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Jiraviriyakul A, Nensat C, Promchai S, Chaiaun Y, Hoiraya Y, Yamnak N, Khutanthong S, Singpan N, Songjang W. High Mobility Group Box 1 Is Potential Target Therapy for Inhibiting Metastasis and Enhancing Drug Sensitivity of Hepatocellular Carcinoma. Int J Mol Sci 2025; 26:3491. [PMID: 40331953 PMCID: PMC12026555 DOI: 10.3390/ijms26083491] [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: 01/28/2025] [Revised: 04/06/2025] [Accepted: 04/07/2025] [Indexed: 05/08/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a lethal malignancy associated with drug resistance, resulting in a poor prognosis. High mobility group box 1 (HMGB1) is a chromatin-binding protein that regulates HCC progression. The overexpression of HMGB1 has been found to promote tumorigenesis and drug resistance. In this study, we aimed to investigate the role of HMGB1 expression in tumorigenesis and metastasis and its impact on sorafenib and oxaliplatin resistance. Tissue samples from patients with HCC (n = 48) were subjected to immunohistochemistry. The expression of HMGB1 was correlated with clinical pathology parameters. Moreover, the HCC cell line HuH-7 was used to study the regulatory effect of HMGB1 on cell proliferation, cell adhesion, migration, and invasion by using the siRNA (small interfering RNA) silencing method. Furthermore, drug challenges were performed to determine the effect of HMGB1 on the sensitivity to chemotherapeutic drugs (sorafenib and oxaliplatin). HMGB1 was significantly overexpressed in tumor tissues, highlighted by the expression increment in patients with M1 advanced metastasis tumors with immunoreactivity scores 2.61 and 6.50 for adjacent and tumor tissues, respectively (p-values = 0.0035). The involved mechanisms were then described through the suppression of HCC cell adhesion, migration, and invasion by HMGB1 silencing. Notably, the inhibition of HMGB1 expression promoted sorafenib/oxaliplatin sensitivity in the HCC cell line by increasing the cell toxicity by about 13-18%. Our study demonstrated that HMGB1 shows potential as a promising biomarker and a target for HCC treatment that is involved in tumorigenesis, metastasis, and chemo-drug resistance.
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Affiliation(s)
- Arunya Jiraviriyakul
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand; (A.J.); (C.N.)
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Chatchai Nensat
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand; (A.J.); (C.N.)
- Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Samitanan Promchai
- Biomedical Sciences Program, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Yanisa Chaiaun
- Medical Technology Program, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand; (Y.C.)
| | - Yanisa Hoiraya
- Medical Technology Program, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand; (Y.C.)
| | - Nutnicha Yamnak
- Medical Technology Program, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand; (Y.C.)
| | - Suphakit Khutanthong
- Department of Pathology, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand; (S.K.)
| | - Nun Singpan
- Department of Pathology, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand; (S.K.)
| | - Worawat Songjang
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand; (A.J.); (C.N.)
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
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Wei Y, Ma Z, Li Z, Kang J, Liao T, Jie L, Liu D, Shi L, Wang P, Mao J, Wu P. Gentiopicroside ameliorates synovial inflammation and fibrosis in KOA rats by modulating the HMGB1-mediated PI3K/AKT signaling axis. Int Immunopharmacol 2025; 147:113973. [PMID: 39764995 DOI: 10.1016/j.intimp.2024.113973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/17/2024] [Accepted: 12/28/2024] [Indexed: 01/29/2025]
Abstract
BACKGROUND Knee osteoarthritis (KOA) is a degenerative joint disease characterized by synovial inflammation and fibrosis. Gentiopicroside (GPS), one of the main active ingredients of Gentiana macrophylla, is widely used in anti-inflammatory and anti-fibrotic therapies. However, the exact mechanism by which GPS treats synovial inflammation and fibrosis in KOA remains unclear. METHODS Fibroblast-like synoviocytes (FLSs) were stimulated with lipopolysaccharide (LPS) to induce inflammation and fibrosis, and CCK-8 was performed to determine the viability of GPS-treated FLSs, using immunofluorescence to examine the expression of P-PI3K and P-AKT, confocal microscopy was used to identify intracellular HMGB1 translocation. The KOA rat model was established by anterior cruciate ligament transection (ACLT) and subsequently subjected to GPS intervention. Inflammatory cytokines (TNF-α, IL-1β, and IL-6), fibrosis-related indicators (TGF-β, collagen I, TIMP1, and α-SMA), and HMGB1/PI3K/AKT signaling axis-related proteins and gene expression of fibroblast-like synoviocytes and synovial tissues were detected by Western blotting and real-time PCR. The histopathology of the synovium of the rats was assessed using Hematoxylin-eosin (HE), Sirius Red, and Masson staining. Immunohistochemistry was performed to detect the expression of HMGB1, P-PI3K, and P-AKT. RESULTS The present study revealed that GPS intervention significantly ameliorated inflammation and fibrosis in LPS-stimulated FLSs and KOA rat synovium. Immunofluorescence demonstrated that GPS inhibited the release of HMGB1 from the nucleus. Furthermore, GPS intervention down-regulates the levels of proteins and gene associated with the HMGB1/PI3K/AKT signaling pathway. CONCLUSION GPS ameliorated synovial inflammation and fibrosis in KOA rats, which may involve HMGB1-mediated activation of the PI3K/AKT signaling axis.
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Affiliation(s)
- Yibao Wei
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Zhenyuan Ma
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Zhenhui Li
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Junfeng Kang
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; The Affiliated Hospital of Shanxi University of Traditional Chinese Medicine, Taiyuan 030002, China
| | - Taiyang Liao
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Lishi Jie
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Deren Liu
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Lei Shi
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Peimin Wang
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Jun Mao
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China.
| | - Peng Wu
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China.
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Coser M, Neamtu BM, Pop B, Cipaian CR, Crisan M. RAGE and its ligands in breast cancer progression and metastasis. Oncol Rev 2025; 18:1507942. [PMID: 39830522 PMCID: PMC11739297 DOI: 10.3389/or.2024.1507942] [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: 10/08/2024] [Accepted: 12/10/2024] [Indexed: 01/22/2025] Open
Abstract
Introduction Breast cancer is the most common form of cancer diagnosed worldwide and the leading cause of death in women globally, according to Globocan 2020. Hence, investigating novel pathways implicated in cancer progression and metastasis could lead to the development of targeted therapies and new treatment strategies in breast cancer. Recent studies reported an interplay between the receptor for advanced glycation end products (RAGE) and its ligands, S100 protein group, advanced glycation end products (AGEs) and high-mobility group box 1 protein (HMGB1) and breast cancer growth and metastasis. Materials and methods We used articles available in the NCBI website database PubMed to write this scoping review. The search words used were 'RAGE receptor' AND/OR 'breast cancer, RAGE ligands, glycation end products'. A total of 90 articles were included. We conducted a meta-analysis to assess the relationship between the RAGE rs1800624 polymorphism and breast cancer risk using fixed-effect or random-effect models to calculate odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs). Results RAGE upon activation by its ligands enhances downstream signaling pathways, contributing to breast cancer cells migration, growth, angiogenesis, metastasis, and drug resistance. In addition, studies have shown that RAGE and its ligands influence the way breast cancer cells interact with immune cells present in the tumor microenvironment (macrophages, fibroblasts), thus regulating it to promote tumor growth and metastasis. Conclusion Breast cancers with a high expression of RAGE are associated with poor prognosis. Targeting RAGE and its ligands impairs cell invasion and metastasis, showing promising potential for further research as potential prognostic biomarkers or targeted onco-therapeutics.
