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Hashemi M, Khosroshahi EM, Daneii P, Hassanpoor A, Eslami M, Koohpar ZK, Asadi S, Zabihi A, Jamali B, Ghorbani A, Nabavi N, Memarkashani MR, Salimimoghadam S, Taheriazam A, Tan SC, Entezari M, Farahani N, Hushmandi K. Emerging roles of CircRNA-miRNA networks in cancer development and therapeutic response. Noncoding RNA Res 2025; 10:98-115. [PMID: 39351450 PMCID: PMC11440256 DOI: 10.1016/j.ncrna.2024.09.006] [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: 02/23/2024] [Revised: 07/18/2024] [Accepted: 09/03/2024] [Indexed: 10/04/2024] Open
Abstract
The complex interplay of epigenetic factors is essential in regulating the hallmarks of cancer and orchestrating intricate molecular interactions during tumor progression. Circular RNAs (circRNAs), known for their covalently closed loop structures, are non-coding RNA molecules exceptionally resistant to enzymatic degradation, which enhances their stability and regulatory functions in cancer. Similarly, microRNAs (miRNAs) are endogenous non-coding RNAs with linear structures that regulate cellular biological processes akin to circRNAs. Both miRNAs and circRNAs exhibit aberrant expressions in various cancers. Notably, circRNAs can function as sponges for miRNAs, influencing their activity. The circRNA/miRNA interaction plays a pivotal role in the regulation of cancer progression, including in brain, gastrointestinal, gynecological, and urological cancers, influencing key processes such as proliferation, apoptosis, invasion, autophagy, epithelial-mesenchymal transition (EMT), and more. Additionally, this interaction impacts the response of tumor cells to radiotherapy and chemotherapy and contributes to immune evasion, a significant challenge in cancer therapy. Both circRNAs and miRNAs hold potential as biomarkers for cancer prognosis and diagnosis. In this review, we delve into the circRNA-miRNA circuit within human cancers, emphasizing their role in regulating cancer hallmarks and treatment responses. This discussion aims to provide insights for future research to better understand their functions and potentially guide targeted treatments for cancer patients using circRNA/miRNA-based strategies.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Pouria Daneii
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Aria Hassanpoor
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maedeh Eslami
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zeinab Khazaei Koohpar
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Abbas Zabihi
- Department of Biology, Faculty of Basic Sciences, Islamic Azad University, Hamedan Branch, Hamedan, Iran
| | - Behdokht Jamali
- Department of Microbiology and Genetics, Kherad Institute of Higher Education, Bushehr, Iran
| | - Amin Ghorbani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia, V8V 1P7, Canada
| | | | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
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Chen M, Yang Y, Hu G, Peng Z, Wen W. The promoting effect of the POU3F2/METTL16/PFKM cascade on glycolysis and tumorigenesis of hepatocellular carcinoma. Ann Hepatol 2025; 30:101776. [PMID: 39756795 DOI: 10.1016/j.aohep.2025.101776] [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: 10/22/2024] [Revised: 12/02/2024] [Accepted: 12/17/2024] [Indexed: 01/07/2025]
Abstract
INTRODUCTION AND OBJECTIVES Deregulation of m6A methylation, the most prevailing RNA modification, participates in cancer pathogenesis. METTL16, an atypical methyltransferase, functions as a pro-tumorigenic factor in hepatocellular carcinoma (HCC). Here, we explored the action of METTL16 on HCC glycolysis and the associated mechanism. MATERIALS AND METHODS Expression analysis was done by quantitative PCR, immunoblotting, or immunohistochemistry. Cell sphere formation, invasiveness, apoptosis, proliferation and viability were detected by sphere formation, transwell, flow cytometry, EdU and CCK-8 assays, respectively. Xenograft studies were performed to analyze the role in vivo. Methylated RNA immunoprecipitation (MeRIP) and RIP assays were used to verify the METTL16/PFKM relationship. PFKM mRNA stability was tested by actinomycin D treatment. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to analyze the POU3F2/METTL16 relationship. RESULTS In HCC, METTL16 expression was elevated, and increased levels of METTL16 transcript predicted poor HCC prognosis. METTL16 deficiency resulted in suppressed HCC cell growth, invasiveness and sphere formation. Moreover, METTL16 depletion diminished HCC cell glycolysis. Mechanistically, PFKM expression was positively associated with METTL16 expression. METTL16 mediated m6A methylation to stabilize PFKM mRNA via an IGF2BP3-dependent manner. Restored PFKM expression exerted a counteracting effect on METTL16 deficiency-mediated in vitro cell phenotype alterations and in vivo xenograft growth suppression. Furthermore, POU3F2 promoted the transcription of METTL16 in HCC cells. CONCLUSIONS Our findings define the crucial role of the POU3F2/METTL16/PFKM axis in HCC pathogenesis, offering the potential opportunity to combat HCC.
