of non-coding RNA molecules with a closed circular structure. CircRNAs are closely related to the occurrence and development of diseases. Due to the time-consuming nature of biological experiments, computational methods have become a better way to predict the interactions between circRNAs and diseases. In this study, we developed a novel computational method called GATCDA utilizing a graph attention network (GAT) to predict circRNA-disease associations with disease symptom similarity, network similarity, and information entropy similarity for both circRNAs and diseases. GAT learns representations for nodes on a graph by an attention mechanism, which assigns different weights to different nodes in a neighborhood. Considering that the circRNA-miRNA-mRNA axis plays an important role in the generation and development of diseases, circRNA-miRNA interactions and disease-mRNA interactions were adopted to construct features, in which mRNAs were related to 88% of miRNAs. As demonstrated by five-fold cross-validation, GATCDA yielded an AUC value of 0.9011. In addition, case studies showed that GATCDA can predict unknown circRNA-disease associations. In conclusion, GATCDA is a useful method for exploring associations between circRNAs and diseases.
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20
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Large-scale circular RNA deregulation in T-ALL: unlocking unique ectopic expression of molecular subtypes. Blood Adv 2021; 4:5902-5914. [PMID: 33259601 DOI: 10.1182/bloodadvances.2020002337] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 10/20/2020] [Indexed: 12/25/2022] Open
Abstract
Circular RNAs (circRNAs) are stable RNA molecules that can drive cancer through interactions with microRNAs and proteins and by the expression of circRNA encoded peptides. The aim of the study was to define the circRNA landscape and potential impact in T-cell acute lymphoblastic leukemia (T-ALL). Analysis by CirComPara of RNA-sequencing data from 25 T-ALL patients, immature, HOXA overexpressing, TLX1, TLX3, TAL1, or LMO2 rearranged, and from thymocyte populations of human healthy donors disclosed 68 554 circRNAs. Study of the top 3447 highly expressed circRNAs identified 944 circRNAs with significant differential expression between malignant T cells and normal counterparts, with most circRNAs displaying increased expression in T-ALL. Next, we defined subtype-specific circRNA signatures in molecular genetic subgroups of human T-ALL. In particular, circZNF609, circPSEN1, circKPNA5, and circCEP70 were upregulated in immature, circTASP1, circZBTB44, and circBACH1 in TLX3, circHACD1, and circSTAM in HOXA, circCAMSAP1 in TLX1, and circCASC15 in TAL-LMO. Backsplice sequences of 14 circRNAs ectopically expressed in T-ALL were confirmed, and overexpression of circRNAs in T-ALL with specific oncogenic lesions was substantiated by quantification in a panel of 13 human cell lines. An oncogenic role of circZNF609 in T-ALL was indicated by decreased cell viability upon silencing in vitro. Furthermore, functional predictions identified circRNA-microRNA gene axes informing modes of circRNA impact in molecular subtypes of human T-ALL.
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21
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Frey L, Klümper N, Schmidt D, Kristiansen G, Toma M, Ritter M, Alajati A, Ellinger J. CircEHD2, CircNETO2 and CircEGLN3 as Diagnostic and Prognostic Biomarkers for Patients with Renal Cell Carcinoma. Cancers (Basel) 2021; 13:cancers13092177. [PMID: 33946584 PMCID: PMC8124893 DOI: 10.3390/cancers13092177] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/20/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Circular RNA (circRNA) plays an important role in cancer, but little is known about its role in clear cell renal cell carcinoma (ccRCC). The study was designed to analyze the role of circRNAs in ccRCC. We show that circEHD2, circENGLN3, and circNETO2 are upregulated in ccRCC compared with non-malignant renal tissue. Increased circEHD2 levels were significant and independent predictors of progression-free and cancer-specific survival of ccRCC patients. Thus, the analysis of circRNAs may be of diagnostic and prognostic relevance in patients with ccRCC. Abstract Background: Circular RNA (circRNA) plays an important role in the carcinogenesis of various tumors. It is assumed that circRNAs have a high tissue and tumor specificity, thus they are discussed as cancer biomarkers. The knowledge about circRNAs in clear cell renal carcinoma (ccRCC) is limited so far, and thus we studied the expression profile of seven circRNAs (circCOL5A1, circEHD2, circEDEM2, circEGNL3, circNETO2, circSCARB1, circSOD2) in a cohort of ccRCC patients. Methods: Fresh-frozen normal and cancerous tissues were prospectively collected from patients with ccRCC undergoing partial/radical nephrectomy. Total RNA was isolated from 121 ccRCC and 91 normal renal tissues, and the circRNA expression profile was determined using quantitative real-time PCR. Results: circEHD2, circENGLN3, and circNETO2 were upregulated in ccRCC compared with non-malignant renal tissue. circENGLN3 expression was highly discriminative between normal and cancerous tissue. None of the circRNAs was correlated with clinicopathological parameters. High circEHD2 and low circNETO2 levels were an independent predictor of a shortened progression-free survival, cancer-specific survival, and overall survival in patients with ccRCC undergoing nephrectomy. Conclusions: The analysis of circRNAs may provide diagnostic and prognostic information. Thus, circRNAs could help to optimize the individual treatment and ultimately improve ccRCC patients’ survival.
