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Huang CJ, Choo KB. Frequent dysregulation of multiple circular RNA isoforms with diverse regulatory mechanisms in cancer - Insights from circFNDC3B and beyond: Why unique circular RNA identifiers matter. Biochem Biophys Res Commun 2025; 758:151627. [PMID: 40112536 DOI: 10.1016/j.bbrc.2025.151627] [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: 12/20/2024] [Revised: 03/09/2025] [Accepted: 03/12/2025] [Indexed: 03/22/2025]
Abstract
Circular RNAs (circRNAs) are post-transcriptional regulators generated through backsplicing of pre-mRNAs, primarily comprising exons of host genes. A single host gene may produce multiple circRNA isoforms with distinct structures and sequences. Dysregulated circRNA expression has been implicated in tumorigenesis. This review aims to investigate the selection and regulatory roles of circRNA isoforms in cancer using the extensively studied hsa_circFNDC3B and thirteen other circRNAs as study models. Interrogation of literature and databases, particularly the circBase, confirms that host genes generate a plethora of circRNA isoforms; however, only a small subset of isoforms is validated as dysregulated in tumor tissues. Notably, two or more isoforms of the same circRNA are frequently dysregulated in cancer. Structurally, short isoforms retaining 5'-proximal exons are preferentially selected, but for long host genes, circRNAs may arise from mid- or 3'-regions. We identify dysregulation of seven circFNDC3B isoforms across twelve cancer types and multi-isoforms in nine of the other thirteen circRNAs also in multiple cancers. MicroRNA sponging appears to be the major regulatory mechanism, but possible biased study designs raise concerns. Using circFNDC3B and circZFR as examples, we show inconsistency and inadequacy in circRNA nomenclature in different databases and the literature, underscoring the urgent need for a universally accepted standardized central circRNA database. As an interim measure, we propose guidelines for circRNA nomenclature in journal publications. Our findings caution against indiscriminate clinical use of specific circRNA isoforms as biomarkers or therapeutic targets without further validation.
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Affiliation(s)
- Chiu-Jung Huang
- Department of Animal Science & Graduate Institute of Biotechnology, College of Environmental Planning & Bioresources (former School of Agriculture), Chinese Culture University, Taipei, 111114, Taiwan.
| | - Kong Bung Choo
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.
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2
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Feng Y, Zhu Y, Zhu Y, Lu Y, He Y, Wu Y, Jiang L, Weng W. Circular RNA NXN (circNXN) promotes diabetic retinopathy by regulating the miR-338-3p/FGFR1 axis. Arch Physiol Biochem 2025; 131:177-187. [PMID: 39988878 DOI: 10.1080/13813455.2024.2404102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/17/2024] [Accepted: 09/09/2024] [Indexed: 02/25/2025]
Abstract
Diabetic retinopathy (DR) is the leading manifestation of diabetic microangiopathy. However, effective biomarkers and therapies are lacking. Circular RNAs (circRNAs) have been implicated in various diseases including DR. However, the role of circRNAs in DR remains elusive. In the present study, circNXN was upregulated in high glucose (HG)-treated human retinal microvascular endothelial cells (hRMECs). circNXN knockdown inhibited the proliferation, migration, and angiogenesis of hRMECs and promoted apoptosis. In addition, circNXN acted as a sponge for miR-338-3p to facilitate the FGFR1 (fibroblast growth factor receptor 1) expression. Furthermore, rescue assays revealed that the reduced promoting effect on hRMECs induced by the knockdown of circNXN could be reversed by a miR-338-3p inhibitor in HG-treated hRMECs. Additionally, in a DR rat model, circNXN downregulation ameliorated retinal vasculature changes. Our findings reveal a new therapeutic strategy for DR that may provide a new approach to clinical DR therapy.
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Affiliation(s)
- Yanbing Feng
- Department of ophthalmology, Jiaxing Hospital of Traditional Chinese Medicine, No.1501 Zhongshan East Road, Jiaxing, Zhejiang, China
| | - Yongwei Zhu
- Department of ophthalmology, Jiaxing Hospital of Traditional Chinese Medicine, No.1501 Zhongshan East Road, Jiaxing, Zhejiang, China
| | - Yixing Zhu
- Department of ophthalmology, Jiaxing Hospital of Traditional Chinese Medicine, No.1501 Zhongshan East Road, Jiaxing, Zhejiang, China
| | - Yanting Lu
- Department of ophthalmology, Jiaxing Hospital of Traditional Chinese Medicine, No.1501 Zhongshan East Road, Jiaxing, Zhejiang, China
| | - Yanyan He
- Department of ophthalmology, Jiaxing Hospital of Traditional Chinese Medicine, No.1501 Zhongshan East Road, Jiaxing, Zhejiang, China
| | - Yibo Wu
- Department of ophthalmology, Jiaxing Hospital of Traditional Chinese Medicine, No.1501 Zhongshan East Road, Jiaxing, Zhejiang, China
| | - Lijun Jiang
- Department of ophthalmology, Jiaxing Hospital of Traditional Chinese Medicine, No.1501 Zhongshan East Road, Jiaxing, Zhejiang, China
| | - Wenqing Weng
- Department of ophthalmology, Jiaxing Hospital of Traditional Chinese Medicine, No.1501 Zhongshan East Road, Jiaxing, Zhejiang, China
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3
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Zhu Y, He Q, Qi M. Exosomal circPTPRK promotes angiogenesis after radiofrequency ablation in hepatocellular carcinoma. Exp Biol Med (Maywood) 2024; 249:10084. [PMID: 39469202 PMCID: PMC11514274 DOI: 10.3389/ebm.2024.10084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 09/02/2024] [Indexed: 10/30/2024] Open
Abstract
Radiofrequency ablation (RFA) is an effective treatment for hepatocellular carcinoma (HCC), but the recurrence rate remains high due to angiogenesis in residual cancer cells. We used thermal stimulation to simulate the post-RFA microenvironment. The expression profile of circRNAs between normal control HCC cell-derived exosomes and exosomes after heat stimulation were analyzed by RNA sequencing. Quantitative real-time PCR was applied to evaluate the expression of circPTPRK in exosomes and human umbilical vein endothelial cells (HUVECs). Then, the functions of heat-stimulated HCC cell-derived exosomes and exosomal circPTPRK on HUVECs were unveiled. Transcriptome sequencing was utilized to determine targeted genes of circPTPRK. Heat-stimulated HCC cell-derived exosomes augmented cell proliferation, migration, and angiogenesis of HUVECs. In total, 229 differentially expressed circRNAs were obtained, including 211 upregulated circRNAs and 18 downregulated circRNAs in heat-stimulated HCC cell-derived exosomes. The expression of circPTPRK was remarkably increased in heat-stimulated HCC cell-derived exosomes and the HUVECs incubated with them. Heat-stimulated HCC cell-derived exosomes with circPTPRK knockdown significantly inhibited cell proliferation, migration, and angiogenesis of HUVECs. Mechanistic studies indicated that PLA2G4E is a downstream target of circPTPRK, and PLA2G4E overexpression reversed the inhibitory effect of circPTPRK knockdown on HUVEC angiogenesis. Our results indicated that exosomal circPTPRK activated HUVEC angiogenesis by upregulating PLA2G4E expression.
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/surgery
- Exosomes/metabolism
- Exosomes/genetics
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/metabolism
- Liver Neoplasms/surgery
- RNA, Circular/genetics
- RNA, Circular/metabolism
- Human Umbilical Vein Endothelial Cells
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Radiofrequency Ablation/methods
- Cell Proliferation/genetics
- Cell Movement/genetics
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic
- Angiogenesis
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Affiliation(s)
- Yufeng Zhu
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
- Liaoning Provincial Key Laboratory of Clinical Oncology Metabonomics, Jinzhou, Liaoning, China
| | - Qianru He
- Zhuhai People’s Hospital Affiliated With Jinan University, Zhuhai, Guangdong, China
| | - Ming Qi
- Department of Ultrasound, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
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4
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Kundu I, Varshney S, Karnati S, Naidu S. The multifaceted roles of circular RNAs in cancer hallmarks: From mechanisms to clinical implications. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102286. [PMID: 39188305 PMCID: PMC11345389 DOI: 10.1016/j.omtn.2024.102286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/28/2024]
Abstract
Circular RNAs (circRNAs) represent a distinct class of covalently closed RNA species lacking conventional 5' to 3' polarity. Derived predominantly from pre-mRNA transcripts of protein-coding genes, circRNAs arise through back-splicing events of exon-exon or exon-intron junctions. They exhibit tissue- and cell-specific expression patterns and play crucial roles in regulating fundamental cellular processes such as cell cycle dynamics, proliferation, apoptosis, and differentiation. CircRNAs modulate gene expression through a plethora of mechanisms at epigenetic, transcriptional, and post-transcriptional levels, and some can even undergo translation into functional proteins. Recently, aberrant expression of circRNAs has emerged as a significant molecular aberration within the intricate regulatory networks governing hallmarks of cancer. The tumor-specific expression patterns and remarkable stability of circRNAs have profound implications for cancer diagnosis, prognosis, and therapy. This review comprehensively explores the multifaceted roles of circRNAs across cancer hallmarks in various tumor types, underscoring their growing significance in cancer diagnosis and therapeutic interventions. It also details strategies for leveraging circRNA-based therapies and discusses the challenges in using circRNAs for cancer management, emphasizing the need for further research to overcome these obstacles.
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Affiliation(s)
- Indira Kundu
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab, India
| | - Shivani Varshney
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab, India
| | - Srikanth Karnati
- Institute of Anatomy and Cell Biology, University of Würzburg, 97070 Würzburg, Germany
- Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany
| | - Srivatsava Naidu
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab, India
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Wu X, Zhou S, Wang L, Ma J, Zhou Y, Ruan Y, Shao H, Zhou X, Li H. Circ_103809 Aggravates the Malignant Phenotype of Pancreatic Cancer Through Modulating miR-197-3p/TSPAN3 Axis. Mol Biotechnol 2024; 66:2455-2466. [PMID: 37740818 DOI: 10.1007/s12033-023-00874-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 08/28/2023] [Indexed: 09/25/2023]
Abstract
Pancreatic cancer (PC) is a malignant tumor with insidious clinical manifestations and dismal prognosis. Emerging reports have demonstrated that circRNAs exert pivotal biological function in PC. Here, we investigated the crucial biological role and underlying regulatory mechanisms of differentially expressed circ_103809 in PC. In this study, hsa_circ_103809 (hsa_circ_0072088) was identified as the research object via analyzing and screening the aberrantly expressed circRNAs in PC by GSE69362 dataset. The levels of circ_103809 in PC tissues and cells were assessed via qRT-PCR. Functional assays were conducted to monitor the impacts of circ_103809 on PC cells. Additionally, the downstream molecular targets and regulatory networks of circ_103809 were predicted by bioinformatics and validated using luciferase assays and rescue experiments. We found that circ_103809 was substantially upregulated in PC tissues and cells. Silencing circ_103809 restrained the growth viability, clonogenic rate, migration, and invasion capabilities of PC cells. Further mechanistic exploration disclosed that miR-197-3p was the downstream gene of circ_103809, while Tetraspanin-3 (TSPAN3) was a direct target of miR-197-3p. The suppressive effect of circ_103809 knockdown on malignant processes of PC cells was eliminated by miR-197-3p downregulation or TSPAN3 upregulation. Our study demonstrated that circ_103809 served as an innovative positive regulator in the growth and metastasis of PC cells. Furthermore, circ_103809 mediated the miR-197-3p/TSPAN3 axis to modulate the malignant progression of PC cells, which was prospected to be a probable biomarker and an efficient therapeutic target for PC.
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Affiliation(s)
- Xiang Wu
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Li Huili Hospital, No.1111 Jiangnan Road, Yinzhou District, Ningbo, 315000, Zhejiang, China
- Health Science Center, Ningbo University, Ningbo, 315000, Zhejiang, China
| | - Shuping Zhou
- Ningbo College of Health Sciences, Ningbo, 315000, Zhejiang, China
| | - Luoluo Wang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Li Huili Hospital, No.1111 Jiangnan Road, Yinzhou District, Ningbo, 315000, Zhejiang, China
| | - Jingyun Ma
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Li Huili Hospital, No.1111 Jiangnan Road, Yinzhou District, Ningbo, 315000, Zhejiang, China
| | - Yang Zhou
- Ningbo Institute of Innovation for Combined Medicine and Engineering, The Affiliated Li Huili Hospital, Ningbo University, Ningbo, 315100, Zhejiang, China
| | - Yi Ruan
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Li Huili Hospital, No.1111 Jiangnan Road, Yinzhou District, Ningbo, 315000, Zhejiang, China
| | - Hanjie Shao
- Health Science Center, Ningbo University, Ningbo, 315000, Zhejiang, China
| | - Xinhua Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Li Huili Hospital, No.1111 Jiangnan Road, Yinzhou District, Ningbo, 315000, Zhejiang, China.
| | - Hong Li
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Li Huili Hospital, No.1111 Jiangnan Road, Yinzhou District, Ningbo, 315000, Zhejiang, China.