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Affiliation(s)
- Ming Chen
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang City, 421001, Hunan, China
| | - Yuan Yang
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang City, 421001, Hunan, China
| | - Guangsheng Hu
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang City, 421001, Hunan, China
| | - Zhong Peng
- Department of Gastroenterology and Hepatology, Yiyang Central Hospital, Yiyang City, 413099, Hunan, China
| | - Wu Wen
- Department of Hepato-Biliary-Pancreatic Surgery, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang City, 421001, Hunan, China.
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Jing F, Shi Y, Jiang D, Li X, Sun J, Guo Q. Circ_0001944 Targets the miR-1292-5p/FBLN2 Axis to Facilitate Sorafenib Resistance in Hepatocellular Carcinoma by Impeding Ferroptosis. Immunotargets Ther 2024; 13:643-659. [PMID: 39624827 PMCID: PMC11611519 DOI: 10.2147/itt.s463556] [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: 02/08/2024] [Accepted: 07/30/2024] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND Sorafenib, an orally active potent tyrosine kinase inhibitor (TKI), represented a primary treatment in patients with advanced hepatocellular carcinoma (HCC). Unfortunately, sorafenib resistance was regarded as a huge obstacle for HCC treatment. METHODS RNA-sequencing including circRNA Sequencing (circRNA-Seq) for circular RNAs (circRNAs), miRNA Sequencing (miRNA-Seq) for microRNAs (miRNAs), as well as mRNA Sequencing (mRNA-Seq) for mRNAs in sorafenib-resistant HCC cells vs sorafenib-sensitive HCC cells, were performed. Then, interaction correlation analysis between differentially expressed circRNAs and miRNAs and their target genes in Huh7/SOR and SMMC7721/SOR cells was exhibited. The "circRNA-miRNA-mRNA" network was constructed through the Cytoscape software application, Circular RNA Interactome and Targetscan prediction, RNA binding protein immunoprecipitation (RIP), RNA pull-down, and Dual luciferase reporter assay. Furthermore, mRNA-Seq, Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for the downstream genes involved in the "circRNA-miRNA-mRNA" network was implemented. Iron detection assay, Lipid peroxidation quantification assay, ROS measurement assay, CCK-8 assay, and tumor challenge in vivo were used to determine the mechanisms promoting sorafenib resistance in HCC, where the "circRNA-miRNA-mRNA" network is clearly involved in. RESULTS circ_0001944 and circ_0078607 with upregulation and 2 downregulated expressed circRNAs (circ_0002874 and circ_0069981), as well as 11 upregulated miRNAs including miR-193a-5p, miR-197-3p, miR-27a-5p, miR-551b-5p, miR-335-3p, miR-767-3p, miR-767-5p, miR-92a-1-5p, miR-92a-3p, miR-3940-3p, and miR-664b-3p and 3 downregulated expressed miRNAs (miR-1292-5p, let-7c-5p, and miR-99a-5p) in sorafenib-resistant HCC cells were determined. Among these non-coding RNAs (ncRNAs), circ_0001944 and miR-1292-5p should not be drop out of sight; circ_0001944 has been proved to target miR-1292-5p to inhibit its expression in HCC. Subsequent findings also raise that miR-1292-5p directly targeted the 3'-noncoding region (3'-UTR) of Fibulin 2 (FBLN2) mRNA. Furthermore, circ_0001944 targets the miR-1292-5p/FBLN2 axis to inhibit cell ferroptosis in which the indicated regulators associated with iron overload and lipid peroxidation were "rearranged". Most importantly, circ_0001944 advanced sorafenib resistance in HCC through mitigating ferroptosis, where the miR-1292-5p/FBLN2 axis cannot be left unrecognized. CONCLUSION Circ_0001944 is a putative target for reversing sorafenib resistance in HCC. Our findings are expected to provide new targets and new directions for sorafenib sensitization in the treatment of HCC.
