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1
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Han Z, Yu X, Wang C, Song X, Zhong X, Guo R, Yu W, Luo C. Circular RNA circHSPA8 Aggravates Metastasis by Acting as a Competitive Inhibitor of miR-195-5p to Upregulate WNT3A Expression in Breast Cancer. J Cell Mol Med 2025; 29:e70499. [PMID: 40099939 PMCID: PMC11915588 DOI: 10.1111/jcmm.70499] [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: 08/22/2024] [Revised: 03/09/2025] [Accepted: 03/10/2025] [Indexed: 03/20/2025] Open
Abstract
Circular RNA (circRNA) plays a vital role in the tumorigenicity and progression of cancer by regulating various biological behaviours. It acts as a microRNA sponge, disrupting transcription and the abnormal expression of oncogenes. Hsa_circ_0024715, a circRNA generated from cyclization at specific sites of the HSPA8 gene, has been found to be highly expressed in breast cancer (BC) tissue based on non-coding RNA high-throughput sequencing. However, its functions remain poorly understood. In this study, we performed qPCR to evaluate the expression of circHSPA8 in BC tissues. Survival analysis in a prospective cohort revealed that high expression of circHSPA8 is associated with poor prognosis and lymphoid node metastasis. Overexpression of circHSPA8 in MCF-7 cells significantly enhanced their proliferative and invasive abilities, whereas knockdown of circHSPA8 in MDA-MB-231 cells significantly reduced their proliferative and invasive abilities. We found that circHSPA8 can promote epithelial-mesenchymal transition (EMT) in BC cells, primarily by upregulating the expression of WNT3A. This process depends on the sponging and inhibition of miR-195-5p, which suppresses the proliferation, invasion, and metastasis of BC cells. In vivo experiments further confirmed that circHSPA8 can promote the intravasation and extravasation of BC cells as well as the formation of metastatic lesions in the lungs. In summary, these data demonstrate that circHSPA8 promotes EMT by acting as a competitive inhibitor of miR-195-5p to upregulate the expression of WNT3A in BC, suggesting that dysregulation of circRNA in BC might be a pathological factor and potential therapeutic target.
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Affiliation(s)
- Zhuoying Han
- Department of Central Laboratory, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, China
| | - Xiaojuan Yu
- Department of Clinical Oncology, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, China
| | - Chenlong Wang
- Department of Central Laboratory, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, China
| | - Xiaoyu Song
- Department of Central Laboratory, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, China
| | - Xiaomin Zhong
- Department of Clinical Oncology, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, China
| | - Renhua Guo
- Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Weiyong Yu
- Department of Clinical Oncology, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, China
| | - Chao Luo
- Department of Central Laboratory, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, China
- Biological Sample Bank, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, China
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Xu Y, Qiu S, Shen Z, Chen J. circTUBD1-hnRNPK Regulates the Proliferation and Migration of LSCC by Targeting CCAR1. Cancer Med 2025; 14:e70834. [PMID: 40130381 PMCID: PMC11933862 DOI: 10.1002/cam4.70834] [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: 12/06/2024] [Revised: 03/18/2025] [Accepted: 03/19/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Laryngeal squamous cell carcinoma (LSCC) is one of the most prevalent malignancies of the head and neck region. Circular RNAs (circRNAs) have been found to exhibit abnormal expression patterns in various tumors and play pivotal roles in tumorigenesis and tumor progression. METHODS Functional assays assessed proliferation, migration, and invasion. Mechanistic studies were performed to explore the interaction between circTUBD1 and heterogeneous nuclear ribonucleoprotein K (hnRNPK), as well as its regulation of Cell Cycle and Apoptosis Regulator 1 (CCAR1). In vivo experiments confirmed circTUBD1's role in tumor growth and metastasis. RESULTS We discovered that circTUBD1 is significantly upregulated in LSCC and promotes the proliferation, invasion, and migration of LSCC cells. circTUBD1 forms a circRNA-protein complex with hnRNPK and facilitates LSCC progression by regulating CCAR1. Furthermore, in vivo experiments in mice demonstrated that silencing circTUBD1 inhibits the proliferation and metastasis of LSCC. CONCLUSIONS This study provides evidence that circTUBD1 is a potential tumor marker for LSCC and underscores the therapeutic potential of targeting circTUBD1 in this cancer type.