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6
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Lu P, Wang Y. RDGAN: Prediction of circRNA-Disease Associations via Resistance Distance and Graph Attention Network. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2024; 21:1445-1457. [PMID: 38787672 DOI: 10.1109/tcbb.2024.3402248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2024]
Abstract
As a series of single-stranded RNAs, circRNAs have been implicated in numerous diseases and can serve as valuable biomarkers for disease therapy and prevention. However, traditional biological experiments demand significant time and effort. Therefore, various computational methods have been proposed to address this limitation, but how to extract features more comprehensively remains a challenge that needs further attention in the future. In this study, we propose a unique approach to predict circRNA-disease associations based on resistance distance and graph attention network (RDGAN). First, the associations of circRNA and disease are obtained by fusing multiple databases, and resistance distance as a similarity matrix is used to further deal with the sparse of the similarity matrices. Then the circRNA-disease heterogeneous network is constructed based on the similiarity of circRNA-circRNA, disease-disease and the known circRNA-disease adjacency matric. Second, leveraging the three neural network modules-ResGatedGraphConv, GAT and MFConv-we gather node feature embeddings collected from the heterogeneous network. Subsequently, all the characteristics are supplied to the self-attention mechanism to predict new potential connections. Finally, our model obtains a remarkable AUC value of 0.9630 through five-fold cross-validation, surpassing the predictive performance of the other eight state-of-the-art models.
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Ashrafizadeh M, Dai J, Torabian P, Nabavi N, Aref AR, Aljabali AAA, Tambuwala M, Zhu M. Circular RNAs in EMT-driven metastasis regulation: modulation of cancer cell plasticity, tumorigenesis and therapy resistance. Cell Mol Life Sci 2024; 81:214. [PMID: 38733529 PMCID: PMC11088560 DOI: 10.1007/s00018-024-05236-w] [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: 12/05/2023] [Revised: 03/05/2024] [Accepted: 04/03/2024] [Indexed: 05/13/2024]
Abstract
The non-coding RNAs comprise a large part of human genome lack of capacity in encoding functional proteins. Among various members of non-coding RNAs, the circular RNAs (circRNAs) have been of importance in the pathogenesis of human diseases, especially cancer. The circRNAs have a unique closed loop structure and due to their stability, they are potential diagnostic and prognostic factors in cancer. The increasing evidences have highlighted the role of circRNAs in the modulation of proliferation and metastasis of cancer cells. On the other hand, metastasis has been responsible for up to 90% of cancer-related deaths in patients, requiring more investigation regarding the underlying mechanisms modulating this mechanism. EMT enhances metastasis and invasion of tumor cells, and can trigger resistance to therapy. The cells demonstrate dynamic changes during EMT including transformation from epithelial phenotype into mesenchymal phenotype and increase in N-cadherin and vimentin levels. The process of EMT is reversible and its reprogramming can disrupt the progression of tumor cells. The aim of current review is to understanding the interaction of circRNAs and EMT in human cancers and such interaction is beyond the regulation of cancer metastasis and can affect the response of tumor cells to chemotherapy and radiotherapy. The onco-suppressor circRNAs inhibit EMT, while the tumor-promoting circRNAs mediate EMT for acceleration of carcinogenesis. Moreover, the EMT-inducing transcription factors can be controlled by circRNAs in different human tumors.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
- Department of General Surgery and Integrated Chinese and Western Medicine, Institute of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518060, China
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jingyuan Dai
- School of computer science and information systems, Northwest Missouri State University, Maryville, MO, 64468, USA.
| | - Pedram Torabian
- Cumming School of Medicine, Arnie Charbonneau Cancer Research Institute, University of Calgary, Calgary, AB, T2N 4Z6, Canada
- Department of Medical Sciences, University of Calgary, Calgary, AB, T2N 4Z6, Canada
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Translational Sciences, Xsphera Biosciences Inc. Boston, Boston, MA, USA
| | - Alaa A A Aljabali
- Faculty of Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid, Jordan
| | - Murtaza Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln, LN6 7TS, UK.
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates.
| | - Minglin Zhu
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
- Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, Hubei, 430071, China.
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8
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Abdullah ST, Abdullah SR, Hussen BM, Younis YM, Rasul MF, Taheri M. Role of circular RNAs and gut microbiome in gastrointestinal cancers and therapeutic targets. Noncoding RNA Res 2024; 9:236-252. [PMID: 38192436 PMCID: PMC10771991 DOI: 10.1016/j.ncrna.2023.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/10/2023] [Accepted: 12/11/2023] [Indexed: 01/10/2024] Open
Abstract
Gastrointestinal cancers are a huge worldwide health concern, which includes a wide variety of digestive tract cancers. Circular RNAs (circRNAs), a kind of non-coding RNA (ncRNAs), are a family of single-stranded, covalently closed RNAs that have become recognized as crucial gene expression regulators, having an impact on several cellular functions in cancer biology. The gut microbiome, which consists of several different bacteria, actively contributes to the regulation of host immunity, inflammation, and metabolism. CircRNAs and the gut microbiome interact significantly to greatly affect the growth of GI cancer. Several studies focus on the complex functions of circRNAs and the gut microbiota in GI cancers, including esophageal cancer, colorectal cancer, gastric cancer, hepatocellular cancer, and pancreatic cancer. It also emphasizes how changed circRNA expression profiles and gut microbiota affect pathways connected to malignancy as well as how circRNAs affect hallmarks of gastrointestinal cancers. Furthermore, circRNAs and gut microbiota have been recommended as biological markers for therapeutic targets as well as diagnostic and prognostic purposes. Targeting circRNAs and the gut microbiota for the treatment of gastrointestinal cancers is also being continued to study. Despite significant initiatives, the connection between circRNAs and the gut microbiota and the emergence of gastrointestinal cancers remains poorly understood. In this study, we will go over the most recent studies to emphasize the key roles of circRNAs and gut microbiota in gastrointestinal cancer progression and therapeutic options. In order to create effective therapies and plan for the future gastrointestinal therapy, it is important to comprehend the functions and mechanisms of circRNAs and the gut microbiota.
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Affiliation(s)
- Sara Tharwat Abdullah
- Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Snur Rasool Abdullah
- Medical Laboratory Science, College of Health Sciences, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Bashdar Mahmud Hussen
- Department of Biomedical Sciences, College of Science, Cihan University-Erbil, Kurdistan Region, 44001, Iraq
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Yousif Mohammed Younis
- Department of Nursing, College of Nursing, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Mohammed Fatih Rasul
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Abaza T, El-Aziz MKA, Daniel KA, Karousi P, Papatsirou M, Fahmy SA, Hamdy NM, Kontos CK, Youness RA. Emerging Role of Circular RNAs in Hepatocellular Carcinoma Immunotherapy. Int J Mol Sci 2023; 24:16484. [PMID: 38003674 PMCID: PMC10671287 DOI: 10.3390/ijms242216484] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly fatal malignancy with limited therapeutic options and high recurrence rates. Recently, immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) have emerged as a new paradigm shift in oncology. ICIs, such as programmed cell death protein 1 (PD-1) inhibitors, have provided a new source of hope for patients with advanced HCC. Yet, the eligibility criteria of HCC patients for ICIs are still a missing piece in the puzzle. Circular RNAs (circRNAs) have recently emerged as a new class of non-coding RNAs that play a fundamental role in cancer pathogenesis. Structurally, circRNAs are resistant to exonucleolytic degradation and have a longer half-life than their linear counterparts. Functionally, circRNAs possess the capability to influence various facets of the tumor microenvironment, especially at the HCC tumor-immune synapse. Notably, circRNAs have been observed to control the expression of immune checkpoint molecules within tumor cells, potentially impeding the therapeutic effectiveness of ICIs. Therefore, this renders them potential cancer-immune biomarkers for diagnosis, prognosis, and therapeutic regimen determinants. In this review, the authors shed light on the structure and functional roles of circRNAs and, most importantly, highlight the promising roles of circRNAs in HCC immunomodulation and their potential as promising biomarkers and immunotherapeutic regimen determinants.
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Affiliation(s)
- Tasneem Abaza
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (T.A.); (M.K.A.E.-A.); (K.A.D.)
- Biotechnology and Biomolecular Chemistry Program, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Mostafa K. Abd El-Aziz
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (T.A.); (M.K.A.E.-A.); (K.A.D.)
- Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71631, Egypt
| | - Kerolos Ashraf Daniel
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (T.A.); (M.K.A.E.-A.); (K.A.D.)
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo 11835, Egypt
| | - Paraskevi Karousi
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (P.K.); (M.P.)
| | - Maria Papatsirou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (P.K.); (M.P.)
| | - Sherif Ashraf Fahmy
- Department of Chemistry, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, R5 New Garden City, New Capital, Cairo 11835, Egypt;
| | - Nadia M. Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt;
| | - Christos K. Kontos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (P.K.); (M.P.)
| | - Rana A. Youness
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (T.A.); (M.K.A.E.-A.); (K.A.D.)
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10
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Xu B, Jia W, Feng Y, Wang J, Wang J, Zhu D, Xu C, Liang L, Ding W, Zhou Y, Kong L. Exosome-transported circHDAC1_004 Promotes Proliferation, Migration, and Angiogenesis of Hepatocellular Carcinoma by the miR-361-3p/NACC1 Axis. J Clin Transl Hepatol 2023; 11:1079-1093. [PMID: 37577235 PMCID: PMC10412708 DOI: 10.14218/jcth.2022.00097] [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: 11/10/2022] [Revised: 01/26/2023] [Accepted: 02/15/2023] [Indexed: 07/03/2023] Open
Abstract
Background and Aims Hepatocellular carcinoma (HCC) is among the most common malignant tumors globally. Circular RNAs (circRNAs), as a type of noncoding RNAs, reportedly participate in various tumor biological processes. However, the role of circHDAC1_004 in HCC remains unclear. Thus, we aimed to explore the role and the underlying mechanisms of circHDAC1_004 in the development and progression of HCC. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect circHDAC1_004 expression (circ_0005339) in HCC. Sanger sequencing and agarose gel electrophoresis were used to determine the structure of circHDAC1_004. In vitro and in vivo experiments were used to determine the biological function of circHDAC1_004 in HCC. Herein, qRT-PCR, RNA immunoprecipitation, western blotting, and a luciferase reporter assay were used to explore the relationships among circHDAC1_004, miR-361-3p, and NACC1. Results circHDAC1_004 was upregulated in HCC and significantly associated with poor overall survival. circHDAC1_004 promoted HCC cell proliferation, stemness, migration, and invasion. In addition, circHDAC1_004 upregulated human umbilical vein endothelial cells (HUVECs) and promoted angiogenesis through exosomes. circHDAC1_004 promoted NACC1 expression and stimulated the epithelial-mesenchymal transition pathway by sponging miR-361-3p. Conclusions We found that circHDAC1_004 overexpression enhanced the proliferation, stemness, and metastasis of HCC via the miR-361-3p/NACC1 axis and promoted HCC angiogenesis through exosomes. Our findings may help develop a possible therapeutic strategy for HCC.
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Affiliation(s)
- Bin Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Wenbo Jia
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Yanzhi Feng
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Jinyi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Jing Wang
- Department of health, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Deming Zhu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Chao Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Litao Liang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Wenzhou Ding
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Yongping Zhou
- Jiangnan University Medical Center, JUMC, Department of Hepatobiliary, Wuxi, Jiangsu, China
| | - Lianbao Kong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
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11
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Yang X, Tian X, Zhao P, Wang Z, Sun X. Paclitaxel inhibits hepatocellular carcinoma tumorigenesis by regulating the circ_0005785/miR-640/GSK3β. Cell Biol Int 2023. [PMID: 37269228 DOI: 10.1002/cbin.11906] [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: 12/03/2021] [Revised: 08/25/2022] [Accepted: 08/29/2022] [Indexed: 06/05/2023]
Abstract
Paclitaxel (PTX) is an effective chemotherapeutic agent for cancer patients. It has been reported that circular RNA (circRNA) circ_0005785is involved in the progression of hepatocellular carcinoma (HCC). The purpose of this study is to explore the role and mechanism of circ_0005785 in the PTX resistance of HCC. Cell viability, proliferation, invasion, migration, apoptosis, and angiogenesis were detected using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation, transwell, wound-healing, flow cytometry, and tube formation assay. Circ_0005785, microRNA-640 (miR-640), and Glycogen synthase kinase-3 beta (GSK3β) levels were detected using real-time quantitative polymerase chain reaction. Protein levels of Proliferating cell nuclear antigen (PCNA), Bcl-2, and GSK3β were measured using western blot assay. After being predicted using Circular RNA interactome or TargetScan, binding between miR-640 and circ_0005785 or GSK3β was verified using dual-luciferase reporter and RNA Immunoprecipitation assay. PTX treatment could repress HCC cell viability, decrease circ_0005785 and GSK3β expression, and increase the miR-640 level in HCC cell lines. Furthermore, circ_0005785 and GSK3β were increased, and miR-640 was decreased in HCC tissues and cell lines. Moreover, circ_0005785 knockdown hindered proliferation, migration, invasion, angiogenesis, and boosted apoptosis in PTX-treated HCC cells in vitro. In addition, circ_0005785 silencing improved the PTX sensitivity of HCC in vivo. Mechanistically, circ_0005785 acted as a sponge of miR-640 to regulate GSK3β expression. PTX restrained HCC tumorigenesis partly via regulating the circ_0005785/miR-640/GSK3β axis, hinting at a promising therapeutic target for the HCC treatment.