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Affiliation(s)
- Lisa Frey
- Department of Urology, University Hospital Bonn, 53127 Bonn, Germany; (L.F.); (N.K.); (D.S.); (M.R.); (A.A.)
| | - Niklas Klümper
- Department of Urology, University Hospital Bonn, 53127 Bonn, Germany; (L.F.); (N.K.); (D.S.); (M.R.); (A.A.)
| | - Doris Schmidt
- Department of Urology, University Hospital Bonn, 53127 Bonn, Germany; (L.F.); (N.K.); (D.S.); (M.R.); (A.A.)
| | - Glen Kristiansen
- Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany; (G.K.); (M.T.)
| | - Marieta Toma
- Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany; (G.K.); (M.T.)
| | - Manuel Ritter
- Department of Urology, University Hospital Bonn, 53127 Bonn, Germany; (L.F.); (N.K.); (D.S.); (M.R.); (A.A.)
| | - Abdullah Alajati
- Department of Urology, University Hospital Bonn, 53127 Bonn, Germany; (L.F.); (N.K.); (D.S.); (M.R.); (A.A.)
| | - Jörg Ellinger
- Department of Urology, University Hospital Bonn, 53127 Bonn, Germany; (L.F.); (N.K.); (D.S.); (M.R.); (A.A.)
- Correspondence: ; Tel.: +49 228-287-14180; Fax: +49-228-287-14185
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Zhi F, Ding Y, Wang R, Yang Y, Luo K, Hua F. Exosomal hsa_circ_0006859 is a potential biomarker for postmenopausal osteoporosis and enhances adipogenic versus osteogenic differentiation in human bone marrow mesenchymal stem cells by sponging miR-431-5p. Stem Cell Res Ther 2021; 12:157. [PMID: 33648601 PMCID: PMC7923524 DOI: 10.1186/s13287-021-02214-y] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 02/07/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND As one of the most common chronic diseases in the world, osteoporosis occurs especially in postmenopausal women. Circular RNAs (circRNAs) are emerging as major drivers in human disease. The aim of the present study was to analyse circRNA expression profiles in osteoporosis and to explore the clinical significance and the regulatory molecular mechanism of hsa_circ_0006859 during osteoporosis. METHODS Exosomes were isolated from clinically collected serum samples. A circRNA microarray was performed to screen differentially expressed circRNAs. Quantitative real-time PCR (qRT-PCR) and western blot were performed to analyse target gene mRNA expression and protein expression. Alizarin red staining (ARS) was performed to evaluate the mineralization ability of human bone marrow mesenchymal stem cells (hBMSCs). Oil Red O staining was performed to evaluate the lipid droplet formation ability of hBMSCs. Bioinformatics analysis and the luciferase reporter assay were performed to investigate the interaction between two genes. RESULTS Hsa_circ_0006859 was identified as one of the most upregulated circRNAs in the microarray analysis. Hsa_circ_0006859 in exosomes was upregulated in osteoporosis patients compared to healthy controls. Hsa_circ_0006859 differentiated osteopenia or osteoporosis patients from healthy controls with high sensitivity and specificity. Hsa_circ_0006859 suppressed osteoblastic differentiation and promoted adipogenic differentiation of hBMSCs. Hsa_circ_0006859 directly bound to miR-431-5p, and ROCK1 was identified as a novel target gene of miR-431-5p. Hsa_circ_0006859 is a competing endogenous RNA (ceRNA) of miR-431-5p that promotes ROCK1 expression. Hsa_circ_0006859 suppressed osteogenesis and promoted adipogenesis by sponging miR-431-5p to upregulate ROCK1. CONCLUSIONS Exosomal hsa_circ_0006859 is a potential biomarker for postmenopausal osteoporosis and controls the balance between osteogenesis and adipogenesis in hBMSCs by sponging miR-431-5p.