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Affiliation(s)
- Madalina Coser
- Department of Histology, Doctoral School “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Bogdan Mihai Neamtu
- Clinical Medical Department, Center for Research in Mathematics and Applications, Faculty of Medicine, “Lucian Blaga” University Sibiu, Sibiu, Romania
- Department of Clinical Research, Pediatric Clinical Hospital Sibiu, Sibiu, Romania
| | - Bogdan Pop
- Department of Pathology, “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
- Department of Pathology, “Prof. Dr. ion Chiricuta” Institute of Oncology Cluj-Napoca, Cluj-Napoca, Romania
| | - Calin Remus Cipaian
- Second Medical Clinic, Sibiu County Clinical Emergency Hospital, Sibiu, Romania
- Clinical Medical Department, Faculty of Medicine, “Lucian Blaga” University Sibiu, Sibiu, Romania
| | - Maria Crisan
- Department of Histology, “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
- Clinic of Dermatology, Emergency Clinical County Hospital, Cluj-Napoca, Romania
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Qi L, Wang C, Deng L, Pan JJ, Suo Q, Wu S, Cai L, Shi X, Sun J, Wang Y, Tang Y, Qiu W, Yang GY, Wang J, Zhang Z. Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice. Stroke Vasc Neurol 2024; 9:505-518. [PMID: 38191183 PMCID: PMC11732924 DOI: 10.1136/svn-2023-002614] [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: 05/25/2023] [Accepted: 11/28/2023] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND Low-intensity focused ultrasound stimulation (LIFUS) has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents. However, the cellular and molecular mechanisms of neurological repair and remodelling after LIFUS in ischaemic stroke are unclear. METHODS Ultrasound stimulation was treated in adult male mice 7 days after transient middle cerebral artery occlusion. Angiogenesis was measured by laser speckle imaging and histological analyses. Electromyography and fibre photometry records were used for synaptogenesis. Brain atrophy volume and neurobehaviour were assessed 0-14 days after ischaemia. iTRAQ proteomic analysis was performed to explore the differentially expressed protein. scRNA-seq was used for subcluster analysis of astrocytes. Fluorescence in situ hybridisation and Western blot detected the expression of HMGB1 and CAMK2N1. RESULTS Optimal ultrasound stimulation increased cerebral blood flow, and improved neurobehavioural outcomes in ischaemic mice (p<0.05). iTRAQ proteomic analysis revealed that the expression of HMGB1 increased and CAMK2N1 decreased in the ipsilateral hemisphere of the brain at 14 days after focal cerebral ischaemia with ultrasound treatment (p<0.05). scRNA-seq revealed that this expression pattern belonged to a subcluster of astrocytes after LIFUS in the ischaemic brain. LIFUS upregulated HMGB1 expression, accompanied by VEGFA elevation compared with the control group (p<0.05). Inhibition of HMGB1 expression in astrocytes decreased microvessels counts and cerebral blood flow (p<0.05). LIFUS reduced CAMK2N1 expression level, accompanied by increased extracellular calcium ions and glutamatergic synapses (p<0.05). CAMK2N1 overexpression in astrocytes decreased dendritic spines, and aggravated neurobehavioural outcomes (p<0.05). CONCLUSION Our results demonstrated that LIFUS promoted angiogenesis and synaptogenesis after focal cerebral ischaemia by upregulating HMGB1 and downregulating CAMK2N1 in a subcluster of astrocytes, suggesting that LIFUS activated specific astrocyte subcluster could be a key target for ischaemic brain therapy.
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MESH Headings
- Animals
- Astrocytes/metabolism
- Astrocytes/pathology
- Astrocytes/enzymology
- Male
- Recovery of Function
- Disease Models, Animal
- Infarction, Middle Cerebral Artery/metabolism
- Infarction, Middle Cerebral Artery/pathology
- Infarction, Middle Cerebral Artery/therapy
- Infarction, Middle Cerebral Artery/physiopathology
- Infarction, Middle Cerebral Artery/genetics
- Infarction, Middle Cerebral Artery/enzymology
- Mice, Inbred C57BL
- HMGB1 Protein/metabolism
- HMGB1 Protein/genetics
- Neovascularization, Physiologic
- Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism
- Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics
- Cerebrovascular Circulation
- Ultrasonic Therapy
- Signal Transduction
- Ischemic Stroke/metabolism
- Ischemic Stroke/physiopathology
- Ischemic Stroke/therapy
- Ischemic Stroke/pathology
- Behavior, Animal
- Time Factors
- Mice
- Proteomics
- Neurogenesis
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Affiliation(s)
- Lin Qi
- Shanghai Jiao Tong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Cheng Wang
- Shanghai Jiao Tong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Lidong Deng
- Shanghai Jiao Tong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Jia-Ji Pan
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical Collage, Fudan University, Shanghai, China
| | - Qian Suo
- Shanghai Jiao Tong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Shengju Wu
- Shanghai Jiao Tong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Lin Cai
- Department of Neurosurgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
| | - Xudong Shi
- Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Beijing, China
| | - Junfeng Sun
- Shanghai Jiao Tong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Yongting Wang
- Shanghai Jiao Tong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Yaohui Tang
- Shanghai Jiao Tong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Weibao Qiu
- Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Beijing, China
| | - Guo-Yuan Yang
- Neuroscience and Neuroengineering Center, Shanghai Jiao Tong University School of Biomedical Engineering, Shanghai, China
- Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
| | - Jixian Wang
- Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
| | - Zhijun Zhang
- Shanghai Jiao Tong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, Shanghai, China
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Vladimirova D, Staneva S, Ugrinova I. Multifaceted role of HMGB1: From nuclear functions to cytoplasmic and extracellular signaling in inflammation and cancer-Review. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 143:271-300. [PMID: 39843137 DOI: 10.1016/bs.apcsb.2024.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
High-mobility group box 1 (HMGB1) is a highly conserved nuclear protein involved in key nuclear processes such as DNA repair, replication, and gene regulation. Beyond its established nuclear roles, HMGB1 has crucial functions in the cytoplasm and extracellular environment. When translocated to the cytoplasm, HMGB1 plays a role in autophagy, cell survival, and immune response modulation. In its extracellular form, HMGB1 acts as a damage-associated molecular pattern molecule, initiating inflammatory responses by interacting with receptors such as Receptor for advanced glycation endproducts and Toll-like receptors. Recent studies have shown its role in promoting tissue regeneration, wound healing, and angiogenesis, highlighting its dual role in both inflammation and tissue repair. Notably, the redox status of HMGB1 influences its function, with the reduced form promoting autophagy and the disulfide form driving inflammation. Dysregulation of HMGB1 contributes to the progression of various diseases, including cancer, where it influences tumor growth, metastasis, and resistance to therapy. This review provides an overview of the nuclear, cytoplasmic, and extracellular roles of HMGB1, discussing its involvement in nuclear homeostasis, rare genetic diseases, autophagy, inflammation, cancer progression, and tissue regeneration.
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Affiliation(s)
- Desislava Vladimirova
- "Roumen Tsanev" Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Sonya Staneva
- "Roumen Tsanev" Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Iva Ugrinova
- "Roumen Tsanev" Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
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Lv G, Yang M, Gai K, Jia Q, Wang Z, Wang B, Li X. Multiple functions of HMGB1 in cancer. Front Oncol 2024; 14:1384109. [PMID: 38725632 PMCID: PMC11079206 DOI: 10.3389/fonc.2024.1384109] [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: 02/08/2024] [Accepted: 04/15/2024] [Indexed: 05/12/2024] Open
Abstract
High mobility group box 1 (HMGB1) is a nuclear DNA-binding protein with a dual role in cancer, acting as an oncogene and a tumor suppressor. This protein regulates nucleosomal structure, DNA damage repair, and genomic stability within the cell, while also playing a role in immune cell functions. This review comprehensively evaluates the biological and clinical significance of HMGB1 in cancer, including its involvement in cell death and survival, its potential as a therapeutic target and cancer biomarker, and as a prosurvival signal for the remaining cells after exposure to cytotoxic anticancer treatments. We highlight the need for a better understanding of the cellular markers and mechanisms involved in the involvement of HMGB1in cancer, and aim to provide a deeper understanding of its role in cancer progression.
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Affiliation(s)
- Guangyao Lv
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Menglin Yang
- Quality Management Department, Marine Biomedical Research Institute of Qingdao, Qingdao, China
| | - Keke Gai
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Qiong Jia
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Zhenzhen Wang
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Bin Wang
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Xueying Li
- School of Health, Binzhou Polytechnic, Binzhou, China
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Wang SS, Ye DX, Wang B, Li MY, Zhao WX. USP15 promotes the progression of papillary thyroid cancer by regulating HMGB1 stability through its deubiquitination. J Cancer 2024; 15:2561-2572. [PMID: 38577597 PMCID: PMC10988300 DOI: 10.7150/jca.92386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 01/16/2024] [Indexed: 04/06/2024] Open
Abstract
Purpose: Papillary thyroid cancer (PTC) stands as one of the most prevalent types of thyroid cancers, characterized by a propensity for in-situ recurrence and distant metastasis. The high mobility group protein (HMGB1), a conserved nuclear protein, plays a pivotal role in carcinogenesis by stimulating tumor cell growth and migration. Nevertheless, the underlying mechanism driving aberrant HMGB1 expression in PTC necessitates further elucidation. Materials and methods: Our study unraveled the impact of low and overexpression of USP15 on the proliferation, invasion, and metastasis of PTC cells. Through a comprehensive array of molecular techniques, we uncovered the intricate relationship between HMGB1 and USP15 in the progression of PTC. Results: In this study, we identified USP15, a deubiquitinase in the ubiquitin-specific proteases family, as a true deubiquitylase of HMGB1 in PTC. USP15 was shown to interact with HMGB1 in a deubiquitination activity-dependent manner, deubiquitinating and stabilizing HMGB1. USP15 depletion significantly decreased PTC cell proliferation, migration, and invasion. In addition, the effects induced by USP15 depletion could be rescued by further HMGB1 overexpression. But when HMGB1 is knocked down, even overexpression of USP15 could not promote the progression of PTC cells. Conclusion: In essence, our discoveries shed light on the previously uncharted catalytic role of USP15 as a deubiquitinating enzyme targeting HMGB1, offering a promising avenue for potential therapeutic interventions in the management of PTC.