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Affiliation(s)
- Xianwu Yang
- Department of Gastroenterology, Shijiazhuang People's Hospital, Shijiazhuang, China
| | - Xiaojuan Tian
- Department of Gastroenterology, Shenzhen University General Hospital, Shenzhen, China
| | - Pengcheng Zhao
- Department of Gastroenterology, Chengdu Seventh People's Hospital, Chengdu, China
| | - Zheng Wang
- Hepatobiliary Surgery, Huai'an Second People's Hospital/Huai'an Hospital, Xuzhou Medical University, Jiangsu, China
| | - Xuedong Sun
- Department of Gastroenterology, Shijiazhuang People's Hospital, Shijiazhuang, China
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12
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Wu C, Huang X, Li M, Wang Z, Zhang Y, Tian B. Crosstalk between circRNAs and the PI3K/AKT and/or MEK/ERK signaling pathways in digestive tract malignancy progression. Future Oncol 2023; 18:4525-4538. [PMID: 36891896 DOI: 10.2217/fon-2022-0429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/10/2023] Open
Abstract
Evidence indicates that circular RNAs (circRNAs) may play an important role in regulating gene expression by binding to miRNAs through miRNA response elements. circRNAs are formed by back-splicing and have a covalently closed structure. The biogenesis of circRNAs also appears to be regulated by certain cell-specific and/or gene-specific mechanisms, and thus some circRNAs are tissue specific and tumor-expression specific. Furthermore, the high stability and tissue specificity of circRNAs may be of value for early diagnosis, survival prediction and precision medicine. This review summarizes current knowledge regarding the classification and functions of circRNAs and the role of circRNAs in regulating the PI3K/AKT and/or MEK/ERK signaling pathways in digestive tract malignancy tumors.
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Affiliation(s)
- Chao Wu
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of Pancreatic Surgery, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, Sichuan Province, China
| | - Xing Huang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, Sichuan Province, China
| | - Mao Li
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, Sichuan Province, China
| | - Zihe Wang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, Sichuan Province, China
| | - Yi Zhang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, Sichuan Province, China
| | - Bole Tian
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, Sichuan Province, China
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13
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The Tumorigenic Role of Circular RNA-MicroRNA Axis in Cancer. Int J Mol Sci 2023; 24:ijms24033050. [PMID: 36769372 PMCID: PMC9917898 DOI: 10.3390/ijms24033050] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/30/2023] [Accepted: 02/02/2023] [Indexed: 02/09/2023] Open
Abstract
Circular RNAs (circRNAs) are a class of endogenous RNAs that control gene expression at the transcriptional and post-transcriptional levels. Recent studies have increasingly demonstrated that circRNAs act as novel diagnostic biomarkers and promising therapeutic targets for numerous cancer types by interacting with other non-coding RNAs such as microRNAs (miRNAs). The miRNAs are presented as crucial risk factors and regulatory elements in cancer by regulating the expression of their target genes. Some miRNAs are derived from transposable elements (MDTEs) that can transfer their location to another region of the genome. Genetic interactions between miRNAs and circular RNAs can form complex regulatory networks with various carcinogenic processes that play critical roles in tumorigenesis and cancer progression. This review focuses on the biological regulation of the correlative axis among circular RNAs, miRNAs, and their target genes in various cancer types and suggests the biological importance of MDTEs interacting with oncogenic or tumor-suppressive circRNAs in tumor progression.
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14
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MicroRNA-377: A therapeutic and diagnostic tumor marker. Int J Biol Macromol 2023; 226:1226-1235. [PMID: 36442575 DOI: 10.1016/j.ijbiomac.2022.11.236] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/15/2022] [Accepted: 11/18/2022] [Indexed: 11/26/2022]
Abstract
Cancer is considered as one of the main causes of human deaths globally. Despite the recent progresses in therapeutic modalities, there is still a high rate of mortality among cancer patients. Late diagnosis in advanced tumor stages is one of the main reasons for treatment failure in cancer patients. Therefore, it is required to suggest the novel strategies for the early tumor detection. MicroRNAs (miRNAs) have critical roles in neoplastic transformation by regulation of cell proliferation, migration, and apoptosis. They are always considered as non-invasive markers due to their high stability in body fluids. Since, all of the miRNAs have tissue-specific functions in different tumors as tumor suppressor or oncogene; it is required to investigate the molecular mechanisms of every miRNA in different tumors to introduce that as a suitable non-invasive diagnostic marker in cancer patients. For the first time in the present review, we discussed the role of miR-377 during tumor progression. It has been reported that miR-377 mainly functions as a tumor suppressor through the regulation of signaling pathways and transcription factors. This review is an important step toward introducing the miR-377 as a novel diagnostic marker as well as a therapeutic target in cancer patients.
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15
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Li H, Liu B, Xu X, Li S, Zhang D, Liu Q. Circ_SNX27 regulates hepatocellular carcinoma development via miR-637/FGFR1 axis. ENVIRONMENTAL TOXICOLOGY 2022; 37:2832-2843. [PMID: 36029209 DOI: 10.1002/tox.23640] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/02/2022] [Accepted: 08/09/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Circular RNAs (circRNAs) serve as critical regulatory factors in cancer development. Nonetheless, the potential regulatory mechanism of circRNA sorting nexin 27 (circ_SNX27) in hepatocellular carcinoma (HCC) is still unknown. METHODS The circ_SNX27, microRNA-637 (miR-637), and fibroblast growth factor receptor 1 (FGFR1) levels were quantified by quantitative real-time polymerase chain reaction and western blot analysis. Next, function experiments were conducted using in vitro assays and in vivo senograft study. The relationship between miR-637 with circ_SNX27 or FGFR1 was uncovered by dual-luciferase reporter and RNA pull-down assays. RESULTS The circ_SNX27 and FGFR1 levels were up-regulated, but miR-637 content was reduced in HCC. Circ_SNX27 down-regulation inhibited HCC cell proliferation, motility, and invasion and promoted apoptosis in vitro, as well as weakened tumor growth in vivo. Circ_SNX27 served as a sponge of miR-637 to promote FGFR1 expression. MiR-637 reduction abolished the restrained effect of circ_SNX27 absence on HCC cell development. Moreover, miR-637 curbed HCC cell malignant phenotype by regulating FGFR1. CONCLUSION Circ_SNX27 contributed to HCC development via miR-637/FGFR1 axis, offering a new idea for the treatment of HCC.
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Affiliation(s)
- Hua Li
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Bingli Liu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xin Xu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shunle Li
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Di Zhang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qingfeng Liu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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16
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HBV Promotes the Proliferation of Liver Cancer Cells through the hsa_circ_0000847/miR-135a Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:7332337. [PMID: 36159567 PMCID: PMC9499759 DOI: 10.1155/2022/7332337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/18/2022] [Accepted: 08/23/2022] [Indexed: 11/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is currently one of the most common tumors, with a high morbidity and mortality rate. HCC induced by persistent hepatitis B virus (HBV) infection is the most common liver cancer subtype at present, and HBV-related HCC is highly malignant and its development mechanism still needs to be explored in depth. This study aimed to explore the molecular mechanism of hsa_circ_0000847 targeting miR-135a-5p (miR-135a) to regulate the proliferation, invasion, and apoptosis of liver cancer cells. The study found that the expression level of hsa_circ_0000847 in liver cancer tissues and cells was significantly increased, while the expression level of miR-135a was significantly decreased. Hsa_circ_0000847 promoted the proliferation of liver cancer cells and elevated the expression of the proliferation-related protein. In addition, hsa_circ_0000847 could promote the invasion of HBV-infected liver cancer cells and inhibit the cell apoptosis of liver cancer cells. At the same time, it significantly promoted the expression of antiapoptotic proteins and inhibited the expression of proapoptotic protein. Interestingly, the dual luciferase experiment proved that hsa_circ_0000847 directly targeted miR-135a. On the other hand, the combined effect of hsa_circ_0000847 and miR-135a further illustrated the effect of hsa_circ_0000847 on the proliferation, invasion, and apoptosis of liver cancer cells. In addition, further experiments have also found that HBV could promote the expression of p-p38, p-ERK, and p-JNK through the hsa_circ_0000847/miR-135a axis, thereby further activating the MAPK pathway. In short, HBV promotes the proliferation and invasion of liver cancer cells and inhibits apoptosis by regulating the hsa_circ_0000847/miR-135a pathway, which provided a theoretical basis for effective treatment of HBV-infected liver cancers.
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17
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Li J, Han T, Li Z, Han H, Yin Y, Zhang B, Zhang H, Li L. A Novel circRNA hsa_circRNA_002178 as a Diagnostic Marker in Hepatocellular Carcinoma Enhances Cell Proliferation, Invasion, and Tumor Growth by Stabilizing SRSF1 Expression. JOURNAL OF ONCOLOGY 2022; 2022:4184034. [PMID: 36065311 PMCID: PMC9440807 DOI: 10.1155/2022/4184034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/15/2022] [Accepted: 07/26/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Previous research studies have shown that the elevation of circular RNA (circRNA), hsa_circRNA_002178, was associated with the poor prognosis of breast cancer and colorectal cancer, while its molecular mechanisms underlying the effects on hepatocellular carcinoma (HCC) are still elusive. METHODS The microarray dataset GSE97332 was obtained from the Gene Expression Omnibus (GEO) database and calculated by using the GEO2R tool to identify differentially expressed circRNAs. Differentially expressed hsa_circRNA_002178, in 7 HCC tissue samples and paracancerous tissues, as well as in HCC cell lines and normal hepatocytes, was checked by RT-qPCR. Cell proliferation, invasion, migration, and epithelial-to-mesenchymal transition (EMT)-related proteins were tested in hsa_circRNA_002178-overexpressed or hsa_circRNA_002178-knocked down HCC cells. Subsequently, we identified whether hsa_circRNA_002178 binds to serine- and arginine-rich splicing factor 1 (SRSF1) and then analyzed their function in regulating HCC cell behavior. The effect on HCC cell xenograft tumor growth was observed by the knockdown of hsa_circRNA_002178 in vivo. RESULTS GEO2R-based analysis displayed that hsa_circRNA_002178 was upregulated in HCC tissues. Overexpression or knockdown of hsa_circRNA_002178 encouraged or impeded HCC cell proliferation, migration, invasion, and EMT program. Mechanically, hsa_circRNA_002178 bound to SRSF1 3'-untranslated region (UTR) and stabilized its expression. SRSF1 weakening eliminated the effects of pcDNA-hsa_circRNA_002178 on cell malignant behavior. Finally, the knockdown of hsa_circRNA_002178 was confirmed to prevent xenograft tumor growth. CONCLUSIONS hsa_circRNA_002178 overexpression encouraged the stability of SRSF1 mRNA expression, and it may serve as an upstream factor of SRSF1 for the diagnosis of HCC.