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Affiliation(s)
- FanJing Jing
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, People’s Republic of China
| | - YunYan Shi
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, People’s Republic of China
| | - Dong Jiang
- Navy Qingdao Special Service Rehabilitation Center, Qingdao, Shandong, 266003, People’s Republic of China
| | - Xiao Li
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, People’s Republic of China
| | - JiaLin Sun
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, People’s Republic of China
| | - Qie Guo
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, People’s Republic of China
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Sanadgol N, Amini J, Khalseh R, Bakhshi M, Nikbin A, Beyer C, Zendehdel A. Mitochondrial genome-derived circRNAs: Orphan epigenetic regulators in molecular biology. Mitochondrion 2024; 79:101968. [PMID: 39321951 DOI: 10.1016/j.mito.2024.101968] [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: 05/17/2024] [Revised: 09/02/2024] [Accepted: 09/18/2024] [Indexed: 09/27/2024]
Abstract
Mitochondria are vital for cellular activities, influencing ATP production, Ca2+ signaling, and reactive oxygen species generation. It has been proposed that nuclear genome-derived circular RNAs (circRNAs) play a role in biological processes. For the first time, this study aims to comprehensively explore experimentally confirmed human mitochondrial genome-derived circRNAs (mt-circRNAs) via in-silico analysis. We utilized wide-ranging bioinformatics tools to anticipate their roles in molecular biology, involving miRNA sponging, protein antagonism, and peptide translation. Among five well-characterized mt-circRNAs, SCAR/mc-COX2 stands out as particularly significant with the potential to sponge around 41 different miRNAs, which target several genes mostly involved in endocytosis, MAP kinase, and PI3K-Akt pathways. Interestingly, circMNTND5 and mecciND1 specifically interact with miRNAs through their unique back-splice junction sequence. These exclusively targeted miRNAs (has-miR-5186, 6888-5p, 8081, 924, 672-5p) are predominantly associated with insulin secretion, proteoglycans in cancer, and MAPK signaling pathways. Moreover, all mt-circRNAs intricately affect the P53 pathway through miRNA sequestration. Remarkably, mc-COX2 and circMNTND5 appear to be involved in the RNA's biogenesis by antagonizing AGO1/2, EIF4A3, and DGCR8. All mt-circRNAs engaged with IGF2BP proteins crucial in redox signaling, and except mecciND1, they all potentially generate at least one protein resembling the immunoglobulin heavy chain protein. Given P53's function as a redox-sensitive transcription factor, and insulin's role as a crucial regulator of energy metabolism, their indirect interplay with mt-circRNAs could influence cellular outcomes. However, due to limited attention and infrequent data availability, it is advisable to conduct more thorough investigations to gain a deeper understanding of the functions of mt-circRNA.
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Affiliation(s)
- Nima Sanadgol
- Institute of Neuroanatomy, RWTH University Hospital Aachen, 52074 Aachen, Germany.