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Affiliation(s)
- Si-si Wang
- Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
- Department of Thyroid Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, P.R. China
| | - Dao-xiong Ye
- Department of Thyroid Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, P.R. China
| | - Bo Wang
- Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Meng-yao Li
- Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Wen-xin Zhao
- Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
- Department of Thyroid Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, P.R. China
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Wang J, Zheng Q, Zhao Y, Chen S, Chen L. HMGB1 enhances the migratory and invasive abilities of A2780/DDP cells by facilitating epithelial to mesenchymal transition via GSK‑3β. Exp Ther Med 2024; 27:102. [PMID: 38356665 PMCID: PMC10865443 DOI: 10.3892/etm.2024.12390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 10/25/2023] [Indexed: 02/16/2024] Open
Abstract
The aim of the present study was to investigate the impact and mechanism of high mobility group box 1 (HMGB1) on the regulation of cell migration and invasion in A2780/DDP cisplatin-resistant ovarian cancer cells. After transfecting small interfering (si)RNA-HMGB1 into A2780/DDP cells, Transwell migration and invasion assays were conducted to assess alterations in the cell migratory and invasive abilities. Additionally, western blotting analyses were performed to examine changes in HMGB1, phosphorylated (p)-GSK-3β, GSK-3β, E-cadherin and vimentin expression levels. The results of the present study demonstrated that the migratory and invasive abilities of A2780/DDP cells were significantly higher compared with those of A2780 cells. Additionally, the expression levels of HMGB1, p-GSK-3β and the mesenchymal phenotype marker, vimentin, in A2780/DDP cells were significantly elevated relative to the levels in A2780 cells. Conversely, the expression level of the epithelial phenotype marker, E-cadherin, was markedly decreased compared with that in A2780 cells. Following transfection of A2780/DDP cells with siRNA-HMGB1, there was a significant reduction in the rate of cell migration and invasion. Simultaneously, the expression levels of HMGB1, p-GSK-3β and vimentin were downregulated while the level of E-cadherin was upregulated. It was therefore concluded that the high expression of HMGB1 in A2780/DDP cells enhanced the cell migration and invasion abilities by facilitating epithelial to mesenchymal transition via GSK-3β.
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Affiliation(s)
- Jinhua Wang
- Department of Obstetrics and Gynecology, Fujian Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Qiaomei Zheng
- Department of Obstetrics and Gynecology, Fujian Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Yanjing Zhao
- Department of Surgery, 92403 Military Hospital, Fuzhou, Fujian 350015, P.R. China
| | - Shaozhan Chen
- Department of Obstetrics and Gynecology, Fujian Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Lihong Chen
- Department of Obstetrics and Gynecology, Fujian Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
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Ren Y, Zhu D, Han X, Zhang Q, Chen B, Zhou P, Wei Z, Zhang Z, Cao Y, Zou H. HMGB1: a double-edged sword and therapeutic target in the female reproductive system. Front Immunol 2023; 14:1238785. [PMID: 37691930 PMCID: PMC10484633 DOI: 10.3389/fimmu.2023.1238785] [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: 06/12/2023] [Accepted: 08/03/2023] [Indexed: 09/12/2023] Open
Abstract
HMGB1 that belongs to the High Mobility Group-box superfamily, is a nonhistone chromatin associated transcription factor. It is present in the nucleus of eukaryotes and can be actively secreted or passively released by kinds of cells. HMGB1 is important for maintaining DNA structure by binding to DNA and histones, protecting it from damage. It also regulates the interaction between histones and DNA, affecting chromatin packaging, and can influence gene expression by promoting nucleosome sliding. And as a DAMP, HMGB1 binding to RAGE and TLRs activates NF-κB, which triggers the expression of downstream genes like IL-18, IL-1β, and TNF-α. HMGB1 is known to be involved in numerous physiological and pathological processes. Recent studies have demonstrated the significance of HMGB1 as DAMPs in the female reproductive system. These findings have shed light on the potential role of HMGB1 in the pathogenesis of diseases in female reproductive system and the possibilities of HMGB1-targeted therapies for treating them. Such therapies can help reduce inflammation and metabolic dysfunction and alleviate the symptoms of reproductive system diseases. Overall, the identification of HMGB1 as a key player in disease of the female reproductive system represents a significant breakthrough in our understanding of these conditions and presents exciting opportunities for the development of novel therapies.
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Affiliation(s)
- Yu Ren
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission (NHC) Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei, Anhui, China
| | - Damin Zhu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Xingxing Han
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Qiqi Zhang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Beili Chen
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Ping Zhou
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Zhaolian Wei
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Zhiguo Zhang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission (NHC) Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei, Anhui, China
| | - Yunxia Cao
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission (NHC) Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei, Anhui, China
| | - Huijuan Zou
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission (NHC) Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei, Anhui, China
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Garza-Campos A, Prieto-Correa JR, Domínguez-Rosales JA, Hernández-Nazará ZH. Implications of receptor for advanced glycation end products for progression from obesity to diabetes and from diabetes to cancer. World J Diabetes 2023; 14:977-994. [PMID: 37547586 PMCID: PMC10401444 DOI: 10.4239/wjd.v14.i7.977] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/31/2023] [Accepted: 04/17/2023] [Indexed: 07/12/2023] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are chronic pathologies with a high incidence worldwide. They share some pathological mechanisms, including hyperinsulinemia, the production and release of hormones, and hyperglycemia. The above, over time, affects other systems of the human body by causing tissue hypoxia, low-grade inflammation, and oxidative stress, which lay the pathophysiological groundwork for cancer. The leading causes of death globally are T2DM and cancer. Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death (i.e., damage-associated molecular patterns) such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products (RAGE) - a multiligand receptor involved in inflammatory and metabolic and neoplastic processes. This review analyzes the latest advanced reports on the role of RAGE in the development of obesity, T2DM, and cancer, with an aim to understand the intracellular signaling mechanisms linked with cancer initiation. This review also explores inflammation, oxidative stress, hypoxia, cellular senescence, RAGE ligands, tumor microenvironment changes, and the “cancer hallmarks” of the leading tumors associated with T2DM. The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.
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Affiliation(s)
- Andrea Garza-Campos
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Roberto Prieto-Correa
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Alfredo Domínguez-Rosales
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Zamira Helena Hernández-Nazará
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
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11
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Kim HS, Park SC, Kim HJ, Lee DY. Inhibition of DAMP actions in the tumoral microenvironment using lactoferrin-glycyrrhizin conjugate for glioblastoma therapy. Biomater Res 2023; 27:52. [PMID: 37210579 DOI: 10.1186/s40824-023-00391-w] [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: 01/30/2023] [Accepted: 05/07/2023] [Indexed: 05/22/2023] Open
Abstract
BACKGROUND High-mobility group box-1 (HMGB1) released from the tumor microenvironment plays a pivotal role in the tumor progression. HMGB1 serves as a damaged-associated molecular pattern (DAMP) that induces tumor angiogenesis and its development. Glycyrrhizin (GL) is an effective intracellular antagonist of tumor released HMGB1, but its pharmacokinetics (PK) and delivery to tumor site is deficient. To address this shortcoming, we developed lactoferrin-glycyrrhizin (Lf-GL) conjugate. METHODS Biomolecular interaction between Lf-GL and HMGB1 was evaluated by surface plasmon resonance (SPR) binding affinity assay. Inhibition of tumor angiogenesis and development by Lf-GL attenuating HMGB1 action in the tumor microenvironment was comprehensively evaluated through in vitro, ex vivo, and in vivo. Pharmacokinetic study and anti-tumor effects of Lf-GL were investigated in orthotopic glioblastoma mice model. RESULTS Lf-GL interacts with lactoferrin receptor (LfR) expressed on BBB and GBM, therefore, efficiently inhibits HMGB1 in both the cytoplasmic and extracellular regions of tumors. Regarding the tumor microenvironment, Lf-GL inhibits angiogenesis and tumor growth by blocking HMGB1 released from necrotic tumors and preventing recruitment of vascular endothelial cells. In addition, Lf-GL improved the PK properties of GL approximately tenfold in the GBM mouse model and reduced tumor growth by 32%. Concurrently, various biomarkers for tumor were radically diminished. CONCLUSION Collectively, our study demonstrates a close association between HMGB1 and tumor progression, suggesting Lf-GL as a potential strategy for coping with DAMP-related tumor microenvironment. HMGB1 is a tumor-promoting DAMP in the tumor microenvironment. The high binding capability of Lf-GL to HMGB1 inhibits tumor progression cascade such as tumor angiogenesis, development, and metastasis. Lf-GL targets GBM through interaction with LfR and allows to arrest HMGB1 released from the tumor microenvironment. Therefore, Lf-GL can be a GBM treatment by modulating HMGB1 activity.