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Affiliation(s)
- Yufeng Xu
- Department of Otorhinolaryngology‐Head and Neck SurgeryThe Affiliated LiHuiLi Hospital of Ningbo UniversityNingboChina
| | - Shijie Qiu
- Department of Otorhinolaryngology‐Head and Neck SurgeryThe Affiliated LiHuiLi Hospital of Ningbo UniversityNingboChina
| | - Zhisen Shen
- Department of Otorhinolaryngology‐Head and Neck SurgeryThe Affiliated LiHuiLi Hospital of Ningbo UniversityNingboChina
| | - Jingjing Chen
- Department of Otorhinolaryngology‐Head and Neck SurgeryThe Affiliated LiHuiLi Hospital of Ningbo UniversityNingboChina
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Fan Z, Yuan X, Yuan Y. Circular RNAs in coronary heart disease: From molecular mechanism to promising clinical application (Review). Int J Mol Med 2025; 55:11. [PMID: 39513584 PMCID: PMC11573316 DOI: 10.3892/ijmm.2024.5452] [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: 08/06/2024] [Accepted: 10/15/2024] [Indexed: 11/15/2024] Open
Abstract
Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide, posing a substantial public health burden. Despite advancements in treatment, the complex etiology of CHD necessitates ongoing exploration of novel diagnostic markers and therapeutic targets. Circular RNAs (circRNAs), a distinct class of non‑coding RNAs with a covalently closed loop structure, have emerged as significant regulators in various diseases, including CHD. Their high stability, tissue‑specific expression and evolutionary conservation underscore their potential as biomarkers and therapeutic agents in CHD. This review discusses the current knowledge on circRNAs in the context of CHD and explores the molecular mechanisms by which circRNAs influence the pathophysiology of CHD, including cardiomyocyte death, endothelial injury, vascular dysfunction and inflammation. It also summarizes the emerging evidence highlighting the differential expression of circRNAs in patients with CHD and their potential utilities as non‑invasive diagnostic and prognostic biomarkers and therapeutic targets for this disease.
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Affiliation(s)
- Zengguang Fan
- Department of Cardiology, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330006, P.R. China
| | - Xingxing Yuan
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, Heilongjiang 150006, P.R. China
| | - Ye Yuan
- Department of Cardiology, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330006, P.R. China
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4
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Saha P, Sharma SS. RNA Interference Unleashed: Current Perspective of Small Interfering RNA (siRNA) Therapeutics in the Treatment of Neuropathic Pain. ACS Pharmacol Transl Sci 2024; 7:2951-2970. [PMID: 39416962 PMCID: PMC11475279 DOI: 10.1021/acsptsci.4c00329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 08/12/2024] [Accepted: 09/09/2024] [Indexed: 10/19/2024]
Abstract
Neuropathic pain (NP) is one of the debilitating pain phenotypes that leads to the progressive degeneration of the central as well as peripheral nervous system. NP is often associated with hyperalgesia, allodynia, paresthesia, tingling, and burning sensations leading to disability, motor dysfunction, and compromised psychological state of the patients. Most of the conventional pharmacological agents are unable to improve the devastating conditions of pain because of their limited efficacy, undesirable side effects, and multifaceted pathophysiology of the diseased condition. A rapid rise in new cases of NP warrants further research for identifying the potential novel therapeutic modalities for treating NP. Recently, small interfering RNA (siRNA) approach has shown therapeutic potential in many disease conditions including NP. Delivery of siRNAs led to potential and selective downregulation of target mRNA and abolished the pain-related behaviors/pathophysiological pain response. The crucial role of siRNA in the treatment of NP by considering all of the pathways associated with NP that could be managed by siRNA therapeutics has been discussed. However, their therapeutic use is limited by several hurdles such as instability in systemic circulation due to their negative charge and membrane impermeability, off-target effects, immunogenicity, and inability to reach the intended site of action. This review also emphasizes several strategies and techniques to overcome these hurdles for translating these therapeutic siRNAs from bench to bedside by opening a new avenue for obtaining a potential therapeutic approach for treating NP.