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Affiliation(s)
- Feng Zhi
- Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou City, 213003, Jiangsu, China.
| | - Yi Ding
- Department of Geriatrics, Third Affiliated Hospital of Soochow University, Changzhou City, 213003, Jiangsu, China
| | - Rong Wang
- Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou City, 213003, Jiangsu, China
| | - Yujiao Yang
- Department of Geriatrics, Third Affiliated Hospital of Soochow University, Changzhou City, 213003, Jiangsu, China
| | - Kaiming Luo
- Department of Endocrinology, Third Affiliated Hospital of Soochow University, Changzhou City, 213003, Jiangsu, China
| | - Fei Hua
- Department of Endocrinology, Third Affiliated Hospital of Soochow University, Changzhou City, 213003, Jiangsu, China.
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Chen L, Shan G. CircRNA in cancer: Fundamental mechanism and clinical potential. Cancer Lett 2021; 505:49-57. [PMID: 33609610 DOI: 10.1016/j.canlet.2021.02.004] [Citation(s) in RCA: 298] [Impact Index Per Article: 74.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 02/07/2023]
Abstract
Circular RNAs (CircRNAs) are a class of single-stranded noncoding RNAs that are formed in a circular conformation via non-canonical splicing or back-splicing events. Aberrant expressions of many circRNAs are observed in diverse cancers, indicating their crucial roles in tumorigenesis and tumor development. Recently, several pieces of evidence have revealed that many circRNAs are involved in the promotion or suppression of cancers to varying degrees via different molecular mechanisms. Here in this review, we present a summary of the characteristics, types, biogenesis, and functions of circRNAs, and outline a series of the most recently studied circRNAs and their functional mechanisms in multiple cancer types with future perspectives. With great advances in nucleic acid-based therapeutic tools, circRNAs could be further explored as targetable molecules in future cancer treatments.0.
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Affiliation(s)
- Liang Chen
- Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, 230027, China.
| | - Ge Shan
- Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, 230027, China.
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24
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Wu M, Li S, Han J, Liu R, Yuan H, Xu X, Li X, Liu Z. Progression Risk Assessment of Post-surgical Papillary Thyroid Carcinoma Based on Circular RNA-Associated Competing Endogenous RNA Mechanisms. Front Cell Dev Biol 2021; 8:606327. [PMID: 33553144 PMCID: PMC7859334 DOI: 10.3389/fcell.2020.606327] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/11/2020] [Indexed: 12/22/2022] Open
Abstract
Background: Accurate risk assessment of post-surgical progression in papillary thyroid carcinoma (PTC) patients is critical. Exploring key differentially expressed mRNAs (DE-mRNAs) regulated by differentially expressed circular RNAs (circRNAs) via the ceRNA mechanism could help establish a novel assessment tool. Methods: ceRNA network was established based on differentially expressed RNAs and correlation analysis. DE-mRNAs within the ceRNA network associated with progression-free interval (PFI) of PTC were identified to construct a prognostic ceRNA regulatory subnetwork. least absolute shrinkage and selection operator (LASSO)-Cox regression was applied to identify hub DE-mRNAs and establish a novel DE-mRNA signature in predicting PFI of PTC. Results: Six hub DE-mRNAs, namely, CLCNKB, FXBO27, FXYD6, RIMS2, SPC24, and CDKN2A, were identified to be most significantly related to the PFI of PTC, and a prognostic DE-mRNA signature was proposed. A nomogram incorporating the DE-mRNA signature and clinical parameters was established to improve the progression risk assessment in post-surgical PTC, which was superior to the American Thyroid Association risk stratification system and distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size (MACIS) score American Joint Committee on Cancer staging system. Conclusions: Based on the circRNA-associated ceRNA RNA mechanism, a DE-mRNA signature and prognostic nomogram was established, which may improve the progression risk assessment in post-surgical PTC.