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Affiliation(s)
- Hyung Shik Kim
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Institute of Nano Science and Technology (INST), Hanyang University, and Elixir Pharmatech Inc, 222 Wangsimni-Ro, Seongdong-Gu, Seoul, 04763, Republic of Korea
| | - Seok Chan Park
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Institute of Nano Science and Technology (INST), Hanyang University, and Elixir Pharmatech Inc, 222 Wangsimni-Ro, Seongdong-Gu, Seoul, 04763, Republic of Korea
| | - Hae Jin Kim
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Institute of Nano Science and Technology (INST), Hanyang University, and Elixir Pharmatech Inc, 222 Wangsimni-Ro, Seongdong-Gu, Seoul, 04763, Republic of Korea
| | - Dong Yun Lee
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Institute of Nano Science and Technology (INST), Hanyang University, and Elixir Pharmatech Inc, 222 Wangsimni-Ro, Seongdong-Gu, Seoul, 04763, Republic of Korea.
- Institute of Nano Science and Technology (INST) & Institute For Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, 04763, Republic of Korea.
- Elixir Pharmatech Inc., Seoul, 07463, Republic of Korea.
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Ghafouri-Fard S, Hussen BM, Shoorei H, Abak A, Poornajaf Y, Taheri M, Samadian M. Interactions between non-coding RNAs and HIF-1α in the context of cancer. Eur J Pharmacol 2023; 943:175535. [PMID: 36731723 DOI: 10.1016/j.ejphar.2023.175535] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 02/03/2023]
Abstract
Hypoxia-inducible factor 1α (HIF-1α) is a subunit of the HIF-1 transcription factor which is encoded by the HIF1A gene. This transcription factor is the main modulator of the cell response to hypoxia. Hypoxia-induced up-regulation of HIF-1α is involved in the pathogenesis of cancer. Recently, the interactions of several long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) with HIF-1α have been reported. These ncRNAs regulate the expression of HIF-1α through different mechanisms. The regulatory roles of ncRNAs on HIF-1α are involved in the response of cancer cells to a wide range of anticancer drugs such as sorafenib, cisplatin, propofol, doxorubicin, and paclitaxel. Therefore, identification of the complex network between ncRNAs and HIF-1α not only facilitates the design of novel therapies but also promotes the efficacy of conventional anticancer treatments. This review aims to explain the interactions between these classes of ncRNAs and HIF-1α in the context of cancer.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran; Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Atefe Abak
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yadollah Poornajaf
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany; Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Samadian
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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13
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Extra-Cellular Vesicles Derived from Thyroid Cancer Cells Promote the Epithelial to Mesenchymal Transition (EMT) and the Transfer of Malignant Phenotypes through Immune Mediated Mechanisms. Int J Mol Sci 2023; 24:ijms24032754. [PMID: 36769076 PMCID: PMC9917007 DOI: 10.3390/ijms24032754] [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: 12/19/2022] [Revised: 01/27/2023] [Accepted: 01/28/2023] [Indexed: 02/04/2023] Open
Abstract
Thyroid cancer is the most common endocrine cancer, and its incidence is increasing in many countries around the world. Among thyroid cancers, the papillary thyroid cancer (PTC) histotype is particularly prevalent. A small percentage of papillary tumors is associated with metastases and aggressive behavior due to de-differentiation obtained through the epithelial-mesenchymal transition (EMT) by which epithelial thyroid cells acquire a fibroblast-like morphology, reduce cellular adhesion, increase motility and expression of mesenchymal proteins. The tumor microenvironment plays an important role in promoting an aggressive phenotype through hypoxia and the secretion of HMGB1 and other factors. Hypoxia has been shown to drastically change the tumor cell phenotype and has been associated with increasing metastatic and migratory behavior. Cells transfer information to neighboring cells or distant locations by releasing extracellular membrane vesicles (EVs) that contain key molecules, such as mRNAs, microRNAs (miRNAs), and proteins, that are able to modify protein expression in recipient cells. In this study, we investigated the potential role of EVs released by the anaplastic cancer cell line CAL-62 in inducing a malignant phenotype in a papillary cancer cell line (BCPAP).
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Cheng W, Xiao X, Liao Y, Cao Q, Wang C, Li X, Jia Y. Conducive target range of breast cancer: Hypoxic tumor microenvironment. Front Oncol 2022; 12:978276. [PMID: 36226050 PMCID: PMC9550190 DOI: 10.3389/fonc.2022.978276] [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: 06/25/2022] [Accepted: 09/07/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer is a kind of malignant tumor disease that poses a serious threat to human health. Its biological characteristics of rapid proliferation and delayed angiogenesis, lead to intratumoral hypoxia as a common finding in breast cancer. HIF as a transcription factor, mediate a series of reactions in the hypoxic microenvironment, including metabolic reprogramming, tumor angiogenesis, tumor cell proliferation and metastasis and other important physiological and pathological processes, as well as gene instability under hypoxia. In addition, in the immune microenvironment of hypoxia, both innate and acquired immunity of tumor cells undergo subtle changes to support tumor and inhibit immune activity. Thus, the elucidation of tumor microenvironment hypoxia provides a promising target for the resistance and limited efficacy of current breast cancer therapies. We also summarize the hypoxic mechanisms of breast cancer treatment related drug resistance, as well as the current status and prospects of latest related drugs targeted HIF inhibitors.
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Affiliation(s)
- Wen Cheng
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Xian Xiao
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yang Liao
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Qingqing Cao
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Chaoran Wang
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Xiaojiang Li
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- *Correspondence: Xiaojiang Li, ; Yingjie Jia,
| | - Yingjie Jia
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- *Correspondence: Xiaojiang Li, ; Yingjie Jia,
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Amornsupak K, Thongchot S, Thinyakul C, Box C, Hedayat S, Thuwajit P, Eccles SA, Thuwajit C. HMGB1 mediates invasion and PD-L1 expression through RAGE-PI3K/AKT signaling pathway in MDA-MB-231 breast cancer cells. BMC Cancer 2022; 22:578. [PMID: 35610613 PMCID: PMC9128129 DOI: 10.1186/s12885-022-09675-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 05/16/2022] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND High-mobility group box 1 (HMGB1) is increased in breast cancer cells as the result of exposure to the secreted substances from cancer-associated fibroblasts and plays a crucial role in cancer progression and drug resistance. Its effect, however, on the expression of programmed death ligand 1 (PD-L1) in breast cancer cells has not been investigated. This study aimed to investigate the mechanism of HMGB1 through receptors for advanced glycation end products (RAGE) on cell migration/invasion and PD-L1 expression in breast cancer cells. METHODS A 3-dimensional (3-D) migration and invasion assay and Western blotting analysis to evaluate the function and the mechanism under recombinant HMGB1 (rHMGB1) treatment with knockdown of RAGE using shRAGE and PI3K/AKT inhibitors was performed. RESULTS The results revealed that rHMGB1 induced MDA-MB-231 cell migration and invasion. The knockdown of RAGE using shRAGE and PI3K/AKT inhibitors attenuated 3-D migration and invasion in response to rHMGB1 compared to mock cells. PD-L1 up-regulation was observed in both parental MDA-MB-231 (P) and MDA-MB-231 metastasis to bone marrow (BM) cells treated with rHMGB1, and these effects were alleviated in RAGE-knock down (KD) breast cancer cells as well as in PI3K/AKT inhibitor-treated cells. CONCLUSIONS Collectively, these findings indicate that HMGB1-RAGE through PI3K/AKT signaling promotes not only breast cancer cell invasion but also PD-L1 expression which leads to the destruction of the effector T cells. The attenuating HMGB1-RAGE-PI3K/AKT pathway may help to attenuate breast cancer cell aggressive phenotypes.