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Affiliation(s)
- Priya Saha
- Department
of Pharmacology and Toxicology, National
Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab 160062, India
| | - Shyam S. Sharma
- Department
of Pharmacology and Toxicology, National
Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab 160062, India
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5
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Liao L, Chen J, Peng S. hsa_circ_0000047 targeting miR-6720-5p/CYB5R2 axis alleviates inflammation and angiogenesis in diabetic retinopathy. Arch Physiol Biochem 2024; 130:537-545. [PMID: 36971486 DOI: 10.1080/13813455.2023.2190055] [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: 09/12/2022] [Accepted: 03/01/2023] [Indexed: 03/29/2023]
Abstract
Context: Diabetic retinopathy (DR) is a common complication of diabetes mellitus (DM). Circular RNAs (circRNAs) act as key regulators of DR development by regulating inflammation and angiogenesis.Objective: This study aimed to elucidate the function and mechanism of hsa_circ_0000047 in DR.Materials and methods: High glucose (HG) was used to induce human retinal microvascular endothelial cells (hRMECs) to construct a DR model in vitro. Qualitative real-time polymerase chain reaction (qRT-PCR) or western blotting were used to detected the levels of hsa_circ_0000047, miR-6720-5p, and CYB5R2 in DR and HG-indeced hRMECs. Cell functional experiments were performed to detect the change of viability, inflammation, migration, invasion, and angiogenesis of HG-induced hRMECs. Besides, the correlation between miR-6720-5p and hsa_circ_0000047/CYB5R2 was confirmed by luciferase assay and Pearson correlation analysis.Results: hsa_circ_0000047 and CYB5R2 were downregulated in DR, whereas miR-6720-5p was upregulated in DR. Cell functional experiments showed that hsa_circ_0000047 overexpression restrained viability, inflammation, migration, invasion, and angiogenesis of HG-induced hRMECs. Regarding mechanism, hsa_circ_0000047 could sponge miR-6720-5p to regulate CYB5R2 expression in hRMECs. Additionally, CYB5R2 knockdown reversed the effects of hsa_circ_0000047 overexpression on HG-induced hRMECs.Conclusion: Our study revealed that hsa_circ_0000047 alleviated inflammation and angiogenesis in HG-induced hRMECs by targeting the miR-6720-5p/CYB5R2 axis, which may be a novel biomarker for DR therapy.
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Affiliation(s)
- Lin Liao
- Department of Ophthalmology, Wuhan Fourth Hospital, Puai Hospital, Wuhan, China
| | - Jinpeng Chen
- Department of Ophthalmology, Ezhou Central Hospital, Ezhou, China
| | - Sheng Peng
- Department of Cardiology, Wuhan Fourth Hospital, Puai Hospital, Wuhan, China
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6
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Conn VM, Chinnaiyan AM, Conn SJ. Circular RNA in cancer. Nat Rev Cancer 2024; 24:597-613. [PMID: 39075222 DOI: 10.1038/s41568-024-00721-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/13/2024] [Indexed: 07/31/2024]
Abstract
Over the past decade, circular RNA (circRNA) research has evolved into a bona fide research field shedding light on the functional consequence of this unique family of RNA molecules in cancer. Although the method of formation and the abundance of circRNAs can differ from their cognate linear mRNA, the spectrum of interacting partners and their resultant cellular functions in oncogenesis are analogous. However, with 10 times more diversity in circRNA variants compared with linear RNA variants, combined with their hyperstability in the cell, circRNAs are equipped to influence every stage of oncogenesis. This is an opportune time to address the breadth of circRNA in cancer focused on their spatiotemporal expression, mutations in biogenesis factors and contemporary functions through each stage of cancer. In this Review, we highlight examples of functional circRNAs in specific cancers, which satisfy critical criteria, including their physical co-association with the target and circRNA abundance at stoichiometrically valid quantities. These considerations are essential to develop strategies for the therapeutic exploitation of circRNAs as biomarkers and targeted anticancer agents.
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Affiliation(s)
- Vanessa M Conn
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, South Australia, Australia
| | - Arul M Chinnaiyan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Urology, University of Michigan, Ann Arbor, MI, USA
| | - Simon J Conn
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, South Australia, Australia.
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7
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Huang Z, Chen P, Liu Y. WTAP-mediated m6A modification of circ_0032463 promotes osteosarcoma progression by sponging miR-145-5p and regulating GFRA1 expression. J Biochem Mol Toxicol 2024; 38:e23833. [PMID: 39243199 DOI: 10.1002/jbt.23833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 08/05/2024] [Accepted: 08/22/2024] [Indexed: 09/09/2024]
Abstract
Osteosarcoma (OS) is the most frequent bone malignancy in humans. Previous evidence suggest that circ_0032463 is an oncogenic circular RNA (circRNA) in various cancers, including OS. However, the molecular mechanism of circ_0032463 involved in OS is still unclear. Circ_0032463, microRNA-145-5p (miR-145-5p), GDNF receptor alpha 1 (GFRA1), and Wilms tumor 1-associated protein (WTAP) levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation, apoptosis, migration, invasion, and angiogenesis were analyzed using 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and tube formation assays. Western blot analysis was performed to measure matrix metalloproteinase 2 (MMP2), MMP9, GFRA1, and WTAP protein levels. Binding between miR-145-5p and circ_0032463 or GFRA1 was confirmed using a dual-luciferase reporter and pull-down assay. The biological role of circ_0032463 on OS cell growth was also analyzed using a xenograft tumor model in vivo. Methylated RNA immunoprecipitation assay validated the interaction between WTAP and circ_0032463. Circ_0032463, GFRA1, and WTAP levels were increased, and miR-145-5p was decreased in OS tissues and cells. Circ_0032463 deficiency might hinder OS cell proliferation, migration, invasion, angiogenesis, and promote apoptosis in vitro. Mechanically, circ_0032463 worked as a miR-145-5p sponge to increase GFRA1 expression. Repression of circ_0032463 knockdown on tumor cell growth was proved in vivo. Besides, N6-methyladenosine (m6A) modification facilitates the biogenesis of circ_0032463. Taken together, m6A-mediated biogenesis of circ_0032463 facilitates OS cell malignant biological behavior partly via regulating the miR-145-5p/GFRA1 axis, suggesting a promising molecular marker for OS treatment.