| | - Javad Amini
- Department of Physiology and Pharmacology, School of Medicine, North Khorasan University of Medical Sciences, 94149-75516 Bojnurd, Iran
| | - Roghayeh Khalseh
- Institute of Neuroanatomy, RWTH University Hospital Aachen, 52074 Aachen, Germany
| | - Mostafa Bakhshi
- Department of Electrical and Computer Engineering, Kharazmi University, 15719-14911 Tehran, Iran
| | - Arezoo Nikbin
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Golestan University of Medical Sciences, Gorgan, Iran
| | - Cordian Beyer
- Institute of Neuroanatomy, RWTH University Hospital Aachen, 52074 Aachen, Germany
| | - Adib Zendehdel
- Institut of Anatomy, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
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Xie C, Hao X, Yuan H, Wang C, Sharif R, Yu H. Crosstalk Between circRNA and Tumor Microenvironment of Hepatocellular Carcinoma: Mechanism, Function and Applications. Onco Targets Ther 2024; 17:7-26. [PMID: 38283733 PMCID: PMC10812140 DOI: 10.2147/ott.s437536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/30/2023] [Indexed: 01/30/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common aggressive tumors in the world. Despite the availability of various treatments, its prognosis remains poor due to the lack of specific diagnostic indicators and the high heterogeneity of HCC cases. CircRNAs are noncoding RNAs with stable and highly specific expression. Extensive research evidence suggests that circRNAs mediate the pathogenesis and progression of HCC through acting as miRNA sponges, protein modulators, and translation templates. Tumor microenvironment (TME) has become a hotspot of immune-related research in recent years due to its effects on metabolism, secretion and immunity of HCC. Accordingly, understanding the role played by circRNAs in TME is important for the study of HCC. This review will discuss the crosstalk between circRNAs and TME in HCC. In addition, we will discuss the current deficiencies and controversies in research on circRNAs and predict future research directions.
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Affiliation(s)
- Chenxi Xie
- Hepatobiliary Center, Department of Hepatobiliary Surgery, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Xiaopei Hao
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, People’s Republic of China
| | - Hao Yuan
- Hepatobiliary Center, Department of Hepatobiliary Surgery, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Chongyu Wang
- The First Clinical Medical College of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Razinah Sharif
- Center for Healthy Ageing & Wellness, Faculty of Health Sciences, University Kebangsaan Malaysia, Kuala Lumpur, 50300, Malaysia
- Biocompatibility Laboratory, Centre for Research and Instrumentation, University Kebangsaan Malaysia, UKM, Bangi, Selangor Darul Ehsan, 43600, Malaysia
| | - Haibo Yu
- Hepatobiliary Center, Department of Hepatobiliary Surgery, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
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Rao G, Peng X, Tian Y, Fu X, Zhang Y. Circular RNAs in hepatocellular carcinoma: biogenesis, function, and pathology. Front Genet 2023; 14:1106665. [PMID: 37485335 PMCID: PMC10361733 DOI: 10.3389/fgene.2023.1106665] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 06/16/2023] [Indexed: 07/25/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Both genetic and environmental factors through a multitude of underlying molecular mechanisms participate in the pathogenesis of HCC. Recently, numerous studies have shown that circular RNAs (circRNAs), an emerging class of non-coding RNAs characterized by the presence of covalent bonds linking 3' and 5' ends, play an important role in the initiation and progression of cancers, including HCC. In this review, we outline the current status of the field of circRNAs, with an emphasis on the functions and mechanisms of circRNAs in HCC and its microenvironment. We also summarize and discuss recent advances of circRNAs as biomarkers and therapeutic targets. These efforts are anticipated to throw new insights into future perspectives about circRNAs in basic, translational and clinical research, eventually advancing the diagnosis, prevention and treatment of HCC.
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Affiliation(s)
- Guocheng Rao
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Xi Peng
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Yan Tian
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xianghui Fu
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Yuwei Zhang
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
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Samavarchi Tehrani S, Esmaeili F, Shirzad M, Goodarzi G, Yousefi T, Maniati M, Taheri-Anganeh M, Anushiravani A. The critical role of circular RNAs in drug resistance in gastrointestinal cancers. Med Oncol 2023; 40:116. [PMID: 36917431 DOI: 10.1007/s12032-023-01980-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 02/20/2023] [Indexed: 03/16/2023]
Abstract
Nowadays, drug resistance (DR) in gastrointestinal (GI) cancers, as the main reason for cancer-related mortality worldwide, has become a serious problem in the management of patients. Several mechanisms have been proposed for resistance to anticancer drugs, including altered transport and metabolism of drugs, mutation of drug targets, altered DNA repair system, inhibited apoptosis and autophagy, cancer stem cells, tumor heterogeneity, and epithelial-mesenchymal transition. Compelling evidence has revealed that genetic and epigenetic factors are strongly linked to DR. Non-coding RNA (ncRNA) interferences are the most crucial epigenetic alterations explored so far, and among these ncRNAs, circular RNAs (circRNAs) are the most emerging members known to have unique properties. Due to the absence of 5' and 3' ends in these novel RNAs, the two ends are covalently bonded together and are generated from pre-mRNA in a process known as back-splicing, which makes them more stable than other RNAs. As far as the unique structure and function of circRNAs is concerned, they are implicated in proliferation, migration, invasion, angiogenesis, metastasis, and DR. A clear understanding of the molecular mechanisms responsible for circRNAs-mediated DR in the GI cancers will open a new window to the management of GI cancers. Hence, in the present review, we will describe briefly the biogenesis, multiple features, and different biological functions of circRNAs. Then, we will summarize current mechanisms of DR, and finally, discuss molecular mechanisms through which circRNAs regulate DR development in esophageal cancer, pancreatic cancer, gastric cancer, colorectal cancer, and hepatocellular carcinoma.