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Affiliation(s)
- Jing Li
- Department of Pathology, Zibo Central Hospital, Zibo 255000, Shandong, China
| | - Ting Han
- Department of Gastroenterology, Qilu Hospital of Shandong University (Qingdao), Qingdao 266035, Shandong, China
| | - Zhenzhen Li
- Department of Pediatrics, Zibo Maternal and Child Health Care Hospital, Zibo 255000, Shandong, China
| | - Hongmei Han
- Department of Pathology, Zibo Central Hospital, Zibo 255000, Shandong, China
| | - Yingchun Yin
- Department of Pathology, Zibo Central Hospital, Zibo 255000, Shandong, China
| | - Baohua Zhang
- Department of Pathology, Zibo Central Hospital, Zibo 255000, Shandong, China
| | - Hengming Zhang
- Department of Pathology, Weifang People's Hospital, Weifang 261000, Shandong, China
| | - Luan Li
- Department of Hepatobiliary Surgery, Qingdao Municipal Hospital of Shandong University, Qingdao 266035, Shandong, China
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18
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Liu Z, Zhang W, Tu C, Li W, Qi L, Zhang Z, Wan L, Yang Z, Ren X, Li Z. Prognostic and clinicopathologic significance of circZFR in multiple human cancers. World J Surg Oncol 2022; 20:268. [PMID: 36008845 PMCID: PMC9413939 DOI: 10.1186/s12957-022-02733-9] [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: 03/22/2022] [Accepted: 08/17/2022] [Indexed: 11/24/2022] Open
Abstract
Background Abnormally expressed in diverse cancers, circZFR has been correlated with clinical outcomes of cancer patients. Aim of this meta-analysis was to elucidate the prognostic role of circZFR in multiple human malignancies. Methods Literature retrieval was conducted by systematically searching on Pubmed, Web of Science, and the Cochrane Library up to December 2nd, 2021. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were pooled to evaluate the association between circZFR expression and overall survival (OS). The reliability of the pooled results was assessed through sensitivity analysis and the publication bias was measured by Begg’s and Egger’s test. Results A total of seventeen studies comprising 1098 Chinese patients were enrolled in this meta-analysis. Results demonstrated that high circZFR expression was correlated with an unfavorable OS (HR = 2.14, 95% CI 1.74, 2.64). High circZFR expression predicted larger tumor size (OR = 2.79, 95% CI 1.52, 5.12), advanced clinical stage (OR = 3.38, 95% CI 1.49, 7.65), tendentiousness of lymph node metastasis (LNM) (OR = 3.08, 95% CI 2.01, 4.71), and malignant grade (OR = 3.18, 95% CI 1.09, 9.30), but not related to age, gender, and distant metastasis (DM). Conclusions High circZFR expression was associated with unfavorable OS and clinicopathologic parameters including tumor size, clinical stage, LNM, and histology grade, implicating a promising prognostic factor in cancers. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-022-02733-9.
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Affiliation(s)
- Zhongyue Liu
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Wenchao Zhang
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Chao Tu
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Wenyi Li
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Lin Qi
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Zhiming Zhang
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Lu Wan
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Zhimin Yang
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Xiaolei Ren
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China. .,Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.
| | - Zhihong Li
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China. .,Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.
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19
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Meng H, Niu R, Huang C, Li J. Circular RNA as a Novel Biomarker and Therapeutic Target for HCC. Cells 2022; 11:cells11121948. [PMID: 35741077 PMCID: PMC9222032 DOI: 10.3390/cells11121948] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/11/2022] [Accepted: 06/14/2022] [Indexed: 02/01/2023] Open
Abstract
Circular RNA (circRNA) is a kind of endogenous non-coding RNA (ncRNA), which is produced by the reverse splicing of precursor mRNA (pre mRNA). It is widely expressed in a variety of biological cells. Due to the special formation mode, circRNA does not have a 5′ terminal cap and 3′ poly (A) tail structure. Compared with linear RNA, circRNA is more stable to exonuclease and ribonuclease. In addition, circRNA is structurally conserved, has a stable sequence and is tissue-specific. With the development of high-throughput sequencing and bioinformatics technology, more and more circRNAs have been found. CircRNA plays an important pathophysiological role in the occurrence and development of alcoholic liver injury (ALI), hepatic fibrosis (HF), hepatocellular carcinoma (HCC), and other liver diseases. Our group has been committed to the research of liver disease diagnosis and treatment targets. We review the function and mechanism of circRNA in ALI, HF and HCC, expecting to provide new ideas for the diagnosis, treatment, and prognosis of liver diseases.
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Affiliation(s)
- Hongwu Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China;
| | - Ruowen Niu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China;
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China;
- Correspondence: (C.H.); (J.L.)
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China;
- Correspondence: (C.H.); (J.L.)
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20
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Niu ZS, Wang WH. Circular RNAs in hepatocellular carcinoma: Recent advances. World J Gastrointest Oncol 2022; 14:1067-1085. [PMID: 35949213 PMCID: PMC9244981 DOI: 10.4251/wjgo.v14.i6.1067] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/22/2021] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) have covalently closed loop structures at both ends, exhibiting characteristics dissimilar to those of linear RNAs. Emerging evidence suggests that aberrantly expressed circRNAs play crucial roles in hepatocellular carcinoma (HCC) by affecting the proliferation, apoptosis and invasive capacity of HCC cells. Certain circRNAs may be used as biomarkers to diagnose and predict the prognosis of HCC. Therefore, circRNAs are expected to become novel biomarkers and therapeutic targets for HCC. Herein, we briefly review the characteristics and biological functions of circRNAs, focusing on their roles in HCC to provide new insights for the early diagnosis and targeted therapy of HCC.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
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Xue C, Li G, Zheng Q, Gu X, Bao Z, Lu J, Li L. The functional roles of the circRNA/Wnt axis in cancer. Mol Cancer 2022; 21:108. [PMID: 35513849 PMCID: PMC9074313 DOI: 10.1186/s12943-022-01582-0] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/22/2022] [Indexed: 01/09/2023] Open
Abstract
CircRNAs, covalently closed noncoding RNAs, are widely expressed in a wide range of species ranging from viruses to plants to mammals. CircRNAs were enriched in the Wnt pathway. Aberrant Wnt pathway activation is involved in the development of various types of cancers. Accumulating evidence indicates that the circRNA/Wnt axis modulates the expression of cancer-associated genes and then regulates cancer progression. Wnt pathway-related circRNA expression is obviously associated with many clinical characteristics. CircRNAs could regulate cell biological functions by interacting with the Wnt pathway. Moreover, Wnt pathway-related circRNAs are promising potential biomarkers for cancer diagnosis, prognosis evaluation, and treatment. In our review, we summarized the recent research progress on the role and clinical application of Wnt pathway-related circRNAs in tumorigenesis and progression.
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Affiliation(s)
- Chen Xue
- grid.13402.340000 0004 1759 700XState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, No. 79 Qingchun Road, Shangcheng District, 310003 Hangzhou, China
| | - Ganglei Li
- grid.13402.340000 0004 1759 700XDepartment of Neurosurgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
| | - Qiuxian Zheng
- grid.13402.340000 0004 1759 700XState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, No. 79 Qingchun Road, Shangcheng District, 310003 Hangzhou, China
| | - Xinyu Gu
- grid.13402.340000 0004 1759 700XState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, No. 79 Qingchun Road, Shangcheng District, 310003 Hangzhou, China
| | - Zhengyi Bao
- grid.13402.340000 0004 1759 700XState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, No. 79 Qingchun Road, Shangcheng District, 310003 Hangzhou, China
| | - Juan Lu
- grid.13402.340000 0004 1759 700XState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, No. 79 Qingchun Road, Shangcheng District, 310003 Hangzhou, China
| | - Lanjuan Li
- grid.13402.340000 0004 1759 700XState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, No. 79 Qingchun Road, Shangcheng District, 310003 Hangzhou, China
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22
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Sun H, Liu F, Zhang H. Circ_0072008, an oncogene in pancreatic ductal adenocarcinoma, contributes to tumour cell malignant progression and glycolysis by regulating miR-545-3p/SLC7A11 axis. Autoimmunity 2022; 55:203-213. [PMID: 35166634 DOI: 10.1080/08916934.2022.2027919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 12/15/2021] [Accepted: 01/07/2022] [Indexed: 11/02/2022]
Abstract
BACKGROUND The hsa_circRNA_103809 (circ_0072088) has been an emerging tumour regulator in human cancers, and is identified as one most aberrantly expressed circRNA in patients with pancreatic ductal adenocarcinoma (PDAC). However, the role of circ_0072088 remains unclear in PDAC cells. METHODS Expression of circ_0072088, microRNA (miR)-545-3p and solute carrier family 7 member 11 (SLC7A11) was detected by real-time quantitative PCR and western blotting. Cell progression was measured by cell counting kit (CCK)-8 assay, transwell assays and flow cytometry, as well as xenograft tumour models. Glycolysis was evaluated by commercial assay kits. The interaction among circ_0072088, miR-545-3p and SLC7A11 was confirmed by dual-luciferase reporter assay. RESULTS Circ_0072088 was upregulated in PDAC tumours and cells; besides, high circ_0072088 level was associated with high tumour-node-metastasis (TNM) stage. The circ_0072088 siRNA suppressed cell viability, migration, invasion, extracellular acidification rate (ECAR), lactate production, glucose uptake, and ATP generation, but promoted apoptosis rate and oxygen consumption rate (OCR) in SW1990 and PANC-1 cells. In vivo, circ_0072088 knockdown retarded tumour growth of PANC-1 cells. Overexpressing miR-545-3p mimicked circ_0072088 siRNA-induced actions, and inhibited cell progression and glycolysis of SW1990 and PANC-1 cells. Moreover, SLC7A11 downregulation could be mediated by both circ_0072008 siRNA and miR-545-3p mimic, and participating in suppressive role in cell progression and glycolysis of SW1990 and PANC-1 cells. In mechanism, miR-545-3p was targeted by circ_0072008, and SLC7A11 was target of miR-545-3p. CONCLUSION Circ_0072088 elicited oncogenic role in malignant cell progression and glycolysis of PDAC cells through circ_0072088/miR-545-3p/SLC7A11 pathway.HighlightsCirc_0072088 was upregulated in PDAC tumours and was associated with high tumour burden.Blocking circ_0072088 suppressed cell proliferation, migration, invasion, and glycolysis in PDAC cells.Circ_0072088 could directly regulate miR-545-3p, and SLC7A11 was a target of miR-545-3p.Restoring miR-545-3p mimicked the effects of circ_0072088 knockdown in PDAC cell in vitro.
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Affiliation(s)
- Hui Sun
- Department of Gastroenterology, Laiyang Central Hospital of Yantai City, Yantai, China
| | - Fang Liu
- Department of Oncology, Zaozhuang Mining Group Central Hospital, Zaozhuang, China
| | - Hongqing Zhang
- Department of Intensive Care Unit, Tengzhou Central People's Hospital of Shandong Province, Tengzhou City, China
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Ji J, Li C, Wang J, Wang L, Huang H, Li Y, Fang J. Hsa_circ_0001756 promotes ovarian cancer progression through regulating IGF2BP2-mediated RAB5A expression and the EGFR/MAPK signaling pathway. Cell Cycle 2022; 21:685-696. [PMID: 35113003 PMCID: PMC8973336 DOI: 10.1080/15384101.2021.2010166] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Hsa_circ_0001756 was reported to be upregulated in serum samples of ovarian cancer (OC) patients and may serve as a potential OC biomarker. This study aimed to investigate the role and molecular mechanisms of hsa_circ_0001756 in OC procession. Herein, we detected the expression of hsa_circ_0001756 in OC tissues and cell lines with RT-qPCR assay, which showed that hsa_circ_0001756 was upregulated in OC tissues and cell lines. Then small interfering RNA targeting hsa_circ_0001756 (si-hsa_circ_0001756) was transfected into SKOV3 and A2780 cells, and the proliferation, invasion, and expression of epithelial-mesenchymal transition (EMT) marker proteins were determined with CCK-8, Transwell and Western blotting assays, respectively. We found that hsa_circ_0001756 knockdown inhibited OC cell proliferation, invasion and EMT. Moreover, RNA pull-down assay verified the binding between hsa_circ_0001756 and IGF2 mRNA binding protein 2 (IGF2BP2), and rescue experiments indicated that IGF2BP2 overexpression reversed the effects of has_circ_0001756 knockdown on OC cell functions. Co-IP assay verified IGF2BP2 could interact with RAB GTPase 5A (RAB5A) protein. Then SKOV3 cells were transfected with si-IGF2BP2 alone or together with pcDNA-RAB5A, followed by the detection of SKOV3 cell functions. We found that IGF2BP2 knockdown inhibited OC cell proliferation, invasion, and EMT, while RAB5A overexpression reversed these effects. Finally, SKOV3 cells transfected with si-hsa_circ_0001756 were injected into nude mice through tail vein. Hsa_circ_0001756 knockdown significantly inhibited the xenograft tumor growth of OC in vivo. In conclusion, hsa_circ_0001756 knockdown inhibits OC cell proliferation, invasion, and EMT, and reduces xenograft tumor growth by suppressing IGF2BP2-mediated RAB5A expression and blocking the EGFR/MAPK signaling pathway.