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Affiliation(s)
- Mengwei Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shuo Li
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jiashu Han
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- MD Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Rui Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hongwei Yuan
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiequn Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaobin Li
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ziwen Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Yang X, Ye T, Liu H, Lv P, Duan C, Wu X, Jiang K, Lu H, Xia D, Peng E, Chen Z, Tang K, Ye Z. Expression profiles, biological functions and clinical significance of circRNAs in bladder cancer. Mol Cancer 2021; 20:4. [PMID: 33397425 PMCID: PMC7780637 DOI: 10.1186/s12943-020-01300-8] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 12/21/2020] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs), which are single-stranded closed-loop RNA molecules lacking terminal 5′ caps and 3′ poly(A) tails, are attracting increasing scientific attention for their crucial regulatory roles in the occurrence and development of various diseases. With the rapid development of high-throughput sequencing technologies, increasing numbers of differentially expressed circRNAs have been identified in bladder cancer (BCa) via exploration of the expression profiles of BCa and normal tissues and cell lines. CircRNAs are critically involved in BCa biological behaviours, including cell proliferation, tumour growth suppression, cell cycle arrest, apoptosis, invasion, migration, metastasis, angiogenesis, and cisplatin chemoresistance. Most of the studied circRNAs in BCa regulate cancer biological behaviours via miRNA sponging regulatory mechanisms. CircRNAs have been reported to be significantly associated with many clinicopathologic characteristics of BCa, including tumour size, grade, differentiation, and stage; lymph node metastasis; tumour numbers; distant metastasis; invasion; and recurrence. Moreover, circRNA expression levels can be used to predict BCa patients’ survival parameters, such as overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). The abundance, conservation, stability, specificity and detectability of circRNAs render them potential diagnostic and prognostic biomarkers for BCa. Additionally, circRNAs play crucial regulatory roles upstream of various signalling pathways related to BCa carcinogenesis and progression, reflecting their potential as therapeutic targets for BCa. Herein, we briefly summarize the expression profiles, biological functions and mechanisms of circRNAs and the potential clinical applications of these molecules for BCa diagnosis, prognosis, and targeted therapy.
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Affiliation(s)
- Xiaoqi Yang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Ye
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haoran Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Lv
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chen Duan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoliang Wu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kehua Jiang
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Hongyan Lu
- Department of Urology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ding Xia
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ejun Peng
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiqiang Chen
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Tang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Zhangqun Ye
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Mishra N, Raina K, Agarwal R. Deciphering the role of microRNAs in mustard gas-induced toxicity. Ann N Y Acad Sci 2020; 1491:25-41. [PMID: 33305460 DOI: 10.1111/nyas.14539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/26/2020] [Accepted: 11/01/2020] [Indexed: 12/16/2022]
Abstract
Mustard gas (sulfur mustard, SM), a highly vesicating chemical warfare agent, was first deployed in warfare in 1917 and recently during the Iraq-Iran war (1980s) and Syrian conflicts (2000s); however, the threat of exposure from stockpiles and old artillery shells still looms large. Whereas research has been long ongoing on SM-induced toxicity, delineating the precise molecular pathways is still an ongoing area of investigation; thus, it is important to attempt novel approaches to decipher these mechanisms and develop a detailed network of pathways associated with SM-induced toxicity. One such avenue is exploring the role of microRNAs (miRNAs) in SM-induced toxicity. Recent research on the regulatory role of miRNAs provides important results to fill in the gaps in SM toxicity-associated mechanisms. In addition, differentially expressed miRNAs can also be used as diagnostic markers to determine the extent of toxicity in exposed individuals. Thus, in our review, we have summarized the studies conducted so far in cellular and animal models, including human subjects, on the expression profiles and roles of miRNAs in SM- and/or SM analog-induced toxicity. Further detailed research in this area will guide us in devising preventive strategies, diagnostic tools, and therapeutic interventions against SM-induced toxicity.