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Affiliation(s)
- Sadra Samavarchi Tehrani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fataneh Esmaeili
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Shirzad
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Golnaz Goodarzi
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tooba Yousefi
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmood Maniati
- Department of English, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Amir Anushiravani
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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8
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Liu Z, Yang F, Xiao Z, Liu Y. Review of novel functions and implications of circular RNAs in hepatocellular carcinoma. Front Oncol 2023; 13:1093063. [PMID: 36890830 PMCID: PMC9986438 DOI: 10.3389/fonc.2023.1093063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/27/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent malignancies, with high incidence and mortality. As the majority of HCC patients are diagnosed at an advanced stage and die of recurrence and metastasis, its pathology and new biomarkers are needed. Circular RNAs (circRNAs) are a large subclass of long non-coding RNAs (lncRNAs) with covalently closed loop structures and abundant, conserved, stable, tissue-specific expression in mammalian cells. CircRNAs exert multiple functions in HCC initiation, growth and progression, serving as promising biomarkers for diagnosis, prognosis and therapeutic targets for this disease. This review briefly describes the biogenesis and biological functions of circRNAs and elucidates the roles of circRNAs in the development and progression of HCC, especially regarding epithelial-mesenchymal transition (EMT), drug resistance and interactions with epigenetic modifications. In addition, this review highlights the implications of circRNAs as potential biomarkers and therapeutic targets for HCC. We hope to provide novel insight into the roles of circRNAs in HCC.
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Affiliation(s)
- Zheng Liu
- Department of Combination of Traditional Chinese Medicine and Western Medicine, School of Medicine, Henan University of Chinese Medicine, Zhengzhou, China
| | - Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Yuexuan Liu
- Department of Combination of Traditional Chinese Medicine and Western Medicine, School of Medicine, Henan University of Chinese Medicine, Zhengzhou, China
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9
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Mesenchymal stem cell-derived exosomes and non-coding RNAs: Regulatory and therapeutic role in liver diseases. Biomed Pharmacother 2023; 157:114040. [PMID: 36423545 DOI: 10.1016/j.biopha.2022.114040] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/16/2022] [Accepted: 11/19/2022] [Indexed: 11/22/2022] Open
Abstract
Liver disease has become a major health problem worldwide due to its high morbidity and mortality. In recent years, a large body of literature has shown that mesenchymal stem cell-derived exosomes (MSC-Exo) are able to play similar physiological roles as mesenchymal stem cells (MSCs). More importantly, there is no immune rejection caused by transplanted cells and the risk of tumor formation, which has become a new strategy for the treatment of various liver diseases. Moreover, accumulating evidence suggests that non-coding RNAs (ncRNAs) are the main effectors by which they exert hepatoprotective effects. Therefore, by searching the databases of Web of Science, PubMed, ScienceDirect, Google Scholar and CNKI, this review comprehensively reviewed the therapeutic effects of MSC-Exo and ncRNAs in liver diseases, including liver injury, liver fibrosis, and hepatocellular carcinoma. According to the data, the therapeutic effects of MSC-Exo and ncRNAs on liver diseases are closely related to a variety of molecular mechanisms, including inhibition of inflammatory response, alleviation of liver oxidative stress, inhibition of apoptosis of hepatocytes and endothelial cells, promotion of angiogenesis, blocking the cell cycle of hepatocellular carcinoma, and inhibition of activation and proliferation of hepatic stellate cells. These important findings will provide a direction and basis for us to explore the potential of MSC-Exo and ncRNAs in the clinical treatment of liver diseases in the future.