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Affiliation(s)
- Kamolporn Amornsupak
- Department of Transfusion Medicine and Clinical Microbiology, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
- Immunomodulation of Natural Products Research Group, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Suyanee Thongchot
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
- Siriraj Center of Research Excellence for Cancer Immunotherapy, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Chanida Thinyakul
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Carol Box
- Centre For Cancer Imaging, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, SW7 3RP, UK
- Present Address: Cancer Research UK, Cancer Therapeutics Unit, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Somaieh Hedayat
- Present Address: Cancer Research UK, Cancer Therapeutics Unit, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Peti Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Suzanne A Eccles
- Present Address: Cancer Research UK, Cancer Therapeutics Unit, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
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Mohammad Mirzaei N, Tatarova Z, Hao W, Changizi N, Asadpoure A, Zervantonakis IK, Hu Y, Chang YH, Shahriyari L. A PDE Model of Breast Tumor Progression in MMTV-PyMT Mice. J Pers Med 2022; 12:807. [PMID: 35629230 PMCID: PMC9145520 DOI: 10.3390/jpm12050807] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/12/2022] [Accepted: 05/12/2022] [Indexed: 02/04/2023] Open
Abstract
The evolution of breast tumors greatly depends on the interaction network among different cell types, including immune cells and cancer cells in the tumor. This study takes advantage of newly collected rich spatio-temporal mouse data to develop a data-driven mathematical model of breast tumors that considers cells' location and key interactions in the tumor. The results show that cancer cells have a minor presence in the area with the most overall immune cells, and the number of activated immune cells in the tumor is depleted over time when there is no influx of immune cells. Interestingly, in the case of the influx of immune cells, the highest concentrations of both T cells and cancer cells are in the boundary of the tumor, as we use the Robin boundary condition to model the influx of immune cells. In other words, the influx of immune cells causes a dominant outward advection for cancer cells. We also investigate the effect of cells' diffusion and immune cells' influx rates in the dynamics of cells in the tumor micro-environment. Sensitivity analyses indicate that cancer cells and adipocytes' diffusion rates are the most sensitive parameters, followed by influx and diffusion rates of cytotoxic T cells, implying that targeting them is a possible treatment strategy for breast cancer.
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Affiliation(s)
- Navid Mohammad Mirzaei
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003, USA; (N.M.M.); (Y.H.)
| | - Zuzana Tatarova
- Department of Radiology, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
| | - Wenrui Hao
- Department of Mathematics, The Pennsylvania State University, University Park, PA 16802, USA;
| | - Navid Changizi
- Department of Civil and Environmental Engineering, University of Massachusetts, Dartmouth, MA 02747, USA; (N.C.); (A.A.)
| | - Alireza Asadpoure
- Department of Civil and Environmental Engineering, University of Massachusetts, Dartmouth, MA 02747, USA; (N.C.); (A.A.)
| | - Ioannis K. Zervantonakis
- Department of Bioengineering, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15219, USA;
| | - Yu Hu
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003, USA; (N.M.M.); (Y.H.)
| | - Young Hwan Chang
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239, USA;
| | - Leili Shahriyari
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, MA 01003, USA; (N.M.M.); (Y.H.)
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Xu J, Tao P, Lü D, Jiang Y, Xia Q. Role of high-mobility group box 1 in cancer. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2022; 47:505-511. [PMID: 35545346 PMCID: PMC10930161 DOI: 10.11817/j.issn.1672-7347.2022.210679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Indexed: 06/15/2023]
Abstract
High-mobility group box 1 (HMGB1) is a non-histone nuclear protein in most eukaryocytes. Inside the nucleus, HMGB1 plays an important role in several DNA events such as DNA repair, transcription, telomere maintenance, and genome stability. While outside the nucleus, it fulfils more complicated functions, including promoting cell proliferation, inflammation, angiogenesis, immune tolerance and immune escape, which may play a pro-tumoral role.Meanwhile, HMGB1 acts as an anti-tumoral protein by regulating immune cell recruitment and inducing immunogenic cell death (ICD) during the carcinogenesis process. Therefore, abnormal expression of HMGB1 is associated with oncogenesis, development, and metastasis of cancer, which may play a dual role of pro-tumor and anti-tumor.
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Affiliation(s)
- Juan Xu
- Second Department of Internal Medicine, People's Hospital of Guandu District, Kunming 650200.
| | - Pengzuo Tao
- Department of Clinical Laboratory, Yunan Cancer Hospital/Third Affiliated Hospital of Kunming Medical University, Kunming 650118
| | - Dongjin Lü
- Third Department of Internal Medicine, Yunan Cancer Hospital/Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China
| | - Yu'e Jiang
- Department of Clinical Laboratory, Yunan Cancer Hospital/Third Affiliated Hospital of Kunming Medical University, Kunming 650118
| | - Quansong Xia
- Department of Clinical Laboratory, Yunan Cancer Hospital/Third Affiliated Hospital of Kunming Medical University, Kunming 650118.
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High Mobility Group Box 1: Biological Functions and Relevance in Oxidative Stress Related Chronic Diseases. Cells 2022; 11:cells11050849. [PMID: 35269471 PMCID: PMC8909428 DOI: 10.3390/cells11050849] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/03/2022] [Accepted: 02/26/2022] [Indexed: 01/27/2023] Open
Abstract
In the early 1970s, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and named high-mobility group (HMG) proteins. High-mobility group box 1 (HMGB1) is the most studied HMG protein that detects and coordinates cellular stress response. The biological function of HMGB1 depends on its subcellular localization and expression. It plays a critical role in the nucleus and cytoplasm as DNA chaperone, chromosome gatekeeper, autophagy maintainer, and protector from apoptotic cell death. HMGB1 also functions as an extracellular alarmin acting as a damage-associated molecular pattern molecule (DAMP). Recent findings describe HMGB1 as a sophisticated signal of danger, with a pleiotropic function, which is useful as a clinical biomarker for several disorders. HMGB1 has emerged as a mediator in acute and chronic inflammation. Furthermore, HMGB1 targeting can induce beneficial effects on oxidative stress related diseases. This review focus on HMGB1 redox status, localization, mechanisms of release, binding with receptors, and its activities in different oxidative stress-related chronic diseases. Since a growing number of reports show the key role of HMGB1 in socially relevant pathological conditions, to our knowledge, for the first time, here we analyze the scientific literature, evaluating the number of publications focusing on HMGB1 in humans and animal models, per year, from 2006 to 2021 and the number of records published, yearly, per disease and category (studies on humans and animal models).
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19
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miR-142-3p simultaneously targets HMGA1, HMGA2, HMGB1, and HMGB3 and inhibits tumorigenic properties and in-vivo metastatic potential of human cervical cancer cells. Life Sci 2021; 291:120268. [PMID: 34973275 DOI: 10.1016/j.lfs.2021.120268] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/14/2021] [Accepted: 12/22/2021] [Indexed: 12/20/2022]
Abstract
AIMS High-mobility group (HMG) proteins are oncogenic in different cancers, including cervical cancer; silencing their individual expression using sh-RNAs, siRNAs, and miRNAs has had anti-tumorigenic effects, but the consequences of their collective downregulation are not known. Since multiple gene targeting is generally very effective in cancer therapy, the present study highlighted the consequences of silencing the expression of HMGA1, A2, B1, and B3 using sh-RNAs or miR-142-3p (that can potentially target HMGA1, A2, B1, and B3) in cervical cancer cell lines. MAIN METHODS 3' UTR luciferase reporter assays were performed to validate HMGA1, A2, B1, and B3 as targets of miR-142-3p in human cervical cancer cells. Annexin V/PI dual staining and flow cytometry analyses were used to detect apoptotic cells. miR-142-3p-mediated regulation of cell death, colony formation, migration, and invasion was investigated in human cervical cancer cells together with in vivo metastasis in zebrafish. KEY FINDINGS Concurrent knockdown of HMGA1, A2, B1, and B3 through their corresponding sh-RNAs inhibited cell viability and colony formation but induced apoptosis, and these effects were relatively reduced upon their individual knockdown. miR-142-3p targeted HMGA1, A2, B1, and B3 by binding to their 3'UTRs and induced apoptosis but inhibited proliferation, migration, and invasion of human cervical cancer cells. In addition, miR-142-3p expression decreased phospho-p65 and EMT-related proteins in cervical cancer cells and their in vivo metastatic potential upon implantation in zebrafish. SIGNIFICANCE These findings suggest that miR-142-3p acts as a tumor-suppressive miRNA by targeting HMGA1, A2, B1, and B3 and may serve as a potential therapeutic agent in human cervical cancer.