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Affiliation(s)
- Jing Ji
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Chen Li
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Jinfeng Wang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Lei Wang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Huifang Huang
- Department of Gynecology, The Northwest Women’s and Children’s Hospital, Xi’an, Shaanxi, China
| | - Ying Li
- Department of Radiology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi, China,CONTACT Ying Li Department of Radiology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi710077, China; Jing Fang Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Jing Fang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
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Knockdown of hsa_circ_0001964 inhibits hepatocellular carcinoma cell proliferation by inactivating PI3K/AKT signaling pathway. Mol Cell Toxicol 2022. [DOI: 10.1007/s13273-021-00185-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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MicroRNA-377-3p promotes cell proliferation and inhibits cell cycle arrest and cell apoptosis in hepatocellular carcinoma by affecting EGR1-mediated p53 activation. Pathol Res Pract 2022; 234:153855. [PMID: 35461040 DOI: 10.1016/j.prp.2022.153855] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 03/14/2022] [Accepted: 03/22/2022] [Indexed: 12/22/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is an aggressive malignant carcinoma with a high fatality rate. MicroRNAs (miRNAs) have been found to regulate the development of multiple cancers, including HCC. MATERIALS AND METHODS Quantitative polymerase chain reaction (qPCR) were implemented to evaluate RNA level and western blot to detect protein level. Cell counting kit-8 (CCK-8), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), flow cytometry and in vivo assays were performed to evaluate the biological functions of RNAs on HCC cell proliferation, cell cycle and apoptosis. Luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays were carried out to evaluate the underlying mechanisms. RESULTS MiR-377-3p promotes cell proliferation and inhibits cell cycle arrest and cell apoptosis in HCC. MiR-377-3p downregulates transcription factor EGR1 expression to weaken the activation of p53. p53 inhibits CCNB1, CCNB2 and CHEK1 expressions and activates THBS1, IGFBP3 and TRIM22 expressions. p53 knockdown promotes the proliferation and inhibits the cell cycle arrest and apoptosis of HCC cells. CONCLUSION Our study demonstrated the role and underlying mechanisms of miR-377-3p in HCC. MiR-377-3p facilitates the proliferation and suppresses the cell cycle arrest and apoptosis in HCC by affecting transcription factor EGR1-mediated p53 activation.
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Chen Z, Du J, Yang C, Si G, Chen Y. circ-CFH promotes the development of HCC by regulating cell proliferation, apoptosis, migration, invasion, and glycolysis through the miR-377-3p/RNF38 axis. Open Life Sci 2022; 17:248-260. [PMID: 35415236 PMCID: PMC8951215 DOI: 10.1515/biol-2022-0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/12/2021] [Accepted: 01/03/2022] [Indexed: 12/24/2022] Open
Abstract
Abstract
Circular RNAs (circRNAs) have previously been confirmed to function as vital regulators in multiple human cancers, including hepatocellular carcinoma (HCC). This study aimed to clarify the role and underlying molecular mechanisms of circ-CFH in HCC. circ-CFH was overexpressed in HCC tissues and cells, and the downregulation of circ-CFH inhibited the development of HCC by repressing cell proliferation, migration, invasion, and glycolysis while enhancing apoptosis in vitro, as well as inhibited tumor growth in vivo. miR-377-3p was negatively regulated by circ-CFH, and silencing of miR-377-3p abolished circ-CFH knockdown-mediated effects on HCC cells. Moreover, overexpression of miR-377-3p could impede the HCC process by targeting RNF38. Mechanistically, the circ-CFH/miR-377-3p/RNF38 axis regulated the progression of HCC cells, which might provide new diagnostic markers for HCC.
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Affiliation(s)
- Zengyin Chen
- Department of Hepatobiliary Surgery, Chengyang District People’s Hospital, Qingdao, 266000, Shandong, China
| | - Juan Du
- Department of Hepatobiliary Surgery, Chengyang District People’s Hospital, Qingdao, 266000, Shandong, China
| | - Chen Yang
- Department of Hepatobiliary Surgery, Qingdao People’s Hospital, No. 600 Changcheng Road, Chengyang District, Qingdao, 266000, Shandong, China
| | - Guangju Si
- Department of Hepatobiliary Surgery, Chengyang District People’s Hospital, Qingdao, 266000, Shandong, China
| | - Yuxin Chen
- Department of Hepatobiliary Surgery, Chengyang District People’s Hospital, Qingdao, 266000, Shandong, China
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Circ-PKD2 promotes Atg13-mediated autophagy by inhibiting miR-646 to increase the sensitivity of cisplatin in oral squamous cell carcinomas. Cell Death Dis 2022; 13:192. [PMID: 35220397 PMCID: PMC8882170 DOI: 10.1038/s41419-021-04497-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 11/03/2021] [Accepted: 12/20/2021] [Indexed: 12/16/2022]
Abstract
Autophagy is an evolutionally conserved catabolic process that degrades cells to maintain homeostasis. Cisplatin-activated autophagy promotes the expression of circ-PKD2, which plays a role as a tumor suppressor gene in the proliferation, migration, and invasion in oral squamous cell carcinoma (OSCC). However, the role of circ-PKD2 in regulating the sensitivity of OSCC patients to cisplatin remains to be elucidated. Overexpression of circ-PKD2 increased the formation of autophagosomes in OSCC cells and activation of proteins, such as LC3 II/I. Its activation effect on autophagy was, however, alleviated by 3-MA. Bioinformatics analyses and double luciferases reporter assays conducted in this study confirmed the existence of targeted relationships between circ-PKD2 and miR-646 and miR-646 and Atg13. Functional experiments further revealed that miR-646 reversed the autophagy and apoptosis effects of circ-PKD2 in OSCC cells treated with cisplatin. In addition, circ-PKD2 promoted the expression of ATG13 by adsorption of miR-646. Its interference with Atg13 alleviated the activation effects of circ-PKD2 on autophagy and apoptosis of miR-646. Notably, the in vivo animal experiments also confirmed that circ-PKD2 inhibited tumor proliferation and activated autophagy in OSCC cells. This study provides a theoretical basis for using circ-PKD2 as a target to regulate the sensitivity of OSCC patients to cisplatin, thus increasing its chemotherapeutic effects.
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Chu J, Fang X, Sun Z, Gai L, Dai W, Li H, Yan X, Du J, Zhang L, Zhao L, Xu D, Yan S. Non-Coding RNAs Regulate the Resistance to Anti-EGFR Therapy in Colorectal Cancer. Front Oncol 2022; 11:801319. [PMID: 35111681 PMCID: PMC8802825 DOI: 10.3389/fonc.2021.801319] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third prevalent cancer worldwide, the morbidity and mortality of which have been increasing in recent years. As molecular targeting agents, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (McAbs) have significantly increased the progression-free survival (PFS) and overall survival (OS) of metastatic CRC (mCRC) patients. Nevertheless, most patients are eventually resistant to anti-EGFR McAbs. With the intensive study of the mechanism of anti-EGFR drug resistance, a variety of biomarkers and pathways have been found to participate in CRC resistance to anti-EGFR therapy. More and more studies have implicated non-coding RNAs (ncRNAs) primarily including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely involved in tumorigenesis and tumor progression. They function as essential regulators controlling the expression and function of oncogenes. Increasing data have shown ncRNAs affect the resistance of molecular targeted drugs in CRC including anti-EGFR McAbs. In this paper, we have reviewed the advance in mechanisms of ncRNAs in regulating anti-EGFR McAbs therapy resistance in CRC. It provides insight into exploring ncRNAs as new molecular targets and prognostic markers for CRC.
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Affiliation(s)
- Jinjin Chu
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Xianzhu Fang
- Department of Pathology and Pathophysiology, Weifang Medical University, Weifang, China
| | - Zhonghou Sun
- Department of Pediatrics of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Linlin Gai
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Wenqing Dai
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Haibo Li
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Xinyi Yan
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Jinke Du
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Lili Zhang
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Lu Zhao
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Donghua Xu
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Shushan Yan
- Department of Gastrointestinal and Anal Diseases Surgery of the Affiliated Hospital, Weifang Medical University, Weifang, China
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Sun K, Wang H, Zhang D, Li Y, Ren L. Depleting circ_0088364 restrained cell growth and motility of human hepatocellular carcinoma via circ_0088364-miR-1270-COL4A1 ceRNA pathway. Cell Cycle 2022; 21:261-275. [PMID: 34951563 PMCID: PMC8855875 DOI: 10.1080/15384101.2021.2016196] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Circular RNA hsa_circ_0088364 (circ_0088364) is a contributory factor in the malignancy of hepatocellular carcinoma (HCC). We aimed to elaborate its role and competing endogenous RNA (ceRNA) mechanism in HCC cell growth and motility. Expression of circ_0088364, microRNA (miR)-1270 and Collagen type IV alpha 1 chain (COL4A1) was measured by real-time quantitative PCR and Western blotting, and their relationships were determined by dual-luciferase reporter assay, RNA immunoprecipitation, biotinylated RNA pull-down, and Spearman's rank correlation analysis. Cellular programs were measured by cell counting kit-8 assay, flow cytometry and transwell assays, Western blotting, and xenograft experiment. Expression of circ_0088364 and COL4A1 was upregulated, and miR-1270 was downregulated in HCC patients' tumors; moreover, there were linear correlations among circ_0088364, miR-1270, and COL4A1 expression. Essentially, circ_0088364 and COL4A1 were ceRNAs for miR-1270 via target binding. In function, silencing circ_0088364 or upregulating miR-1270 could suppress cell proliferation, cell cycle entrance, transwell migration and invasion in Huh7 and HCCLM3 cells, as well as promote apoptosis rate. Moreover, above-mentioned effects were accompanied with reduced B-cell lymphoma (Bcl)-2, N-cadherin and Vimentin levels, and elevated Bcl-2-associated X protein (Bax) and E-cadherin levels. Contrarily, exhausting miR-1270 and restoring COL4A1 could severally abrogate the tumor-suppressive roles of circ_0088364 knockdown and miR-1270 overexpression in HCC cells in vitro. In vivo, silencing circ_0088364 retarded xenograft tumor growth in nude mice induced by Huh7 cells by upregulating miR-1270 and downregulating COL4A1. Blocking circ_0088364 suppressed HCC by inhibiting cell growth and motility via targeting miR-1270-COL4A1 axis.
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Affiliation(s)
- Kai Sun
- Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China
| | - Haochen Wang
- Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China
| | - Dongyuan Zhang
- Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China
| | - Yupeng Li
- Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China
| | - Lei Ren
- Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China,CONTACT Lei Ren Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, No. 16766, Jingshi Road, Lixia District, Jinan City, Shandong Province, China
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Louis C, Leclerc D, Coulouarn C. Emerging roles of circular RNAs in liver cancer. JHEP Rep 2022; 4:100413. [PMID: 35036887 PMCID: PMC8749337 DOI: 10.1016/j.jhepr.2021.100413] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma and cholangiocarcinoma are the most common primary liver tumours, whose incidence and associated mortality have increased over recent decades. Liver cancer is often diagnosed late when curative treatments are no longer an option. Characterising new molecular determinants of liver carcinogenesis is crucial for the development of innovative treatments and clinically relevant biomarkers. Recently, circular RNAs (circRNAs) emerged as promising regulatory molecules involved in cancer onset and progression. Mechanistically, circRNAs are mainly known for their ability to sponge and regulate the activity of microRNAs and RNA-binding proteins, although other functions are emerging (e.g. transcriptional and post-transcriptional regulation, protein scaffolding). In liver cancer, circRNAs have been shown to regulate tumour cell proliferation, migration, invasion and cell death resistance. Their roles in regulating angiogenesis, genome instability, immune surveillance and metabolic switching are emerging. Importantly, circRNAs are detected in body fluids. Due to their circular structure, circRNAs are often more stable than mRNAs or miRNAs and could therefore serve as promising biomarkers - quantifiable with high specificity and sensitivity through minimally invasive methods. This review focuses on the role and the clinical relevance of circRNAs in liver cancer, including the development of innovative biomarkers and therapeutic strategies.