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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 S, Qian L, Cao T, Xu L, Jin Y, Hu H, Fu Q, Li Q, Wang Y, Wang J, Xia Y, Huang X. Advances in the Study of CircRNAs in Tumor Drug Resistance. Front Oncol 2022; 12:868363. [PMID: 35615158 PMCID: PMC9125088 DOI: 10.3389/fonc.2022.868363] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/22/2022] [Indexed: 11/13/2022] Open
Abstract
Recent studies have revealed that circRNAs can affect tumor DNA damage and repair, apoptosis, proliferation, and invasion and influence the transport of intratumor substances by acting as miRNA sponges and transcriptional regulators and binding to proteins in a variety of ways. However, research on the role of circRNAs in cancer radiotherapy and chemoresistance is still in its early stages. Chemotherapy is a common approach to oncology treatment, but the development of tumor resistance limits the overall clinical efficacy of chemotherapy for cancer patients. The current study suggests that circRNAs have a facilitative or inhibitory effect on the development of resistance to conventional chemotherapy in a variety of tumors, suggesting that circRNAs may serve as a new direction for the study of antitumor drug resistance. In this review, we will briefly discuss the biological features of circRNAs and summarize the recent progression of the involvement of circRNAs in the development and pathogenesis of cancer chemoresistance.
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Affiliation(s)
- Song Wang
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Long Qian
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China
| | - Tingting Cao
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Li Xu
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China
| | - Yan Jin
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China
| | - Hao Hu
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China
| | - Qingsheng Fu
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China
| | - Qian Li
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China
| | - Ye Wang
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China
| | - Jiawei Wang
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China
| | - Yabin Xia
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China
| | - Xiaoxu Huang
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China
- *Correspondence: Xiaoxu Huang,
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12
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Xu Q, Shi J, Zhang L, Sheng Y, Zhang Y, Chu D, Xu A. Circ_0006006 facilitates non-small cell lung cancer progression by modulating miR-924/SRSF7 axis. J Gene Med 2022; 24:e3411. [PMID: 35037349 DOI: 10.1002/jgm.3411] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 11/26/2021] [Accepted: 01/04/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is an aggressive tumor with high mortality. Circular RNAs (CircRNAs) played crucial roles in the development of cancers, including NSCLC. In this study, the action of circ_0006006 in NSCLC was investigated. METHODS Using real-time quantitative PCR (RT-qPCR), the relative gene expression was detected. The structure of circ_0006006 was identified using RNase R digestion and Actinomycin D treatment. The functional role of circ_0006006 in cell proliferation, migration, invasion, apoptosis and angiogenesis was explored using Cell Counting Kit-8 (CCK-8), EdU, colony formation, wound healing, transwell, flow cytometry, and tube formation assays, respectively. Using western blot, the relative proteins expression was measured. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were employed to verify the correlation between microRNA-924 (miR-924) and circ_0006006 or serine/arginine-rich splicing factor 7 (SRSF7). Xenograft tumor experiment was used to investigate the effect of circ_0006006 on tumor growth in vivo. Immunohistochemistry (IHC) assay was performed to detect Ki-67, Bax, Bcl-2 and SRSF7 expression in tissues of mice. RESULTS Circ_0006006 was increased in NSCLC tissues and cells. Loss-of-function assays demonstrated that circ_0006006 silencing repressed the proliferative ability, cell migration and invasion, angiogenesis, and promoted cell apoptosis in A549 and H1299 cells. Follow-up mechanism experiments depicted that circ_0006006 sponged miR-924 and miR-924 inhibitor rescued circ_0006006 knockdown-mediated inhibition effect on the progression of NSCLC. Additionally, the inhibition effect of circ_0006006 knockdown on SRSF7 expression was reversed by miR-924 inhibitor. Moreover, the suppressive effect of miR-924 on NSCLC progression was reversed by SRSF7 overexpression. Xenograft tumor experiment unveiled that circ_0006006 knockdown inhibited tumor growth in vivo. CONCLUSION Circ_0006006 stimulated NSCLC progression by targeting miR-924 to regulate SRSF7 expression.