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20
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Kim R, Kin T. Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer. Cancers (Basel) 2021; 13:cancers13194756. [PMID: 34638242 PMCID: PMC8507525 DOI: 10.3390/cancers13194756] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/16/2021] [Accepted: 09/21/2021] [Indexed: 12/28/2022] Open
Abstract
Simple Summary How a cure for primary breast cancer after (neo)adjuvant therapy can be achieved at the molecular level remains unclear. Immune activation by anticancer drugs may contribute to the eradication of residual tumor cells by postoperative (neo)adjuvant chemotherapy. In addition, chemotherapy-induced immunogenic cell death (ICD) may result in long-term immune activation by memory effector T cells, leading to the curing of primary breast cancer. In this review, we discuss the molecular mechanisms by which anticancer drugs induce ICD and immunogenic modifications for antitumor immunity and targeted therapy against damage-associated molecular patterns. Our aim was to gain a better understanding of how to eradicate residual tumor cells treated with anticancer drugs and cure primary breast cancer by enhancing antitumor immunity with immune checkpoint inhibitors and vaccines. Abstract How primary breast cancer can be cured after (neo)adjuvant therapy remains unclear at the molecular level. Immune activation by anticancer agents may contribute to residual tumor cell eradication with postsurgical (neo)adjuvant chemotherapy. Chemotherapy-induced immunogenic cell death (ICD) may result in long-term immune activation with memory effector T cells, leading to a primary breast cancer cure. Anthracycline and taxane treatments cause ICD and immunogenic modulations, resulting in the activation of antitumor immunity through damage-associated molecular patterns (DAMPs), such as adenosine triphosphate, calreticulin, high mobility group box 1, heat shock proteins 70/90, and annexin A1. This response may eradicate residual tumor cells after surgical treatment. Although DAMP release is also implicated in tumor progression, metastasis, and drug resistance, thereby representing a double-edged sword, robust immune activation by anticancer agents and the subsequent acquisition of long-term antitumor immune memory can be essential components of the primary breast cancer cure. This review discusses the molecular mechanisms by which anticancer drugs induce ICD and immunogenic modifications for antitumor immunity and targeted anti-DAMP therapy. Our aim was to improve the understanding of how to eradicate residual tumor cells treated with anticancer drugs and cure primary breast cancer by enhancing antitumor immunity with immune checkpoint inhibitors and vaccines.
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Affiliation(s)
- Ryungsa Kim
- Department of Breast Surgery, Hiroshima Mark Clinic, 1-4-3F, 2-Chome Ohte-machi, Naka-ku, Hiroshima 730-0051, Japan
- Correspondence:
| | - Takanori Kin
- Department of Breast Surgery, Hiroshima City Hospital, 7-33, Moto-machi, Naka-ku, Hiroshima 730-8518, Japan;
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Gao W, He R, Ren J, Zhang W, Wang K, Zhu L, Liang T. Exosomal HMGB1 derived from hypoxia-conditioned bone marrow mesenchymal stem cells increases angiogenesis via the JNK/HIF-1α pathway. FEBS Open Bio 2021; 11:1364-1373. [PMID: 33711197 PMCID: PMC8091582 DOI: 10.1002/2211-5463.13142] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/27/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been described to induce angiogenesis in various tissues and have been used for the development of novel cell‐based therapies. Increasing evidence suggests that MSCs execute their paracrine function via the secretion of exosomes, especially under hypoxic conditions. However, the mechanisms by which MSC‐derived exosomes secreted under hypoxia enhance angiogenesis still remain unclear. To study exosome physiology under hypoxic or normoxic conditions, we isolated exosomes from bone marrow mesenchymal stem cells (BMSCs). Furthermore, we detected the uptake of exosomes by human umbilical vein endothelial cells (HUVECs) by immunofluorescence staining. In addition, we determined the effects of exosomes on cell viability, migration and tube formation in HUVECs by Cell Counting Kit‐8, migration and tube formation assays, respectively. We examined the expression of key proteins related to exosome‐induced angiogenesis by BMSCs cultured under hypoxic conditions by western blot. Exosomes released by BMSCs cultured under hypoxic conditions enhanced cell proliferation, migration and angiogenesis of HUVECs. Hypoxia induced the expression of high mobility group box 1 protein (HMGB1) in BMSC‐derived exosomes, and silencing of HMGB1 abolished the angiogenic effect in HUVECs. Furthermore, exosomal HMGB1 activated the JNK signaling pathway and induced hypoxia‐inducible factor‐1α/vascular endothelial growth factor expression, consequently enhancing angiogenesis in HUVECs. Our data reveal that exosomal HMGB1 promotes angiogenesis via JNK/hypoxia‐inducible factor‐1α signaling. Therefore, BMSC exosomes derived under hypoxia may have potential for development of novel treatment strategies for angiogenesis‐related diseases.
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Affiliation(s)
- Wenling Gao
- Department of Orthodontics, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Ronghan He
- Department of Orthopaedic Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jianhua Ren
- Department of Orthopaedic Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wenhui Zhang
- Department of Orthopaedic Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Kun Wang
- Department of Orthopaedic Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lei Zhu
- Department of Plastic and Reconstructive Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Tangzhao Liang
- Department of Orthopaedic Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Wang S, Ge F, Cai T, Qi S, Qi Z. [Dihydromyricetin inhibits proliferation and migration of gastric cancer cells through regulating Akt/STAT3 signaling pathways and HMGB1 expression]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2021; 41:87-92. [PMID: 33509758 DOI: 10.12122/j.issn.1673-4254.2021.01.12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVE To investigate the inhibitory effects of dihydromyricetin on the proliferation and migration of gastric cancer BGC-823 cells and explore the molecular mechanisms. METHODS BGC-823 cells in routine culture were treated with different concentrations of dihydromyricetin (0, 40, 60, 80, 100, and 120 μg/mL) for 24 h, and the changes in cell viability were detected using CCK-8 assay; colony forming assay and Transwell assay were performed to assess the changes in colonyforming and migration abilities of the cells, respectively. The levels of MMP-2 and MMP-9 in the treated cells were determined using ELISA, and Western blotting was used to detect the expressions of E-cadherin, N-cadherin, cyclin D1, cyclin E1, HSP70 and HMGB1 and the phosphorylation levels of Akt and Stat3. RESULTS CCK-8 assay showed that dihydromyricetin treatment dose-dependently inhibited the viability of BGC-823 cells (P < 0.05). Treatment with dihydromyricetin obviously suppressed the proliferation and migration of BGC-823 cells, significantly reduced the expression levels of cyclin D1, cyclin E1 and Ncadherin, enhanced E-cadherin expression, inhibited the phosphorylation of Akt and stat3, and downregulated HMGB1 expression in the cells. The results of ELISA demonstrated significantly lowered levels of MMP-2 and MMP-9 in dihydromyricetin-treated cells. CONCLUSIONS Dihydromyricetin inhibits the proliferation and migration of BGC-823 cells through suppressing the activation of Akt/stat3 signaling pathways and HMGB1 expression.
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Affiliation(s)
- Shengnan Wang
- Department of Biochemistry and Molecular Biology, Wannan Medical College, Wuhu 241002, China.,Anhui Provincial Key Laboratory of Active Biological Macro-molecules, Wannan Medical College, Wuhu 241002, China
| | - Fei Ge
- School of Pharmacy, Wannan Medical College, Wuhu 241002, China
| | - Tianyu Cai
- Anhui Provincial Key Laboratory of Active Biological Macro-molecules, Wannan Medical College, Wuhu 241002, China.,School of Clinical Medicine, Wannan Medical College, Wuhu 241002, China
| | - Shimei Qi
- Department of Biochemistry and Molecular Biology, Wannan Medical College, Wuhu 241002, China.,Anhui Provincial Key Laboratory of Active Biological Macro-molecules, Wannan Medical College, Wuhu 241002, China
| | - Zhilin Qi
- Department of Biochemistry and Molecular Biology, Wannan Medical College, Wuhu 241002, China.,Anhui Provincial Key Laboratory of Active Biological Macro-molecules, Wannan Medical College, Wuhu 241002, China
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Xu Q, Liao B, Hu S, Zhou Y, Xia W. Circular RNA 0081146 facilitates the progression of gastric cancer by sponging miR-144 and up-regulating HMGB1. Biotechnol Lett 2021; 43:767-779. [PMID: 33496921 DOI: 10.1007/s10529-020-03058-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 12/10/2020] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Recent studies have revealed that circular RNA (circRNA) plays a pivotal role in cancer development. The study aimed to investigate the role of circ_0081146 in gastric cancer (GC). RESULTS Circ_0081146 was upregulated in GC tissues and cells. Patients with high expression of circ_0081146 had a significantly reduced 5-year overall survival rate. Circ_0081146 knockdown restrained the growth, migration and invasion of GC cells in vitro as well as tumorigenesis in vivo. Circ_0081146 targeted miR-144 and HMGB1 was targeted by miR-144. Circ_0081146 was negatively correlated with miR-144 expression, while positively correlated with HMGB1 expression in GC tissues. Moreover, the inhibitory effect of circ_0081146 knockdown on the progression of GC cells were reversed by silencing miR-144 or HMGB1 overexpression. Mechanically, circ_0081146 increased HMGB1 expression by targeting miR-144. CONCLUSION Circ_0081146 functions as an oncogene in GC to promote cell growth, migration and invasion via modulating the miR-144/HMGB1 axis.