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Affiliation(s)
- Zhong Huang
- Orthopedic Center, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China
| | - Pengcheng Chen
- Orthopedic Center, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China
| | - Yiheng Liu
- Orthopedic Center, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China
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8
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Peña-Flores JA, Muela-Campos D, Guzmán-Medrano R, Enríquez-Espinoza D, González-Alvarado K. Functional Relevance of Extracellular Vesicle-Derived Long Non-Coding and Circular RNAs in Cancer Angiogenesis. Noncoding RNA 2024; 10:12. [PMID: 38392967 PMCID: PMC10891584 DOI: 10.3390/ncrna10010012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/02/2024] [Accepted: 02/04/2024] [Indexed: 02/25/2024] Open
Abstract
Extracellular vesicles (EVs) are defined as subcellular structures limited by a bilayer lipid membrane that function as important intercellular communication by transporting active biomolecules, such as proteins, amino acids, metabolites, and nucleic acids, including long non-coding RNAs (lncRNAs). These cargos can effectively be delivered to target cells and induce a highly variable response. LncRNAs are functional RNAs composed of at least 200 nucleotides that do not code for proteins. Nowadays, lncRNAs and circRNAs are known to play crucial roles in many biological processes, including a plethora of diseases including cancer. Growing evidence shows an active presence of lnc- and circRNAs in EVs, generating downstream responses that ultimately affect cancer progression by many mechanisms, including angiogenesis. Moreover, many studies have revealed that some tumor cells promote angiogenesis by secreting EVs, which endothelial cells can take up to induce new vessel formation. In this review, we aim to summarize the bioactive roles of EVs with lnc- and circRNAs as cargo and their effect on cancer angiogenesis. Also, we discuss future clinical strategies for cancer treatment based on current knowledge of circ- and lncRNA-EVs.
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Affiliation(s)
- José A. Peña-Flores
- Doctoral Program in Biomedical and Stomatological Sciences, Faculty of Dentistry, Autonomous University of Chihuahua, Chihuahua 31000, Mexico; (D.M.-C.); (R.G.-M.); (D.E.-E.); (K.G.-A.)
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9
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Meng L, Wu H, Wu J, Ding P, He J, Sang M, Liu L. Mechanisms of immune checkpoint inhibitors: insights into the regulation of circular RNAS involved in cancer hallmarks. Cell Death Dis 2024; 15:3. [PMID: 38177102 PMCID: PMC10766988 DOI: 10.1038/s41419-023-06389-5] [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: 09/15/2023] [Revised: 12/06/2023] [Accepted: 12/11/2023] [Indexed: 01/06/2024]
Abstract
Current treatment strategies for cancer, especially advanced cancer, are limited and unsatisfactory. One of the most substantial advances in cancer therapy, in the last decades, was the discovery of a new layer of immunotherapy approach, immune checkpoint inhibitors (ICIs), which can specifically activate immune cells by targeting immune checkpoints. Immune checkpoints are a type of immunosuppressive molecules expressed on immune cells, which can regulate the degree of immune activation and avoid autoimmune responses. ICIs, such as anti-PD-1/PD-L1 drugs, has shown inspiring efficacy and broad applicability across various cancers. Unfortunately, not all cancer patients benefit remarkably from ICIs, and the overall response rates to ICIs remain relatively low for most cancer types. Moreover, the primary and acquired resistance to ICIs pose serious challenges to the clinical application of cancer immunotherapy. Thus, a deeper understanding of the molecular biological properties and regulatory mechanisms of immune checkpoints is urgently needed to improve clinical options for current therapies. Recently, circular RNAs (circRNAs) have attracted increasing attention, not only due to their involvement in various aspects of cancer hallmarks, but also for their impact on immune checkpoints in shaping the tumor immune microenvironment. In this review, we systematically summarize the current status of immune checkpoints in cancer and the existing regulatory roles of circRNAs on immune checkpoints. Meanwhile, we also aim to settle the issue in an evidence-oriented manner that circRNAs involved in cancer hallmarks regulate the effects and resistance of ICIs by targeting immune checkpoints.