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Affiliation(s)
- Qinfu Xu
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiang Shi
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Long Zhang
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanbing Sheng
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yang Zhang
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dan Chu
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Aiguo Xu
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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13
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Lin JC, Zhu NX, Wu LF. Research progress of circRNAs in chemotherapy resistance of digestive system neoplasms. Shijie Huaren Xiaohua Zazhi 2021; 29:1237-1247. [DOI: 10.11569/wcjd.v29.i21.1237] [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] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) are a novel class of noncoding RNA molecules with a unique closed continuous loop structure. CircRNAs are abundant in eukaryotic cells, have unique stability and tissue specificity, and can play a biological regulatory role at various levels, such as transcriptional and posttranscriptional levels. Accumulating evidence indicates that circRNAs play critical roles in tumor genesis, development, and chemotherapy. Chemotherapy is a primary type of intervention for most cancers, but its therapeutic efficacy is usually retarded by intrinsic and acquired resistance. CircRNAs regulate tumor chemoresistance through various molecular mechanisms, such as affecting apoptosis, promoting drug transportation, promoting DNA repair, promoting epithelial-mesenchymal transformation, regulating the characteristics of tumor stem cells, and affecting autophagy. This review summarizes the recent progress and mechanisms of circRNAs in cancer cell resistance to chemotherapy.
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Affiliation(s)
- Jie-Chun Lin
- Department of Gastroenterology, the Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Nan-Xing Zhu
- Department of Gastroenterology, the Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ling-Fei Wu
- Department of Gastroenterology, the Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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14
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Xu XF, Yang XK, Song Y, Chen BJ, Yu X, Xu T, Chen ZL. Dysregulation of Non-coding RNAs mediates Cisplatin Resistance in Hepatocellular Carcinoma and therapeutic strategies. Pharmacol Res 2021; 176:105906. [PMID: 34543740 DOI: 10.1016/j.phrs.2021.105906] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/06/2021] [Accepted: 09/14/2021] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fourth major contributor to cancer-related deaths worldwide, and patients mostly have poor prognosis. Although several drugs have been approved for the treatment of HCC, cisplatin (CDDP) is still applied in treatment of HCC as a classical chemotherapeutic drug. Unfortunately, the emergence of CDDP resistance has caused HCC patients to exhibit poor drug response. How to mitigate or even reverse CDDP resistance is an urgent clinical issue to be solved. Because of critical roles in biological functional processes and disease developments, non-coding RNAs (ncRNAs) have been extensively studied in HCC in recent years. Importantly, ncRNAs have also been demonstrated to be involved in the development of HCC to CDDP resistance process. Therefore, this review highlighted the regulatory roles of ncRNAs in CDDP resistance of HCC, elucidated the multiple potential mechanisms by which HCC develops CDDP resistance, and attempted to propose multiple drug delivery systems to alleviate CDDP resistance. Recently, ncRNA-based therapy may be a feasible strategy to alleviate CDDP resistance in HCC. Meanwhile, nanoparticles can overcome the deficiencies in ncRNA-based therapy and make it possible to reverse tumor drug resistance. The combined use of these strategies provides clues for reversing CDDP resistance and overcoming the poor prognosis of HCC.
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Affiliation(s)
- Xu-Feng Xu
- Department of Hemorrhoid and Fistula of Traditional Chinese Medicine, Chaohu Hospital Affiliated to Anhui Medical University, Chaohu, Anhui, 238000, P.R. China.
| | - Xiao-Ke Yang
- Department of Rheumatology and Immunology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230032, P.R. China.
| | - Yang Song
- Department of Pain Treatment, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230032, P.R. China.
| | - Bang-Jie Chen
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230032, P.R. China.
| | - Xiao Yu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, P. R. China.
| | - Tao Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, P. R. China; School of Pharmacy, Anhui Key Lab. of Bioactivity of Natural Products, Anhui Medical University, Hefei, Anhui, 230032, P. R. China.
| | - Zhao-Lin Chen
- Department of Pharmacy, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, Anhui, 230001, P.R. China.