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Affiliation(s)
- Neha Mishra
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, Colorado
| | - Komal Raina
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, Colorado.,Department of Pharmaceutical Sciences, South Dakota State University, Brookings, South Dakota
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, Colorado
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Cai Z, Li H. Circular RNAs and Bladder Cancer. Onco Targets Ther 2020; 13:9573-9586. [PMID: 33061440 PMCID: PMC7535116 DOI: 10.2147/ott.s268859] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 09/03/2020] [Indexed: 12/17/2022] Open
Abstract
Bladder cancer (BC) is the most common urinary system malignancy and is a serious threat to human health. Circular RNAs (circRNAs) are members of a newly defined class of noncoding RNAs (ncRNAs) that can regulate gene expression at the transcriptional or posttranscriptional level. Studies have shown that circRNAs are related to the clinicopathological characteristics, prognosis, and chemosensitivity of BC, and basic research has further confirmed that changes in the expression of circRNAs in BC are closely related to various tumor biological functions. CircRNAs promote tumor development by interacting with miRNAs to regulate transcription factors and both classical and nonclassical tumor signaling pathways. The nonclassical signaling pathways are related to cell cycle progression, epithelial–mesenchymal transition (EMT), extracellular matrix maintenance, and tumor stem cell maintenance. In this article, the relationships between circRNAs and the clinical characteristics of BC are reviewed, and the molecular mechanisms by which circRNAs promote tumor development are explored.
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Affiliation(s)
- Zhonglin Cai
- Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Hongjun Li
- Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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Li X, Lou X, Xu S, Du J, Wu J. Hypoxia inducible factor-1 (HIF-1α) reduced inflammation in spinal cord injury via miR-380-3p/ NLRP3 by Circ 0001723. Biol Res 2020; 53:35. [PMID: 32819442 PMCID: PMC7439692 DOI: 10.1186/s40659-020-00302-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 07/29/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Spinal cord injury (SCI) is a severe central nervous system trauma. The present study aimed to evaluate the effect of HIF-1α on inflammation in spinal cord injury (SCI) to uncover the molecular mechanisms of anti-inflammation. RESULTS HIF-1α was reduced in SCI model rats and HIF-1α activation reduced TNF-α, IL-1β, IL-6 and IL-18 levels in SCI model rats. Meanwhile, Circ 0001723 expression was down-regulated and miR-380-3p expression was up-regulated in SCI model rats. In vitro model, down-regulation of Circ 0001723 promoted TNF-α, IL-1β, IL-6 and IL-18 levels, compared with control negative group. However, over-expression of Circ 0001723 reduced TNF-α, IL-1β, IL-6 and IL-18 levels in vitro model. Down-regulation of Circ 0001723 suppressed HIF-1α protein expressions and induced NLRP3 and Caspase-1 protein expressions in vitro model by up-regulation of miR-380-3p. Next, inactivation of HIF-1α reduced the pro-inflammation effects of Circ 0001723 in vitro model. Then, si-NLRP3 also inhibited the pro-inflammation effects of Circ 0001723 in vitro model via promotion of autophagy. CONCLUSIONS We concluded that HIF-1α reduced inflammation in spinal cord injury via miR-380-3p/ NLRP3 by Circ 0001723.