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Affiliation(s)
- Lingjiao Meng
- Department of Tumor Immunotherapy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050035, China
- Research Center and Tumor Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050017, China
| | - Haotian Wu
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011, China
| | - Jiaxiang Wu
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011, China
| | - Ping'an Ding
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011, China
| | - Jinchen He
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011, China
| | - Meixiang Sang
- Research Center and Tumor Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050017, China.
- Science and Education Department, Shanghai Electric Power Hospital, Shanghai, 20050, China.
| | - Lihua Liu
- Department of Tumor Immunotherapy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050035, China.
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10
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Szymanowska A, Rodriguez-Aguayo C, Lopez-Berestein G, Amero P. Non-Coding RNAs: Foes or Friends for Targeting Tumor Microenvironment. Noncoding RNA 2023; 9:52. [PMID: 37736898 PMCID: PMC10514839 DOI: 10.3390/ncrna9050052] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 09/23/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are a group of molecules critical for cell development and growth regulation. They are key regulators of important cellular pathways in the tumor microenvironment. To analyze ncRNAs in the tumor microenvironment, the use of RNA sequencing technology has revolutionized the field. The advancement of this technique has broadened our understanding of the molecular biology of cancer, presenting abundant possibilities for the exploration of novel biomarkers for cancer treatment. In this review, we will summarize recent achievements in understanding the complex role of ncRNA in the tumor microenvironment, we will report the latest studies on the tumor microenvironment using RNA sequencing, and we will discuss the potential use of ncRNAs as therapeutics for the treatment of cancer.
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Affiliation(s)
- Anna Szymanowska
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; (A.S.); (C.R.-A.); (G.L.-B.)
| | - Cristian Rodriguez-Aguayo
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; (A.S.); (C.R.-A.); (G.L.-B.)
- Center for RNA Interference and Non-Coding RNA, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; (A.S.); (C.R.-A.); (G.L.-B.)
- Center for RNA Interference and Non-Coding RNA, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Paola Amero
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; (A.S.); (C.R.-A.); (G.L.-B.)
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11
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Li J, Song Y, Cai H, Zhou B, Ma J. Roles of circRNA dysregulation in esophageal squamous cell carcinoma tumor microenvironment. Front Oncol 2023; 13:1153207. [PMID: 37384299 PMCID: PMC10299836 DOI: 10.3389/fonc.2023.1153207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 05/30/2023] [Indexed: 06/30/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the most prevalent histological esophageal cancer characterized by advanced diagnosis, metastasis, resistance to treatment, and frequent recurrence. In recent years, numerous human disorders such as ESCC, have been linked to abnormal expression of circular RNAs (circRNAs), suggesting that they are fundamental to the intricate system of gene regulation that governs ESCC formation. The tumor microenvironment (TME), referring to the area surrounding the tumor cells, is composed of multiple components, including stromal cells, immune cells, the vascular system, extracellular matrix (ECM), and numerous signaling molecules. In this review, we briefly described the biological purposes and mechanisms of aberrant circRNA expression in the TME of ESCC, including the immune microenvironment, angiogenesis, epithelial-to-mesenchymal transition, hypoxia, metabolism, and radiotherapy resistance. As in-depth research into the processes of circRNAs in the TME of ESCC continues, circRNAs are promising therapeutic targets or delivery systems for cancer therapy and diagnostic and prognostic indicators for ESCC.