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Mu Q, Lv Y, Luo C, Liu X, Huang C, Xiu Y, Tang L. Research Progress on the Functions and Mechanism of circRNA in Cisplatin Resistance in Tumors. Front Pharmacol 2021; 12:709324. [PMID: 34566636 PMCID: PMC8458655 DOI: 10.3389/fphar.2021.709324] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022] Open
Abstract
Cisplatin is a common chemotherapeutic drug that has been used to treat of numerous tumors, including testicular, lung, bladder, ovarian, liver and head and neck cancers. Although clinical chemotherapy based on cisplatin has shown a remarkable therapeutic effect, the resistance to cisplatin becomes increasingly obvious as a patient uses it for a prolonged period. It not only affects the prognosis of these tumors, but also causes the recurrence of cancer and decreases the overall survival rate. The development of cisplatin resistance involves several mechanisms, including DNA damage repair, ATP-binding cassette (ABC) transporter, autophagy, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), and other related signaling pathways. Interestingly, these mechanisms have been found to be influenced by circular RNAs (circRNAs) to regulate tumor proliferation, invasion, chemosensitivity, and other biological behaviors in the tumor microenvironment (TME). In recent years, circRNAs in cisplatin resistance in tumors, especially lung cancer and gastric cancer, have gradually drawn peoples' attention. This review summarizes recent studies on the functions and mechanisms of circRNAs in cisplatin resistance. We emphasize that circRNA can be used as a promising target gene to improve drug resistance and therapeutic efficacy.
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Affiliation(s)
- Qingchun Mu
- The People’s Hospital of Gaozhou, Gaozhou, China
| | - Yue Lv
- Department of Urology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Chunmei Luo
- The People’s Hospital of Gaozhou, Gaozhou, China
| | - Xiaojing Liu
- The People’s Hospital of Gaozhou, Gaozhou, China
| | | | - Youcheng Xiu
- Department of Urology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
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Liao R, Liu L, Zhou J, Wei X, Huang P. Current Molecular Biology and Therapeutic Strategy Status and Prospects for circRNAs in HBV-Associated Hepatocellular Carcinoma. Front Oncol 2021; 11:697747. [PMID: 34277444 PMCID: PMC8284075 DOI: 10.3389/fonc.2021.697747] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/11/2021] [Indexed: 12/15/2022] Open
Abstract
Circular RNAs (circRNAs) are newly classified noncoding RNA (ncRNA) members with a covalently closed continuous loop structure that are involved in immune responses against hepatitis B virus (HBV) infections and play important biological roles in the occurrence and pathogenesis of HCC progression. The roles of circRNAs in HBV-associated HCC (HBV-HCC) have gained increasing attention. Substantial evidence has revealed that both tissue and circulating circRNAs may serve as potential biomarkers for diagnostic, prognostic and therapeutic purposes. So far, at least four circRNA/miRNA regulatory axes such as circRNA_101764/miR-181, circRNA_100338/miR-141-3p, circ-ARL3/miR-1305, circ-ATP5H/miR-138-5p, and several circulating circRNAs were reported to be associated with HBV-HCC development. Notably, TGF/SMAD, JAK/STAT, Notch and Wnt/β-catenin signaling pathways may play pivotal roles in this HBV-driven HCC via several circRNAs. Moreover, in non-HBV HCC patients or HCC patients partially infected by HBV, numerous circRNAs have been identified to be important regulators impacting the malignant biological behavior of HCC. Furthermore, the role of circRNAs in HCC drug resistance has become a focus of research with the aim of reversing chemoresistance and immune resistance. Herein, we review the molecular biology of circRNAs in HBV-HCC and their potential in therapeutic strategies.
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Affiliation(s)
- Rui Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lei Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jian Zhou
- Department of Hepatobiliary Surgery, The People's Rongchang Hospital, Chongqing, China
| | - Xufu Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ping Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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