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Affiliation(s)
- Qihua Xu
- Department of Gastroenterology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358, Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Bingling Liao
- Department of Gastroenterology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358, Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Sheng Hu
- Department of Gastrointestinal Surgery, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Ying Zhou
- Department of Gastroenterology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358, Datong Road, Pudong New Area, Shanghai, 200137, China.
| | - Wei Xia
- Department of Nuclear Medicine, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358, Datong Road, Pudong New Area, Shanghai, 200137, China.
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Zhou P, Zheng ZH, Wan T, Wu J, Liao CW, Sun XJ. Vitexin Inhibits Gastric Cancer Growth and Metastasis through HMGB1-mediated Inactivation of the PI3K/AKT/mTOR/HIF-1α Signaling Pathway. J Gastric Cancer 2021; 21:439-456. [PMID: 35079445 PMCID: PMC8753280 DOI: 10.5230/jgc.2021.21.e40] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 11/29/2021] [Accepted: 12/14/2021] [Indexed: 11/20/2022] Open
Affiliation(s)
- Peng Zhou
- Department of General Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People's Republic of China
- Department of Gastrointestinal Surgery, Jiangxi Provincial People’s Hospital, Nanchang, People's Republic of China
| | - Zi-Han Zheng
- Department of Gastrointestinal Surgery, Jiangxi Provincial People’s Hospital, Nanchang, People's Republic of China
| | - Tao Wan
- Department of Gastrointestinal Surgery, Jiangxi Provincial People’s Hospital, Nanchang, People's Republic of China
| | - Jie Wu
- Department of Gastrointestinal Surgery, Jiangxi Provincial People’s Hospital, Nanchang, People's Republic of China
| | - Chuan-Wen Liao
- Department of Gastrointestinal Surgery, Jiangxi Provincial People’s Hospital, Nanchang, People's Republic of China
| | - Xue-Jun Sun
- Department of General Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People's Republic of China
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Tang T, Wang S, Cai T, Cheng Z, Meng Y, Qi S, Zhang Y, Qi Z. High mobility group box 1 regulates gastric cancer cell proliferation and migration via RAGE-mTOR/ERK feedback loop. J Cancer 2021; 12:518-529. [PMID: 33391448 PMCID: PMC7739007 DOI: 10.7150/jca.51049] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 10/30/2020] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer (GC) is a common malignancy tumour in China. Despite various therapeutic approaches to improve the survival rate of GC patients, the effectiveness of currently available treatments remains unsatisfactory. High mobility group box 1 (HMGB1) is reported to play a role in tumour development. However, the molecular mechanisms involved in HMGB1-mediated regulation of proliferation and migration of GC cells remain unclear. In the present study, we demonstrated that HMGB1 is highly expressed in GC cells and tissue. In HGC-27 GC cells, HMGB1 overexpression or HMGB1 RNA interference both demonstrated that HMGB1 could promote GC cell proliferation and migration. Investigation of the underlying molecular mechanisms revealed that HMGB1 enhanced cyclins expression, induced epithelial-to-mesenchymal transition and matrix metalloproteinase (MMPs) expression and promoted RAGE expression as well as RAGE-mediated activation of Akt/mTOR/P70S6K and ERK/P90RSK/CREB signalling pathways. We also found that inhibition of ERK and mTOR using specific inhibitors reduced recombinant human HMGB1-induced RAGE expression, suggesting that the RAGE-mTOR/ERK positive feedback loop is involved in HMGB1-induced GC cell proliferation and migration. Our study highlights a novel mechanism by which HMGB1 promotes GC cell proliferation and migration via RAGE-mediated Akt-mTOR and ERK-CREB signalling pathways which also involves the RAGE-mTOR/ERK feedback loop. These findings indicate that HMGB1 is a potential therapeutic target for GC.
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Affiliation(s)
- Tuo Tang
- Department of Biochemistry and Molecular Biology.,Anhui Province Key Laboratory of Active Biological Macro-molecules
| | - Shengnan Wang
- Department of Biochemistry and Molecular Biology.,Anhui Province Key Laboratory of Active Biological Macro-molecules
| | - Tianyu Cai
- School of Clinical Medicine, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
| | - Zhenyu Cheng
- School of Clinical Medicine, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
| | - Yu Meng
- Department of Biochemistry and Molecular Biology.,Anhui Province Key Laboratory of Active Biological Macro-molecules
| | - Shimei Qi
- Department of Biochemistry and Molecular Biology.,Anhui Province Key Laboratory of Active Biological Macro-molecules
| | - Yao Zhang
- Department of Biochemistry and Molecular Biology.,Anhui Province Key Laboratory of Active Biological Macro-molecules
| | - Zhilin Qi
- Department of Biochemistry and Molecular Biology.,Anhui Province Key Laboratory of Active Biological Macro-molecules
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26
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Liu J, Wei E, Wei J, Zhou W, Webster KA, Zhang B, Li D, Zhang G, Wei Y, Long Y, Qi X, Zhang Q, Xu D. MiR-126-HMGB1-HIF-1 Axis Regulates Endothelial Cell Inflammation during Exposure to Hypoxia-Acidosis. DISEASE MARKERS 2021; 2021:4933194. [PMID: 34970357 PMCID: PMC8714334 DOI: 10.1155/2021/4933194] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 11/20/2021] [Indexed: 02/05/2023]
Abstract
Crosstalk between molecular regulators miR-126, hypoxia-inducible factor 1-alpha (HIF-1-α), and high-mobility group box-1 (HMGB1) contributes to the regulation of inflammation and angiogenesis in multiple physiological and pathophysiological settings. Here, we present evidence of an overriding role for miR-126 in the regulation of HMGB1 and its downstream proinflammatory effectors in endothelial cells subjected to hypoxia with concurrent acidosis (H/A). Methods. Primary mouse endothelial cells (PMEC) were exposed to hypoxia or H/A to simulate short or chronic low-flow ischemia, respectively. RT-qPCR quantified mRNA transcripts, and proteins were measured by western blot. ROS were quantified by fluorogenic ELISA and luciferase reporter assays employed to confirm an active miR-126 target in the HMGB1 3'UTR. Results. Enhanced expression of miR-126 in PMECs cultured under neutral hypoxia was suppressed under H/A, whereas the HMGB1 expression increased sequentially under both conditions. Enhanced expression of HMGB1 and downstream inflammation markers was blocked by the premiR-126 overexpression and optimized by antagomiR. Compared with neutral hypoxia, H/A suppressed the HIF-1α expression independently of miR-126. The results show that HMGB1 and downstream effectors are optimally induced by H/A relative to neutral hypoxia via crosstalk between hypoxia signaling, miR-126, and HIF-1α, whereas B-cell lymphoma 2(Bcl2), a HIF-1α, and miR-126 regulated gene expressed optimally under neutral hypoxia. Conclusion. Inflammatory responses of ECs to H/A are dynamically regulated by the combined actions of hypoxia, miR-126, and HIF-1α on the master regulator HMGB1. The findings may be relevant to vascular diseases including atherosclerotic occlusion and interiors of plaque where coexisting hypoxia and acidosis promote inflammation as a defining etiology.
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Affiliation(s)
- Jinxue Liu
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Eileen Wei
- Gulliver High School, Miami, FL 33156, USA
| | - Jianqin Wei
- Department of Medicine Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Wei Zhou
- Department of Ophthalmology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Keith A. Webster
- Integene International, LLC, Miami, FL 33137, USA
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA
- Everglades Biopharma, LLC, Houston, TX 77030, USA
| | - Bin Zhang
- Department of Cardiology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Dong Li
- Department of Intensive Care Unit and Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Gaoxing Zhang
- Department of Cardiology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Yidong Wei
- Department of Surgery, Youjiang Medical University for Nationalities, Chengxiang Rd, Baise, Guangxi 533000, China
| | - Yusheng Long
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangzhou 510080, China
- Department of Cardiology, Guangdong Cardiovascular Institute and Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Xiuyu Qi
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangzhou 510080, China
- Department of Cardiology, Guangdong Cardiovascular Institute and Shantou University Medical College, Shantou 515041, China
| | - Qianhuan Zhang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangzhou 510080, China
| | - Dingli Xu
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Gao W, Liang T, He R, Ren J, Yao H, Wang K, Zhu L, Xu Y. Exosomes from 3D culture of marrow stem cells enhances endothelial cell proliferation, migration, and angiogenesis via activation of the HMGB1/AKT pathway. Stem Cell Res 2020; 50:102122. [PMID: 33316600 DOI: 10.1016/j.scr.2020.102122] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 10/12/2020] [Accepted: 12/07/2020] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Angiogenesis is an essential step in tissue engineering. MSC exosomes play an important role in angiogenesis. Functional biomolecules in exosomes vested by the culture microenvironment can be transferred to recipient cells and affects their effect. 3D culture can improve the proliferation and activity of MSCs. However, whether exosomes derived from 3D culture of MSCs have an enhanced effect on angiogenesis is unclear. METHODS Herein, we compared the bioactivity of exosomes produced by conventional 2D culture (2D-exos) and 3D culture (3D-exos) of bone marrow stem cells (BMSCs) in angiogenesis. RESULTS A series of in vitro and in vivo experiments indicated that 3D-exos exhibited stronger effects on HUVEC cell proliferation, migration, tube formation, and in vivo angiogenesis compared with 2D-exos. Moreover, the superiority of 3D-exos might be attributed to the activation of HMGB1/AKT signaling. CONCLUSIONS These results indicate that exosomes from 3D culture of MSCs may serve as a potential therapeutic approach for pro-angiogenesis.