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Key Words
- ASO, antisense oligonucleotide
- CCA, cholangiocarcinoma
- CLIP, cross-linking immunoprecipitation
- EMT, epithelial-to-mesenchymal transition
- EVs, extracellular vesicles
- HCC, hepatocellular carcinoma
- HN1, haematopoietic- and neurologic-expressed sequence 1
- IRES, internal ribosome entry sites
- NGS, next-generation sequencing
- QKI, Quaking
- RBP, RNA-binding protein
- RISC, RNA-induced silencing complex
- TAM, tumour-associated macrophage
- TSB, target site blockers
- biomarker
- cancer hallmarks
- cholangiocarcinoma
- circRNA
- circRNA, circular RNA
- hepatocellular carcinoma
- miRNA, microRNA
- shRNA, small-hairpin RNA
- snRNP, small nuclear ribonuclear proteins
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Affiliation(s)
- Corentin Louis
- Inserm, Univ Rennes 1, COSS (Chemistry, Oncogenesis Stress Signaling), UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
| | - Delphine Leclerc
- Inserm, Univ Rennes 1, COSS (Chemistry, Oncogenesis Stress Signaling), UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
| | - Cédric Coulouarn
- Inserm, Univ Rennes 1, COSS (Chemistry, Oncogenesis Stress Signaling), UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
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MicroRNA-377-3p inhibits hepatocellular carcinoma growth and metastasis through negative regulation of CPT1C-mediated fatty acid oxidation. Cancer Metab 2022; 10:2. [PMID: 35057851 PMCID: PMC8772112 DOI: 10.1186/s40170-021-00276-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 10/12/2021] [Indexed: 12/19/2022] Open
Abstract
Background Altered lipid metabolism is closely related to the occurrence and development of hepatocellular carcinoma (HCC). Carnitine palmitoyltransferase 1C (CPT1C) is a member of CPT1 family and plays a key role in cancer development and progression. However, how microRNAs (miRNAs) regulate CPT1C-mediated fatty acid transport and oxidation remains to be elucidated. Methods Oil Red O staining, mitochondrial, and lipid droplets immunofluorescence staining were used to detect the functions of miR-377-3p and CPT1C in fatty acid oxidation. Colocalization of palmitate and mitochondria was performed to investigate the function of miR-377-3p and CPT1C in fatty acid transport into mitochondria. Fatty acid oxidation (FAO) assay was used to detect the function of miR-377-3p and CPT1C in FAO. Cell proliferation, migration and invasion assays and animal experiments were used to evaluate the role of miR-377-3p/CPT1C axis in HCC progression in vitro and in vivo. Immunofluorescence staining was used to identify the clinical significance of miR-377-3p and CPT1C in HCC patients. Results MiR-377-3p inhibits CPT1C expression by targeting its 3’-untranslated region. Through repression of CPT1C, miR-377-3p suppresses fatty acid oxidation by preventing fatty acid from entering into mitochondria and decreasing ATP production in HCC cells. Inhibiting fatty acid oxidation abolishes the ability of miR-377-3p/CPT1C axis to regulate HCC proliferation, migration, invasion and metastasis in vitro and in vivo. In HCC patients, CPT1C is significantly upregulated, and miR-377-3p expression and lipid droplets are negatively correlated with CPT1C expression. High expression of miR-377-3p and CPT1C predict better and worse clinical outcomes, respectively. Conclusions We uncover the key function and the relevant mechanisms of the miR-377-3p/CPT1C axis in HCC, which might provide a potential target for the treatment of HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s40170-021-00276-3.
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Li JX, Wang JJ, Deng ZF, Zheng H, Yang CM, Yuan Y, Yang C, Gu FF, Wu WQ, Qiao GL, Ma LJ. Circular RNA circ_0008934 promotes hepatocellular carcinoma growth and metastasis through modulating miR-1305/TMTC3 axis. Hum Cell 2022; 35:498-510. [PMID: 35015267 DOI: 10.1007/s13577-021-00657-2] [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: 09/30/2021] [Accepted: 11/30/2021] [Indexed: 11/29/2022]
Abstract
Circular RNAs (circRNAs) play important roles in the progression of hepatocellular carcinoma (HCC). However, the exact function of circ_0008934 in HCC is unknown. Our study aimed to investigate the expression characteristics of circ_0008934 in HCC and its effects on the proliferation and metastasis of HCC, and to explore the potential mechanism. In this study, circ_0008934 expression was found to be significantly upregulated in HCC tissues and cell lines by qRT-PCR. High level of circ_0008934 is closely associated with higher serum AFP (P < 0.001), larger tumor diameter (P = 0.012), microvascular invasion (P = 0.008) and poorer prognosis (P = 0.007) of HCC patients. Functionally, knockdown of circ_0008934 inhibited HCC cell proliferation, invasion and migration in vitro and vivo. Mechanically, circ_0008934 was a sponge of miR-1305 to facilitate the TMTC3 expression, and the TMTC3 expression in HCC tissues was negatively associated with the survival of HCC patients. Furthermore, rescued assays revealed that the circ_0008934 facilitated HCC proliferation, invasion and migration by regulating miR-1305/ TMTC3 signaling pathways. Overall, these results demonstrate that downregulation of circ_0008934 repress HCC growth and metastasis by upregulating miR-1305 to inhibit TMTC3, suggesting circ_0008934/ miR-1305/ TMTC3 regulatory axis may be a possible novel therapeutic target for HCC.
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Affiliation(s)
- Jia-Xi Li
- Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111, Xianxia Road, Shanghai, 200336, China
| | - Jin-Jiang Wang
- Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111, Xianxia Road, Shanghai, 200336, China
| | - Zhou-Feng Deng
- Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111, Xianxia Road, Shanghai, 200336, China
| | - Hao Zheng
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.,The Department of Reproductive Genetic Center, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Chun-Mei Yang
- Department of Laboratory, Shunyi District Hospital, Beijing, 101300, China
| | - Ying Yuan
- Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111, Xianxia Road, Shanghai, 200336, China
| | - Cheng Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Fang-Fang Gu
- Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111, Xianxia Road, Shanghai, 200336, China
| | - Wei-Qi Wu
- Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111, Xianxia Road, Shanghai, 200336, China.
| | - Guang-Lei Qiao
- Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111, Xianxia Road, Shanghai, 200336, China.
| | - Li-Jun Ma
- Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111, Xianxia Road, Shanghai, 200336, China.
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Huang J, Zhou H, Diao Y, Yang Z. Hsa_circ_0000285 knockdown inhibits the progression of hepatocellular carcinoma by sponging miR-582-3p to regulate CCNB2 expression. Hum Exp Toxicol 2022; 41:9603271221115400. [PMID: 35839486 DOI: 10.1177/09603271221115400] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
AIM Hsa_circ_0000285, a novel circular RNA, has been proven to extensively take part in the pathogenesis of numerous tumors. In hepatocellular carcinoma (HCC), very little is known about hsa_circ_0000285 until now. Hence, this research aims to determine hsa_circ_0000285's functional role and underlying mechanisms in HCC. METHODS The expressions of miR-582-3p, hsa_circ_000028, and cyclin B2 (CCNB2) among the HCC cells and tumor samples were determined by performing western blotting and qRT-PCR analyses. The impacts of hsa_circ_000028 on the proliferative and migratory abilities of HCC cells were examined through the execution of CCK-8 and wound-healing assays. Meanwhile, the expressions of the proteins Bcl-2 and Bax were detected via western blotting. Tumor xenograft models were established to examine how hsa_circ_000028 functions during the mediation of HCC tumor growth in vivo. RNA immunoprecipitation and luciferase reporter experiments were performed for the validation of the interactions of miR-582-3p, hsa_circ_000028, and CCNB2 with each other. RESULTS Elevated hsa_circ_0000285 and CCNB2 expressions, and a decreased miR-582-3p expression were observed among the HCC cell lines and tumors. Hsa_circ_0000285 bound to miR-582-3p competitively to improve CCNB2 levels. Silencing of hsa_circ_0000285 promoted apoptosis and repressed proliferation and migration among HCC cells. Moreover, silencing hsa_circ_0000285 also impeded the growth of HCC tumors in vivo. Inhibiting hsa_circ_0000285 or CCNB2 reversed the miR-582-3p-knockdown-mediated promotion of malignant HCC cell phenotypes. CONCLUSION Our study has demonstrated that hsa_circ_0000285 fosters the development of malignant HCC cells phenotypes through the modulation of the miR-582-3p/CCNB2 axis. Thus, these results suggest that hsa_circ_0000285 is a prospective target for HCC treatment.
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Affiliation(s)
- Jing Huang
- Department of Hepatobiliary & Vascular Surgery, 580504School of Clinical Medicine & The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Hongchi Zhou
- Department of Hepatobiliary & Vascular Surgery, 580504School of Clinical Medicine & The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Yun Diao
- Operation Room, 580504School of Clinical Medicine & The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Zhiming Yang
- Department of Hepatobiliary & Vascular Surgery, 580504School of Clinical Medicine & The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
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Jiang F, Liu X, Cui X, Hu J, Wang L, Xue F, Guo S, Wang X. Circ_0000518 promotes macrophage/microglia M1 polarization via the FUS/CaMKKβ/AMPK pathway to aggravate multiple sclerosis. Neuroscience 2021; 490:131-143. [PMID: 34920022 DOI: 10.1016/j.neuroscience.2021.12.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 12/07/2021] [Accepted: 12/08/2021] [Indexed: 12/28/2022]
Abstract
Evidence has shown that circ_0000518 is upregulated in peripheral of multiple sclerosis (MS) patients, suggesting that it may play an important role in the progression of MS. However, its specific mechanism in MS progression is unclear. In this study, the human microglial clone 3 (HMC3) cells were treated with 100 ng/mL of LPS for 24 h, then the short hairpin RNA against hsa_circ_0000518 (sh-hsa_circ_0000518) was transfected into cells and incubated for 48 h. We found increased circ_0000518 expressions, increased apoptosis and oxidative stress, increased M1 phenotype marker expression, and decreased M2 phenotype marker expression in cells, and that interfering with circ_0000518 expression reversed the effect of LPS on HMC3 cells. Online bioinformatics database analysis indicated that FUS is an RNA binding protein of circ_0000518. Next, we observed increased FUS expression in LPS treated HMC3 cells, and interfering with FUS expression reduced LPS triggered apoptosis and oxidative stress, decreased M1 phenotype marker expression, and promoted M2 phenotype marker expression. Mechanistic studies revealed that interfering with FUS promoted the polarization of HMC3 cells from the M1 phenotype to the M2 phenotype via activation of CaMKKβ/AMPK-PGC-1α pathway, whereas this promoting effect was counteracted by STO-609. In an experimental autoimmune encephalomyelitis (EAE) mouse model, we observed that circ_0000518 knockdown reduced circ_0000518 and FUS expression in brain and spinal cord tissues, reduced neurological scores in mice, and alleviated inflammatory cell infiltration in the CNS. Summarily, our study identified that circ_0000518 promotes macrophage/microglial M1 polarization through the FUS/CaMKKβ/AMPK pathway and aggravates MS.
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Affiliation(s)
- Feng Jiang
- Department of Neurology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Xiaoling Liu
- Department of Neurology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Xiaoli Cui
- Department of Neurology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Jun Hu
- Department of Neurology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Le Wang
- Department of Neurology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Fang Xue
- Department of Neurology, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Shuying Guo
- Department of Neurology, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - XiaoHui Wang
- Department of Neurology, Shaanxi Provincial People's Hospital, Xi'an 710068, China.
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Xue C, Li G, Lu J, Li L. Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression. Signal Transduct Target Ther 2021; 6:400. [PMID: 34815385 PMCID: PMC8611092 DOI: 10.1038/s41392-021-00788-w] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/30/2021] [Accepted: 10/08/2021] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs), covalently closed noncoding RNAs, are widely expressed in eukaryotes and viruses. They can function by regulating target gene expression, linear RNA transcription and protein generation. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays key roles in many biological and cellular processes, such as cell proliferation, growth, invasion, migration, and angiogenesis. It also plays a pivotal role in cancer progression. Emerging data suggest that the circRNA/PI3K/AKT axis modulates the expression of cancer-associated genes and thus regulates tumor progression. Aberrant regulation of the expression of circRNAs in the circRNA/PI3K/AKT axis is significantly associated with clinicopathological characteristics and plays an important role in the regulation of biological functions. In this review, we summarized the expression and biological functions of PI3K-AKT-related circRNAs in vitro and in vivo and assessed their associations with clinicopathological characteristics. We also further discussed the important role of circRNAs in the diagnosis, prognostication, and treatment of cancers.
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Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Ganglei Li
- Department of Neurosurgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.
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[Research Progress in CircRNA and Radiotherapy Resistance of Non-small Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 24:770-776. [PMID: 34802208 PMCID: PMC8607291 DOI: 10.3779/j.issn.1009-3419.2021.101.37] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
As the main type of lung cancer, non-small cell lung cancer (NSCLC) is a common cancer which is characterized by low 5-year survival rate and worse prognosis. Nowadays, some studies show that the low survival rate and worse prognosis are due to the resistance to radiotherapy caused by circRNA. Therefore, to find out the relationship between circRNA and radiotherapy resistance of NSCLC was imoprtant. According to research the relevant literatures, the relationship between circRNA and radiotherapy resistance of NSCLC was explored. CircRNA plays an important role in the invasion, metastasis, proliferation and treatment resistance of NSCLC. The radiation resistance of tumor cells induced by circRNA has become a crucial problem in radiotherapy. CircRNA plays an important role in the radiotherapy resistance of NSCLC.