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Affiliation(s)
- Jingyi Li
- Department of Clinical Laboratory, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuxia Song
- Department of Reproductive Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Huihong Cai
- Department of Clinical Laboratory, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Bo Zhou
- Medical Research Center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jun Ma
- Department of Clinical Laboratory, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Samavarchi Tehrani S, Esmaeili F, Shirzad M, Goodarzi G, Yousefi T, Maniati M, Taheri-Anganeh M, Anushiravani A. The critical role of circular RNAs in drug resistance in gastrointestinal cancers. Med Oncol 2023; 40:116. [PMID: 36917431 DOI: 10.1007/s12032-023-01980-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 02/20/2023] [Indexed: 03/16/2023]
Abstract
Nowadays, drug resistance (DR) in gastrointestinal (GI) cancers, as the main reason for cancer-related mortality worldwide, has become a serious problem in the management of patients. Several mechanisms have been proposed for resistance to anticancer drugs, including altered transport and metabolism of drugs, mutation of drug targets, altered DNA repair system, inhibited apoptosis and autophagy, cancer stem cells, tumor heterogeneity, and epithelial-mesenchymal transition. Compelling evidence has revealed that genetic and epigenetic factors are strongly linked to DR. Non-coding RNA (ncRNA) interferences are the most crucial epigenetic alterations explored so far, and among these ncRNAs, circular RNAs (circRNAs) are the most emerging members known to have unique properties. Due to the absence of 5' and 3' ends in these novel RNAs, the two ends are covalently bonded together and are generated from pre-mRNA in a process known as back-splicing, which makes them more stable than other RNAs. As far as the unique structure and function of circRNAs is concerned, they are implicated in proliferation, migration, invasion, angiogenesis, metastasis, and DR. A clear understanding of the molecular mechanisms responsible for circRNAs-mediated DR in the GI cancers will open a new window to the management of GI cancers. Hence, in the present review, we will describe briefly the biogenesis, multiple features, and different biological functions of circRNAs. Then, we will summarize current mechanisms of DR, and finally, discuss molecular mechanisms through which circRNAs regulate DR development in esophageal cancer, pancreatic cancer, gastric cancer, colorectal cancer, and hepatocellular carcinoma.
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Affiliation(s)
- Sadra Samavarchi Tehrani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fataneh Esmaeili
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Shirzad
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Golnaz Goodarzi
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tooba Yousefi
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmood Maniati
- Department of English, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Amir Anushiravani
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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13
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Cheng L, Liu Z, Xia J. New insights into circRNA and its mechanisms in angiogenesis regulation in ischemic stroke: a biomarker and therapeutic target. Mol Biol Rep 2023; 50:829-840. [PMID: 36331748 DOI: 10.1007/s11033-022-07949-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 09/14/2022] [Indexed: 11/06/2022]
Abstract
Ischemic stroke accounts for about 71% of strokes worldwide. Due to limited recommended therapeutics for ischemic stroke, more attention is focused on angiogenesis in ischemic stroke. Not long after ischemic stroke, angiogenesis arises and is vital for the prognosis. Various pro-angiogenic, anti-angiogenic factors and their downstream pathways engage in angiogenesis regulation. CircRNAs are differentially expressed after ischemic stroke. Up to now, circRNAs have been found to exert many functions in regulating apoptosis, autophagy, proliferation, and differentiation of neurons and neural stem cells mainly as miRNAs sponges or proteins decoy. Thus, many circRNAs are considered promising biomarkers or therapeutic targets for ischemic stroke. Besides, circRNAs participate in the modulation of endothelial-mesenchymal transition and blood-brain barrier maintenance. Moreover, circRNAs play significant roles in endothelial dysfunction concerning inflammation responses, apoptosis, proliferation, and migration. They correlate with many angiogenesis-related signaling pathways and genes via the circRNA/miRNA/mRNA network. Novel insights into circRNAs significance in angiogenesis regulation in ischemic stroke could be provided for further researches on the clinical application of circRNAs in ischemic stroke.
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Affiliation(s)
- Liuyang Cheng
- Department of Neurology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, P.R. China
| | - Zeyu Liu
- Department of Neurology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, P.R. China
| | - Jian Xia
- Department of Neurology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, P.R. China.
- Clinical Research Center for Cerebrovascular Disease of Hunan Province, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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14
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Hussen BM, Abdullah SR, Hama Faraj GS, Rasul MF, Salihi A, Ghafouri-Fard S, Taheri M, Mokhtari M. Exosomal circular RNA: a signature for lung cancer progression. Cancer Cell Int 2022; 22:378. [PMID: 36457039 PMCID: PMC9714134 DOI: 10.1186/s12935-022-02793-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 11/15/2022] [Indexed: 12/03/2022] Open
Abstract
Membrane vesicles having a diameter of 30-150 nm are known as exosomes. Several cancer types secrete exosomes, which may contain proteins, circular RNAs (circRNAs), microRNAs, or DNA. CircRNAs are endogenous RNAs that do not code for proteins and can create continuous and covalently closed loops. In cancer pathogenesis, especially metastasis, exosomal circRNAs (exo-circRNAs) have a crucial role mainly due to the frequently aberrant expression levels within tumors. However, neither the activities nor the regulatory mechanisms of exo-circRNAs in advancing lung cancer (LC) are obvious. A better understanding of the regulation and network connections of exo-circRNAs will lead to better treatment for LCs. The main objective of the current review is to highlight the functions and mechanisms of exo-circRNAs in LC and assess the relationships between exo-circRNA dysregulation and LC progression. In addition, underline the possible therapeutic targets based on exo-circRNA modulating.