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Affiliation(s)
- Xigong Li
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhejiang University, No.79 Qingchun Road, Hangzhou, 310003, China
| | - Xianfeng Lou
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhejiang University, No.79 Qingchun Road, Hangzhou, 310003, China
| | - Sanzhong Xu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhejiang University, No.79 Qingchun Road, Hangzhou, 310003, China.
| | - Junhua Du
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhejiang University, No.79 Qingchun Road, Hangzhou, 310003, China
| | - Junsong Wu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhejiang University, No.79 Qingchun Road, Hangzhou, 310003, China
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Wu HB, Huang SS, Lu CG, Tian SD, Chen M. CircAPLP2 regulates the proliferation and metastasis of colorectal cancer by targeting miR-101-3p to activate the Notch signalling pathway. Am J Transl Res 2020; 12:2554-2569. [PMID: 32655790 PMCID: PMC7344090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 04/30/2020] [Indexed: 06/11/2023]
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, and it has a poor prognosis. Emerging evidence shows that circular RNAs (circRNAs) may act as good therapeutic targets for cancers due to their abundance and stability. However, their regulatory role in CRC needs further investigation. This study revealed that circAPLP2 was upregulated and miR-101-3p was downregulated in CRC tissues and cells compared to normal controls. Knockdown of circAPLP2 and overexpression of miR-101-3p inhibited the cell proliferation, migration and invasion and induced the apoptosis of CRC cells. circAPLP2 acted as a miR-101-3p sponge to upregulate its target gene Notch1, which activated cascades of proliferation- and metastasis-related proteins (c-Myc, cyclin D1, MMP-2 and MMP-9). Additionally, knockdown of circAPLP2 suppressed tumour growth and liver metastases of CRC in nude mice. Taken together, these results indicate that circAPLP2 promotes proliferation and metastasis by targeting miR-101-3p to activate the Notch signalling pathway in CRC, which provides new insights into the mechanisms underlying CRC malignancy and suggests a new therapeutic target.
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Affiliation(s)
- Han-Bing Wu
- Department of Oncology, The First People’s Hospital of Huaihua CityHuaihua 418000, Hunan, P. R. China
| | - Shi-Si Huang
- Department of Oncology, Central South University Xiangya School of Medicine Affiliated Haikou HospitalHaikou 570208, P. R. China
| | - Chang-Geng Lu
- Department of Oncology, The First People’s Hospital of Huaihua CityHuaihua 418000, Hunan, P. R. China
| | - Shao-Dong Tian
- Department of Oncology, The First People’s Hospital of Huaihua CityHuaihua 418000, Hunan, P. R. China
| | - Ming Chen
- Department of Gastroenterology, The First People’s Hospital of Huaihua CityHuaihua 418000, Hunan, P. R. China
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Hsa_circ_0068307 mediates bladder cancer stem cell-like properties via miR-147/c-Myc axis regulation. Cancer Cell Int 2020; 20:151. [PMID: 32398967 PMCID: PMC7204228 DOI: 10.1186/s12935-020-01235-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 04/28/2020] [Indexed: 12/24/2022] Open
Abstract
Background Circular RNAs (circRNAs) play an essential role in the regulation of gene expression. However, the underlying mechanisms remain unknown. This study aimed to evaluate the role of hsa_circ_0068307 in bladder cancer (BCa). Methods Rt-qPCR was used to detect hsa_circ_0068307 expression in BCa cell lines. The CCK8, colony formation, and Transwell assays were used to evaluate the effect of hsa_circ_0068307 on BCa cell migration and proliferation. Bioinformatics and luciferase reporter experiments were used to study the regulatory mechanism. Nude mouse xenografts were generated to examine the effect of hsa_circ_0068307 on tumor growth. Results The results showed that hsa_circ_0068307 was upregulated in BCa cell lines. Downregulation of hsa_circ_0068307 suppressed cell migration and proliferation in T24 and UMUC3 cells. Hsa_circ_0068307 silencing suppressed cancer stem cell differentiation by upregulating miR-147 expression. Upregulation of miR-147 suppressed c-Myc expression, which is involved in cancer stem cell differentiation. Luciferase reporter assays confirmed that hsa_circ_0068307 upregulated c-Myc expression by targeting miR-147. In vivo studies showed that hsa_circ_0068307 knockdown suppressed T24 tumor growth. Conclusions These data indicate that downregulation of hsa_circ_0068307 reversed the stem cell-like properties of human bladder cancer through the regulation of the miR-147/c-Myc axis.
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