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Geng F, Jia WC, Li T, Li N, Wei W. Knockdown of lncRNA NEAT1 suppresses proliferation and migration, and induces apoptosis of cervical cancer cells by regulating the miR‑377/FGFR1 axis. Mol Med Rep 2021; 25:10. [PMID: 34779493 PMCID: PMC8600400 DOI: 10.3892/mmr.2021.12526] [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: 08/11/2020] [Accepted: 03/08/2021] [Indexed: 11/16/2022] Open
Abstract
To investigate the role of NEAT1 and the microRNA (miR)-377/fibroblast growth factor receptor 1 (FGFR1) axis in cervical cancer (CC), the expression levels of NEAT1, FGFR1 and miR-377 were detected in CC tissues and cell lines. NEAT1 or FGFR1 was knocked down by transfection with short hairpin RNA (sh)-NEAT1 or sh-FGFR1, and miR-377 was overexpressed by transfection with miR-377 mimics in HeLa and C33A cells. Cell viability and migration were measured using MTT and Transwell assays, respectively. Cell apoptosis was determined by flow cytometry. A dual luciferase reporter assay was performed to confirm the presence of binding sites between miR-377 and FGFR1. The results revealed that the expression levels of NEAT1 and FGFR1 were significantly elevated, whereas miR-377 expression was markedly decreased in CC tissues and cell lines. In HeLa and C33A cells, after NEAT1 knockdown, miR-377 expression was increased, cell viability and migration were inhibited, and apoptosis was induced. Similarly, silencing FGFR1 inhibited cell viability and migration, and induced apoptosis of HeLa and C33A cells. A dual luciferase reporter gene assay verified a targeting relationship between NEAT1 and miR-377. Inhibition of miR-377 or overexpression of FGFR1 reversed the effects of NEAT1 knockdown on cell function in HeLa and C33A cells. Moreover, a dual luciferase reporter assay confirmed that FGFR1 was a direct target of miR-377. In conclusion, suppression of NEAT1 inhibited cell viability and migration, and promoted apoptosis of CC cells, and these effects were achieved through regulation of the miR-377/FGFR1 axis.
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Affiliation(s)
- Feng Geng
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Wen-Cong Jia
- Department of Obstetrics and Gynecology, Binzhou Second People's Hospital, Binzhou, Shandong 256800, P.R. China
| | - Tao Li
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Na Li
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Wei Wei
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
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Lai Q, Wang M, Hu C, Tang Y, Li Y, Hao S. Circular RNA regulates the onset and progression of cancer through the mitogen-activated protein kinase signaling pathway. Oncol Lett 2021; 22:817. [PMID: 34671431 PMCID: PMC8503804 DOI: 10.3892/ol.2021.13078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/27/2021] [Indexed: 01/04/2023] Open
Abstract
The rapid increase in cancer morbidity and mortality worldwide is a major challenge for public health providers. Therefore, there is an urgent need to explore the molecular mechanism of tumorigenesis and identify potential diagnostic biomarkers and therapeutic methods. Circular RNA (circRNA) is characterized by a stable structure and tissue-specific expression; these features are useful in medical research and clinical applications. In recent years, with the development of high-throughput sequencing technology, the potential use of circRNA in cancer prognosis and treatment has been extensively explored. Abnormal circRNA expression interferes with specific signaling pathways such as the MAPK pathway; this phenomenon may provide potential diagnostic biomarkers and new therapeutic targets. The present article discusses the research progress on the regulatory roles of MAPK/ERK pathway-related circRNA molecules in the development and progression of different types of tumors. This review may provide insight into the development of circRNA-based cancer management strategies.
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Affiliation(s)
- Qun Lai
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Min Wang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Chunmei Hu
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Yan Tang
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Yarong Li
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Shuhong Hao
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
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Yao F, Xiang X, Zhou C, Huang Q, Huang X, Xie Z, Wang Q, Wu Q. Identification of Circular RNAs Associated With Chemoresistance in Colorectal Cancer. Front Genet 2021; 12:696948. [PMID: 34603369 PMCID: PMC8484910 DOI: 10.3389/fgene.2021.696948] [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: 04/18/2021] [Accepted: 08/16/2021] [Indexed: 01/14/2023] Open
Abstract
Chemoresistance is a major clinical obstacle for the treatment of colorectal cancer (CRC). Circular RNAs (circRNAs) are a new type of non-coding RNA that participated in the development of chemoresistance. However, the profiles and effects of circRNAs in 5-fluorouracil (5-Fu) and cisplatin resistance of CRC are still unclear and need to be elucidated. In the present study, the profiles of circRNAs in CRC chemoresistant (HCT8/5-Fu and HCT8/DDP) and chemosensitive (HCT8) cell lines were identified via RNA-sequencing. In total, 48 and 90 differentially expressed (DE)-circRNAs were detected in HCT8/5-Fu and HCT8/DDP cell lines, respectively. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted on the host genes of DE-circRNAs; the results showed that the most significant enrichment pathways in HCT8/5-Fu and HCT8/DDP cell lines were base excision repair and Hippo signaling pathway, respectively. In addition, 11 common DE-circRNAs in the two drug-resistant cell lines (two are upregulated and nine are downregulated) were screened and verified by quantitative real-time PCR; hsacirc_023607 and hsacirc_007420 were found to be the circRNAs with the highest upregulation and downregulation fold changes. However, functional studies showed hsacirc_023607 has no effect on CRC chemoresistance. Therefore, the regulatory networks of targeted miRNAs related to 5-Fu or cisplatin resistance were predicted and constructed, in which hsacirc_002482 was identified as a hub gene, and its overexpression could suppress HCT8/5-Fu and HCT8/DDP cell proliferation and promote cell apoptosis, and enhance cell chemosensitivity. Taken together, these results of the study suggested that hsacirc_002482 may play important roles in chemoresistance of CRC.
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Affiliation(s)
- Fei Yao
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Xiaochen Xiang
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Chuanren Zhou
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Qiyou Huang
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Xiaoying Huang
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Zhufu Xie
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Qiang Wang
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Qingming Wu
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan, China
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40
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Wang F, Zhang Y, Zhou X, Chen X, Xiang J, Fan M, Yu Y, Cai Y, Wu H, Huang S, He N, Hu Z, Ding G, Jin X. Circular RNA CircPPP1CB Suppresses Tumorigenesis by Interacting With the MiR-1307-3p/SMG1 Axis in Human Bladder Cancer. Front Cell Dev Biol 2021; 9:704683. [PMID: 34595165 PMCID: PMC8476764 DOI: 10.3389/fcell.2021.704683] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 08/16/2021] [Indexed: 12/23/2022] Open
Abstract
Circular RNA (circRNA) is a newly discovered endogenous non-coding RNA (ncRNA), which is characterized with a closed circular structure. A growing body of evidence has verified the vital roles of circRNAs in human cancer. In this research, we selected circPPP1CB as a study object by circRNA sequencing and quantitative real-time PCR (qRT-PCR) validation in human bladder cancer (BC). CircPPP1CB is downregulated in BC and is negatively correlated with clinical stages and histological grades. Functionally, circPPP1CB modulated cell growth, metastasis, and epithelial-to-mesenchymal transition (EMT) process in vitro and in vivo. Mechanically, we performed various experiments to verify the circPPP1CB/miR-1307-3p/SMG1 regulatory axis. Taken together, our results demonstrated that circPPP1CB participates in tumor growth, metastasis, and EMT process by interacting with the miR-1307-3p/SMG1 axis, and that circPPP1CB might be a novel therapeutic target and diagnostic biomarker in human BC.
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Affiliation(s)
- Feifan Wang
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yan Zhang
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuejian Zhou
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xianwu Chen
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiayong Xiang
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mengjing Fan
- Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanlan Yu
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yueshu Cai
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hongshen Wu
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shihan Huang
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ning He
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhenghui Hu
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guoqing Ding
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaodong Jin
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Huang Z, Xia H, Liu S, Zhao X, He R, Wang Z, Shi W, Chen W, Kang P, Su Z, Cui Y, Yam JWP, Xu Y. The Mechanism and Clinical Significance of Circular RNAs in Hepatocellular Carcinoma. Front Oncol 2021; 11:714665. [PMID: 34540684 PMCID: PMC8445159 DOI: 10.3389/fonc.2021.714665] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/09/2021] [Indexed: 01/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. In view of the lack of early obvious clinical symptoms and related early diagnostic biomarkers with high specificity and sensitivity, most HCC patients are already at the advanced stages at the time of diagnosis, and most of them are accompanied by distant metastasis. Furthermore, the unsatisfactory effect of the follow-up palliative care contributes to the poor overall survival of HCC patients. Therefore, it is urgent to identify effective early diagnosis and prognostic biomarkers and to explore novel therapeutic approaches to improve the prognosis of HCC patients. Circular RNA (CircRNA), a class of plentiful, stable, and highly conserved ncRNA subgroup with the covalent closed loop, is dysregulated in HCC. Increasingly, emerging evidence have confirmed that dysregulated circRNAs can regulate gene expression at the transcriptional or post-transcriptional level, mediating various malignant biological behaviors of HCC cells, including proliferation, invasion, metastasis, immune escape, stemness, and drug resistance, etc.; meanwhile, they are regarded as potential biomarkers for early diagnosis and prognostic evaluation of HCC. This article reviews the research progress of circRNAs in HCC, expounding the potential molecular mechanisms of dysregulated circRNAs in the carcinogenesis and development of HCC, and discusses those application prospects in the diagnosis and prognosis of HCC.
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Affiliation(s)
- Ziyue Huang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Haoming Xia
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shuqiang Liu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xudong Zhao
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Risheng He
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhongrui Wang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenguang Shi
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wangming Chen
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Pengcheng Kang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhilei Su
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong, SAR China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong, SAR China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
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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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Huang Y, Zhang C, Xiong J, Ren H. Emerging important roles of circRNAs in human cancer and other diseases. Genes Dis 2021; 8:412-423. [PMID: 34179306 PMCID: PMC8209354 DOI: 10.1016/j.gendis.2020.07.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/08/2020] [Accepted: 07/27/2020] [Indexed: 12/14/2022] Open
Abstract
CircRNAs are a large class of endogenous single-stranded RNA that is different from other linear RNA, which are produced by back-splicing and fusion of either exons, introns, or both exon-intron into covalently closed loops. CircRNAs are found in almost all living organisms and have emerged as potentially important players effecting on all life activities. It was characterized by stable structure, resistant to RNA degradation, highly abundance and conservation and tissue-specific expression. Early circRNAs were ignored as a by-product of meaningless abnormally cut RNA and had little biological function. Currently, circRNAs have become a research hotspot due to its special characteristics. CircRNAs could function as miRNA sponges, interfere with splicing and bind to protein to regulate the expression of parental genes and so on. In recent years, an increasing number of studies have revealed that circRNAs are closely related to a series of physiological and pathological processes. Additionally, circRNAs play an important role in the occurrence and development of a variety of diseases, suggesting circRNAs may be as novel indicators or biomarkers for cancer and other diseases with which they are associated. In this article, we review the biogenesis, biological functions of circRNAs and recent advances in circRNAs research in human diseases. Results will provide new insights on the roles and new ideas of circRNAs for the diagnosis and treatment of diseases and possible directions and approach for future circRNA applications.
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Affiliation(s)
- Yong Huang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan Province, 471023, PR China
| | - Cai Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan Province, 471023, PR China
| | - Jianli Xiong
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan Province, 471023, PR China
| | - Hongtao Ren
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan Province, 471023, PR China
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Wang Y, Chen H, Wei X. Circ_0007142 downregulates miR-874-3p-mediated GDPD5 on colorectal cancer cells. Eur J Clin Invest 2021; 51:e13541. [PMID: 33797091 DOI: 10.1111/eci.13541] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 03/05/2021] [Accepted: 03/10/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Ferroptosis is an iron-dependent and oxidative cell death form. Recent studies suggested that circular RNAs (circRNAs) regulated ferroptosis in tumour cells. Circ_0007142 was identified as a carcinogenic molecule in colorectal cancer (CRC), but its function on ferroptosis in CRC remains unknown. METHODS Circ_0007142, microRNA-874-3p (miR-874-3p) and glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) levels were assayed using the quantitative real-time polymerase chain reaction (qRT-PCR). Cell survival and proliferation were measured by Cell Counting Kit-8 (CCK-8) assay. Protein detection was performed by Western blot. Cell apoptosis was analysed by flow cytometry. Ferroptosis was assessed by iron accumulation and oxidative stress. Target binding was evaluated by dual-luciferase reporter assay. In vivo research was conducted by tumour xenograft in mice. RESULTS Circ_0007142 was overexpressed in CRC. After expression inhibition of circ_0007142, proliferation was reduced, while apoptosis and ferroptosis were facilitated in CRC cells. Mechanically, circ_0007142 was found as a miR-874-3p sponge and miR-874-3p inhibitor eliminated the regulation of si-circ_0007142 in CRC cells. MiR-874-3p targeted GDPD5 and upregulation of GDPD5 reversed the miR-874-3p-triggered tumour inhibition and ferroptosis promotion in CRC cells. Moreover, GDPD5 was regulated by the circ_0007142/miR-874-3p axis. Circ_0007142 also affected CRC tumorigenesis in vivo through the regulation of miR-874-3p and GDPD5. CONCLUSION All these findings proved that circ_0007142/miR-874-3p/GDPD5 axis regulated tumorigenesis and ferroptosis of CRC cells. Circ_0007142 might be an available marker for ferroptosis in CRC therapy.