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Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq
- Medical Laboratory Science, Lebanese French University, Erbil, Kurdistan Region, Iraq
| | - Snur Rasool Abdullah
- Medical Laboratory Science, Lebanese French University, Erbil, Kurdistan Region, Iraq
| | - Goran Sedeeq Hama Faraj
- Department of Medical Laboratory Science, Komar University of Science and Technology, Sulaymaniyah, Iraq
| | - Mohammed Fatih Rasul
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Abbas Salihi
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region, Iraq
- Department of Biomedical Sciences, Cihan University-Erbil, Kurdistan Region, Erbil, 44001, Iraq
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Institute of Human Genetics, Jena University Hospital, Jena, Germany.
| | - Majid Mokhtari
- Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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15
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CircNRIP1 Exerts Oncogenic Functions in Papillary Thyroid Carcinoma by Sponging miR-653-5p and Regulating PBX3 Expression. JOURNAL OF ONCOLOGY 2022; 2022:2081501. [PMID: 35646117 PMCID: PMC9135513 DOI: 10.1155/2022/2081501] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/18/2022] [Accepted: 04/22/2022] [Indexed: 12/04/2022]
Abstract
Background Circular RNA circ_0004771 (termed circNRIP1) was identified by RNA-Seq previously and was elevated in papillary thyroid carcinoma (PTC) tissues. A series of studies also showed that circNRIP1 was upregulated in some tumors and could promote the malignant progression of tumors. This research intended to focus on the role of circNRIP1 in PTC progression and explore the mechanisms underlying circNRIP1 functions. Methods RT-PCR or western blot determined circNRIP1, miR-653-5p, and pre-B-cell leukemia homeobox 3 (PBX3) expression. EdU, CCK-8, Tunel, and transwell assays determined cell proliferation, apoptosis, invasion, and migration, respectively. Luciferase reporter assay, RNA immunoprecipitation (RIP), and RNA pull down assays clarified the target relation between miR-653-5p and circNRIP1 or PBX3. Xenograft models were applied to explore the role of circNRIP1 in vivo. Results circNRIP1 significantly increased in PTC tissues and PTC cell lines than that in normal ones. Higher circNRIP1 expression was associated with the TNM stage and poorer overall survival. circNRIP1 knockdown attenuated the malignant progression of PTC, specifically by inhibiting proliferation and invasion/migration and promoting apoptosis. circNRIP1 was a miR-653-5p sponge; miR-653-5p knockdown reversed the suppressive role of circNRIP1 silence in PTC progression. PBX3, a target of miR-653-5p, was positively medicated through circNRIP1 via competitively sponging miR-653-5p. Knockdown of circNRIP1 attenuated the PTC tumor progression via miR-653-5p/PBX3 axis. Conclusion Silencing of circNRIP1 suppressed PTC development via miR-653-5p elevation and PBX3 reduction, providing a novel perspective for understanding PTC pathogenesis.
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16
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He Z, Cai K, Zeng Z, Lei S, Cao W, Li X. Autophagy-associated circRNA circATG7 facilitates autophagy and promotes pancreatic cancer progression. Cell Death Dis 2022; 13:233. [PMID: 35288538 PMCID: PMC8921308 DOI: 10.1038/s41419-022-04677-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 02/05/2022] [Accepted: 02/18/2022] [Indexed: 12/18/2022]
Abstract
Dysregulation of autophagy and circular RNAs (circRNAs) are involved in the pancreatic cancer (PC) progression. However, the regulatory network between circRNAs, autophagy, and PC progression remains unknown. Herein, we demonstrated that autophagy-associated circRNA circ-autophagy related 7 (circATG7) was elevated in PC tissues compared to adjacent tissues, and in PC cells treated with EBSS and hypoxia. circATG7 expression was positively associated with tumor diameter and lymph node invasion in patients with PC. circATG7 overexpression promoted PC cell proliferation, mobility, and autophagy in vitro, while circATG7 knockdown induced the opposite effects. ATG7 inhibition attenuated the effects of circATG7 on the biological functions of PC cells. CircATG7 is located in the cell cytoplasm and nucleus. Cytoplasmic circATG7 sponged miR-766-5p and decreased its expression, and increased the expression of ATG7, a target gene of miR-766-5p. Nuclear circATG7 acted as a scaffold to increase the interaction between the human antigen R protein and ATG7 mRNA and enhanced ATG mRNA stability. Furthermore, we demonstrated that circATG7 regulates PC cell proliferation and metastasis in vivo via ATG7-dependent autophagy. In conclusion, our results demonstrated that circATG7 accelerates PC progression via miR-766-5p/ATG7 and that HUR/ATG7 depends on autophagic flux. Thus, circATG7 may be a potential therapeutic target for PC.