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Affiliation(s)
- Yueqing Wang
- Department of Proctology, Jining Hospital of Traditional Chinese Medicine, Jining, China
| | - Hongshu Chen
- Department of Gastroenterology, Yidu Central Hospital of Weifang, Weifang, China
| | - Xueling Wei
- Department of General Medicine, Jinan Central Hospital (Jinan Central Hospital Affiliated to Shandong University), Jinan, China
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Li L, Xiao C, He K, Xiang G. Circ_0072088 promotes progression of hepatocellular carcinoma by activating JAK2/STAT3 signaling pathway via miR-375. IUBMB Life 2021; 73:1153-1165. [PMID: 34148288 DOI: 10.1002/iub.2520] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/26/2021] [Accepted: 06/08/2021] [Indexed: 11/11/2022]
Abstract
Circular RNAs feature prominently in cancer development. Nonetheless, the role of circ_0072088 in hepatocellular carcinoma (HCC) remains unclear. GEO databases (GSE97332, GSE108724, GSE36915, and GSE33006) were used to screen out the differentially expressed circRNAs, miRNAs, and mRNA in HCC. The expressions of circ_0072088, miR-375, and Janus Kinase 2 (JAK2) mRNA in HCC tissue and cell lines were determined with quantitative real-time polymerase chain reaction. RNase R treatment assay was used to measure the stability of circ_0072088, and subcellular fraction assay was used to detect the localization of circ_0072088. Cell counting kit-8 assay, flow cytometry, and Transwell assay were used to measure proliferation, apoptosis, migration, and invasion of HCC cells. RNA immunoprecipitation and dual-luciferase reporter gene assay were employed for investigating the binding sequence between circ_0072088 and miR-375, as well as miR-375 and JAK2 3'UTR. Western blot assay was used to detect the expression of JAK2 and p-STAT3 after circ_0072088 and miR-375 were selectively regulated. Circ_0072088 and JAK2 mRNA expressions were highly expressed in HCC tissues and cell lines while miR-375 expression was remarkably downregulated. Circ_0072088 was resistant to RNase R treatment and mainly located in the cytoplasm of HCC cells. The transfection of circ_0072088 overexpression plasmid or miR-375 inhibitors promoted the proliferation, migration, and invasion, and inhibited the apoptosis of HCC cells, whereas transfection of circ_0072088 siRNA or miR-375 mimics exerted opposite effects. Besides, miR-375 was confirmed as a target of circ_0072088 and miR-375 could further downregulate the expression of JAK2. MiR-375 mimics could reverse the upregulation of JAK2 and p-STAT3 protein induced by circ_0072088 overexpression. Circ_0072088 can enhance the proliferation, migration, and invasion, and impede apoptosis of HCC cells. Mechanistically, circ_0072088 activates JAK2/STAT3 signaling pathway by serving as a molecular sponge of miR-375.
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Affiliation(s)
- Liheng Li
- Department of Intervention, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
| | - Chengjiang Xiao
- Department of Intervention, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
| | - Ke He
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
| | - Guoan Xiang
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
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Chen Q, Guo H, Zong Y, Zhao X. Curcumin restrains hepatocellular carcinoma progression depending on the regulation of the circ_0078710/miR-378b/PRIM2 axis. J Recept Signal Transduct Res 2021; 42:313-324. [PMID: 34139933 DOI: 10.1080/10799893.2021.1936554] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Curcumin has shown anti-tumor activity in multiple malignancies. The aim of our study was to explore the molecular mechanism behind the anti-tumor activity of curcumin in hepatocellular carcinoma (HCC). METHODS The proliferation, migration, invasion, and apoptosis were analyzed by 5-ethynyl-2'-deoxyuridine (EDU) assay, transwell migration assay, transwell invasion assay, and flow cytometry. Western blot assay and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were conducted to analyze protein and RNA expression. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA-pull down assay were performed to confirm the interaction between microRNA-378b (miR-378b) and circular RNA_0078710 (circ_0078710) or DNA primase, polypeptide 2 (PRIM2). Tumor xenograft assay was conducted to assess the roles of curcumin and circ_0078710 in vivo. RESULTS Curcumin stimulation restrained the proliferation, migration, and invasion, and triggered the apoptosis of HCC cells. Curcumin down-regulated the expression of circ_0078710 in HCC cells in a dose-dependent manner. Circ_0078710 knockdown aggravated curcumin-mediated anti-tumor effects in HCC cells. Circ_0078710 acted as a molecular sponge for miR-378b. Circ_0078710 interference-induced effects in curcumin-stimulated HCC cells were partly abolished by the silence of miR-378b. MiR-378b bound to the 3' untranslated region (3'UTR) of PRIM2. PRIM2 overexpression partly reversed circ_0078710 interference-mediated influences in curcumin-treated HCC cells. Circ_0078710 silencing aggravated curcumin-mediated suppressive effect in tumor growth in vivo. CONCLUSIONS Circ_0078710 silencing aggravated curcumin-mediated anti-tumor effects through mediating the miR-378b/PRIM2 signaling in HCC cells.
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Affiliation(s)
- Qian Chen
- Department of Traditional Chinese Medicine, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian City, Jiangsu Province, China
| | - Hai Guo
- Department of Traditional Chinese Medicine, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian City, Jiangsu Province, China
| | - Yan Zong
- Department of Traditional Chinese Medicine, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian City, Jiangsu Province, China
| | - Xiaofeng Zhao
- Department of Traditional Chinese Medicine, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian City, Jiangsu Province, China
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Liu S, Li Q, Ma Y, Corpe C, Wang J. Circular RNAs as novel potential biomarkers for pancreatic cancer. J Cancer 2021; 12:4604-4615. [PMID: 34149924 PMCID: PMC8210554 DOI: 10.7150/jca.58640] [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: 01/25/2021] [Accepted: 05/19/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer (PaCa) is the fourth leading cause of cancer-related deaths in the United States, and the vast majority of these malignancies are pancreatic ductal adenocarcinomas (PDAC), but there is still a lack of early detection biomarkers for PaCa. Unlike linear RNAs, circRNAs form covalently closed continuous loops and can act as mammalian gene regulators. They may be diagnostic or predictive biomarkers for some tumors, also be novel potential therapeutic targets in different diseases. This review focuses on (1) the biogenesis of circRNAs, RNA binding proteins (RBPs) and complementary sequences of circRNAs; (2) the characteristics of circRNAs which allow them to interact with miRNAs; (3) the roles of circRNAs playing in the regulation of gene expression, cell behavior and cancer, and their potential role as novel biomarkers and therapeutic targets in pancreatic cancer.
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Affiliation(s)
- Shanshan Liu
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai 201508, China
| | - Qiuyue Li
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai 201508, China
| | - Yan Ma
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai 201508, China
| | - Christopher Corpe
- King's College London, London, Nutritional Science Department, 150 Stamford street, waterloo, London, SE19NH, United Kingdom
| | - Jin Wang
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai 201508, China
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Hussen BM, Honarmand Tamizkar K, Hidayat HJ, Taheri M, Ghafouri-Fard S. The role of circular RNAs in the development of hepatocellular carcinoma. Pathol Res Pract 2021; 223:153495. [PMID: 34051512 DOI: 10.1016/j.prp.2021.153495] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/20/2021] [Accepted: 05/20/2021] [Indexed: 12/30/2022]
Abstract
Circular RNAs (circRNAs) are a group of regulatory non-coding transcripts, which partake in the pathobiology of hepatocellular carcinoma (HCC). Numerous micro-array based investigations have discovered aberrant expression of circRNAs in HCC samples in comparison with para-cancerous sections. Furthermore, a number of in vitro and in vivo experimentations have aimed at understanding the molecular pathways of circRNAs contribution in the evolution of HCC. CircRNAs have interplay with a number of transcription factors such as ZEB1 that possibly mediates the effects of these transcripts in the epithelial-mesenchymal transition. Moreover, circRNAs functionally interact with miRNAs. CircRNA_0000502/ miR-124, circ_0001955/ miR-145-5p, circ_0001955/ miR-516a-5p and hsa_circ_0001955/miR-145-5p are examples of such interactions in the context of HCC. CircRNAs not only predict the course of HCC, but also, they can differentiate HCC samples from non-malignant liver tissues. In this review article, we have provided an inclusive summary of researches that quantified circRNAs profile in HCC. We also provide evidence for application of circRNAs as HCC biomarkers.
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Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Kasra Honarmand Tamizkar
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahadddin University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Cao Y, Tao Q, Kao X, Zhu X. Hsa-circRNA-103809 Promotes Hepatocellular Carcinoma Development via MicroRNA-1270/PLAG1 Like Zinc Finger 2 Axis. Dig Dis Sci 2021; 66:1524-1532. [PMID: 32683589 DOI: 10.1007/s10620-020-06416-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 06/14/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death in the worldwide. A great number of reports manifested that circular RNA hsa-circRNA-103809 (circRNA-103809) could work in several cancers. AIMS This study aimed to explore the function and mechanism of circRNA-103809 in HCC. METHODS Gene expressions were detected by quantitative real-time polymerase chain reaction. Colony formation, cell counting kit-8, transwell and wound healing assays were implemented to check the role of circRNA-103809 in HCC. Subcellular fractionation analysis was designed to figure out the cellular location of circRNA-103809. Luciferase reporter assay and RNA pull down assay were employed to verify the relationships among RNAs. RESULTS CircRNA-103809 was highly expressed in HCC cell lines. After interfering circRNA-103809, the proliferation, migration, invasion and epithelial-to-mesenchymal transition process were all hindered in HCC cells. Significantly, circRNA-103809 competed with PLAG1 like zinc finger 2 (PLAGL2) for binding with microRNA-1270 (miR-1270), which formulated a competing endogenous RNA network in HCC. Thereafter, we verified the tumor-facilitating effect of circRNA-103809/miR-1270/PLAGL2 axis on biological behaviors of HCC cells. CONCLUSION Hsa-circRNA-103809 promoted development of HCC via sequestering miR-1270 and up-regulating PLAGL2.
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Affiliation(s)
- Yajuan Cao
- Department of General Surgery, Nanjing Drum Tower Hospital, No. 321 Zhongshan Road, Nanjing, 210000, Jiangsu, China
| | - Qingsong Tao
- Department of General Surgery, Zhongda Hospital, Clinical School of Southeast University, Nanjing, 210000, Jiangsu, China
| | - Xiaoming Kao
- Department of General Surgery, Jinling Hospital, Nanjing Medical School of Nanjing University, Nanjing, 210000, Jiangsu, China
| | - Xinhua Zhu
- Department of General Surgery, Nanjing Drum Tower Hospital, No. 321 Zhongshan Road, Nanjing, 210000, Jiangsu, China.
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CircRNAs: a new target for the diagnosis and treatment of digestive system neoplasms. Cell Death Dis 2021; 12:205. [PMID: 33627631 PMCID: PMC7904779 DOI: 10.1038/s41419-021-03495-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/27/2021] [Accepted: 02/01/2021] [Indexed: 02/06/2023]
Abstract
A circRNA is a type of endogenous noncoding RNA that consists of a closed circular RNA molecule formed by reverse splicing; these RNAs are widely distributed in a variety of biological cells. In contrast to linear RNAs, circRNAs have no 5′ cap or 3′ poly(A) tail. They have a stable structure, a high degree of conservation, and high stability, and they are richly and specifically expressed in certain tissues and developmental stages. CircRNAs play a very important role in the occurrence and progression of malignant tumors. According to their origins, circRNAs can be divided into four types: exon-derived circRNAs (ecRNAs), intron-derived circRNAs (ciRNAs), circRNAs containing both exons and introns (EIciRNAs) and intergenic circRNAs. A large number of studies have shown that circRNAs have a variety of biological functions, participate in the regulation of gene expression and play an important role in the occurrence and progression of tumors. In this paper, the structure and function of circRNAs are reviewed, along with their biological role in malignant tumors of the digestive tract, in order to provide a reference for the diagnosis and treatment of digestive system neoplasms.
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