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Affiliation(s)
- Zhiwei He
- Department of Hepatobiliary Surgery, Shenzhen Key Laboratory, Shenzhen University General Hospital, Shenzhen, Guangdong, 518055, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, 518060, China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases & Carson International Cancer Center, Shenzhen University, Shenzhen, Guangdong, 518055, China
- Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Kun Cai
- Guizhou Medical University, Guiyang, China
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550000, Guizhou, China
| | - Zhirui Zeng
- School of Basic Medicine, Guizhou Medical University, Guiyang, 550025, Guizhou, China
| | - Shan Lei
- School of Basic Medicine, Guizhou Medical University, Guiyang, 550025, Guizhou, China
| | - Wenpeng Cao
- School of Basic Medicine, Guizhou Medical University, Guiyang, 550025, Guizhou, China.
| | - Xiaowu Li
- Department of Hepatobiliary Surgery, Shenzhen Key Laboratory, Shenzhen University General Hospital, Shenzhen, Guangdong, 518055, China.
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, 518060, China.
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases & Carson International Cancer Center, Shenzhen University, Shenzhen, Guangdong, 518055, China.
- Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, Guangdong, 518055, China.
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17
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Deldar Abad Paskeh M, Mirzaei S, Ashrafizadeh M, Zarrabi A, Sethi G. Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways. J Hepatocell Carcinoma 2021; 8:1415-1444. [PMID: 34858888 PMCID: PMC8630469 DOI: 10.2147/jhc.s336858] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/05/2021] [Indexed: 12/14/2022] Open
Abstract
Liver cancers cause a high rate of death worldwide and hepatocellular carcinoma (HCC) is considered as the most common primary liver cancer. HCC remains a challenging disease to treat. Wnt/β-catenin signaling pathway is considered a tumor-promoting factor in various cancers; hence, the present review focused on the role of Wnt signaling in HCC, and its association with progression and therapy response based on pre-clinical and clinical evidence. The nuclear translocation of β-catenin enhances expression level of genes such as c-Myc and MMPs in increasing cancer progression. The mutation of CTNNB1 gene encoding β-catenin and its overexpression can lead to HCC progression. β-catenin signaling enhances cancer stem cell features of HCC and promotes their growth rate. Furthermore, β-catenin prevents apoptosis in HCC cells and increases their migration via triggering EMT and upregulating MMP levels. It is suggested that β-catenin signaling participates in mediating drug resistance and immuno-resistance in HCC. Upstream mediators including ncRNAs can regulate β-catenin signaling in HCC. Anti-cancer agents inhibit β-catenin signaling and mediate its proteasomal degradation in HCC therapy. Furthermore, clinical studies have revealed the role of β-catenin and its gene mutation (CTNBB1) in HCC progression. Based on these subjects, future experiments can focus on developing novel therapeutics targeting Wnt/β-catenin signaling in HCC therapy.
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Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul, Turkey
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer, Istanbul, 34396, Turkey
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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18
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Chen YH, Li CL, Chen WJ, Liu J, Wu HT. Diverse roles of FOXO family members in gastric cancer. World J Gastrointest Oncol 2021; 13:1367-1382. [PMID: 34721771 PMCID: PMC8529928 DOI: 10.4251/wjgo.v13.i10.1367] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/06/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the fifth most diagnosed cancer and the third leading cause of cancer-related death worldwide. Although progress has been made in diagnosis, surgical resection, systemic chemotherapy, and immunotherapy, patients with GC still have a poor prognosis. The overall 5-year survival rate in patients with advanced GC is less than 5%. The FOXO subfamily, of the forkhead box family of transcription factors, consists of four members, FOXO1, FOXO3, FOXO4, and FOXO6. This subfamily plays an important role in many cellular processes, such as cell cycle, cell growth, apoptosis, autophagy, stress resistance, protection from aggregate toxicity, DNA repair, tumor suppression, and metabolism, in both normal tissue and malignant tumors. Various studies support a role for FOXOs as tumor suppressors based on their ability to inhibit angiogenesis and metastasis, and promote apoptosis, yet several other studies have shown that FOXOs might also promote tumor progression in certain circumstances. To elucidate the diverse roles of FOXOs in GC, this article systematically reviews the cellular functions of FOXOs in GC to determine potential therapeutic targets and treatment strategies for patients with GC.
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Affiliation(s)
- Yu-Han Chen
- Department of Clinical Medicine, Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Chun-Lan Li
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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