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Affiliation(s)
- Wenling Gao
- Department of Orthodontics, Hospital of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, 510060 Guangzhou, China.
| | - Tangzhao Liang
- Department of Orthopaedic Surgery, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, 510630 Guangzhou, China.
| | - Ronghang He
- Department of Orthopaedic Surgery, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, 510630 Guangzhou, China
| | - Jianhua Ren
- Department of Orthopaedic Surgery, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, 510630 Guangzhou, China
| | - Hui Yao
- Department of Orthopaedic Surgery, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, 510630 Guangzhou, China
| | - Kun Wang
- Department of Orthopaedic Surgery, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, 510630 Guangzhou, China
| | - Lei Zhu
- Department of Plastic and Reconstructive Surgery, the Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, 510630 Guangzhou, China.
| | - Yue Xu
- Department of Orthodontics, Hospital of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, 510060 Guangzhou, China.
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Zhu J, Han S. DARS-AS1 Knockdown Inhibits the Growth of Cervical Cancer Cells via Downregulating HMGB1 via Sponging miR-188-5p. Technol Cancer Res Treat 2020; 19:1533033820971669. [PMID: 33176595 PMCID: PMC7672739 DOI: 10.1177/1533033820971669] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Background: Evidence has been shown that long noncoding RNAs (lncRNAs) play an important role in the development of cervical cancer. Recently, lncRNA DARS-AS1 was shown to be dysregulated in several cancer types, but the role of DARS-AS1 in cervical cancer remains unclear. Methods: Immunofluorescence staining, flow cytometry and transwell invasion assays were used to determine proliferation, apoptosis and invasion in cervical cancer cells, respectively. The dual luciferase reporter system assay was performed to assess the interaction between DARS-AS1, miR-188-5p, and high mobility group box 1 (HMGB1) in cervical cancer cells. Results: Downregulation of DARS-AS1 markedly inhibited the proliferation and invasion of cervical cancer cells. Moreover, DARS-AS1 knockdown obviously induced the apoptosis of SiHa and HeLa cells. Meanwhile, luciferase reporter assay identified that miR-188-5p was the potential miRNA binding of DARS-AS1, and HMGB1 was the potential binding target of miR-188-5p. Mechanistic analysis indicated that downregulation of DARS-AS1 decreased the expression of HMGB1 by acting as a competitive “sponge” of miR-188-5p. Conclusion: In this study, we found that DARS-AS1 knockdown suppressed the growth of cervical cancer cells via downregulating HMGB1 via sponging miR-188-5p. Therefore, DARS-AS1 might serve as a potential target for the treatment of cervical cancer.
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Affiliation(s)
- Jinming Zhu
- Department of Oncology, Affiliated Zhongshan Hospital, Dalian University, Dalian, People's Republic of China
| | - Shichao Han
- Department of Gynecology, The 2nd Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China
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Aggarwal V, Miranda O, Johnston PA, Sant S. Three dimensional engineered models to study hypoxia biology in breast cancer. Cancer Lett 2020; 490:124-142. [PMID: 32569616 PMCID: PMC7442747 DOI: 10.1016/j.canlet.2020.05.030] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/13/2020] [Accepted: 05/22/2020] [Indexed: 12/14/2022]
Abstract
Breast cancer is the second leading cause of mortality among women worldwide. Despite the available therapeutic regimes, variable treatment response is reported among different breast cancer subtypes. Recently, the effects of the tumor microenvironment on tumor progression as well as treatment responses have been widely recognized. Hypoxia and hypoxia inducible factors in the tumor microenvironment have long been known as major players in tumor progression and survival. However, the majority of our understanding of hypoxia biology has been derived from two dimensional (2D) models. Although many hypoxia-targeted therapies have elicited promising results in vitro and in vivo, these results have not been successfully translated into clinical trials. These limitations of 2D models underscore the need to develop and integrate three dimensional (3D) models that recapitulate the complex tumor-stroma interactions in vivo. This review summarizes role of hypoxia in various hallmarks of cancer progression. We then compare traditional 2D experimental systems with novel 3D tissue-engineered models giving accounts of different bioengineering platforms available to develop 3D models and how these 3D models are being exploited to understand the role of hypoxia in breast cancer progression.
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Affiliation(s)
- Vaishali Aggarwal
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Oshin Miranda
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Paul A Johnston
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; UPMC-Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Shilpa Sant
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; UPMC-Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
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Zhang Z, Sui Y, Luan L, Li B, Qin C. Retracted: A Novel CircRNA Circ_0095424 Regulates Proliferation, Metastasis, and Apoptosis of Osteosarcoma Cells Via the PI3K/AKT Signaling Pathway Through Targeting the miR-1238/ HMGB1 Axis. Cancer Biother Radiopharm 2020; 35:e802-e813. [PMID: 32822247 DOI: 10.1089/cbr.2020.3563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Cancer Biotherapy and Radiopharmaceuticals is officially retracting the article entitled, A Novel CircRNA Circ_0095424 Regulates Proliferation, Metastasis, and Apoptosis of Osteosarcoma Cells Via the PI3K/AKT Signaling Pathway Through Targeting the miR-1238/HMGB1 Axis by Zhang et al., (Cancer Biother Radiopharm epub 19 Aug 2020; DOI: 10.1089/cbr.2020.3563), due to manipulated images appearing in the published paper. The Editor of the journal received an email on August 31, 2020 from the corresponding author of the article, Dr. Chuan Qin, indicating that, ''due to our negligence in organizing the pictures, the protein pictures are repeatedly placed in Figure 7G PI3K. For this, we express our sincerest apologies. We need to [issue] an [erratum] on this issue. We have replaced the protein picture of Figure 7G with the correct picture.'' However, one of the attachments submitted with the request appeared to be the original version of Figure 7 from the accepted manuscript. A second attachment appeared to be the data from three replicates to be used (by the journal) to construct a revised version of Figure 7. The Editor, in turn, informed the authors that it was not at the journal's discretion to create a new image for them, and asked the authors to create the revised figure and supply it to the publisher. Below is the response from Dr. Qin, dated September 2, 2020. "In fact, our team's Western blot experiment commissioned a third-party company for testing. At present, some peers have found that the company has forged experimental reports. We believe that the authenticity of the data provided by the company is problematic. After contacting the company, they were unable to provide the original images. In view of the problems in this manuscript, all the authors discussed and agreed to withdraw the manuscript." As the entirety of the situation is unacceptable, the Editor officially retracts the article based on the "forged experimental reports" and the questionable validity of the data provided. The Editor and Publisher of Cancer Biotherapy and Radiopharmaceuticals is dedicated to preserving the integrity of the scientific literature and the community it serves.
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Affiliation(s)
- Zhiguo Zhang
- Department of Orthopedics, Rizhao City Traditional Chinese Medicine Hospital, Rizhao, China
| | - Yutong Sui
- State Key Laboratory for Molecular Biology of Special Economic Animals, Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Liyi Luan
- Department of Orthopedic, The People's Hospital of Gaotang, Liaocheng, China
| | - Bo Li
- Department of Joint Surgery, No. 1 Hospital of Jilin University, Changchun, China
| | - Chuan Qin
- Department of Orthopedics, The No. 4 Hospital of Jinan, Jinan, China
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Chen ZG, Zhao HJ, Lin L, Liu JB, Bai JZ, Wang GS. Circular RNA CirCHIPK3 promotes cell proliferation and invasion of breast cancer by sponging miR-193a/HMGB1/PI3K/AKT axis. Thorac Cancer 2020; 11:2660-2671. [PMID: 32767499 PMCID: PMC7471055 DOI: 10.1111/1759-7714.13603] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 07/15/2020] [Accepted: 07/15/2020] [Indexed: 12/19/2022] Open
Abstract
Background The aim of this study was to explore the potential mechanism of circular RNA (circRNA) CirCHIPK3 on the malignant proliferation and metastasis of breast cancer (BC). Methods Human BC samples and their matched normal adjacent tissues were obtained from 50 patients to assess the expression of CirCHIPK3 and its relationship with BC prognosis. A series of in vitro and in vivo functional experiments were carried out to elucidate the role of CirCHIPK3 in BC progression and its underlying molecular mechanisms. Moreover, the interaction of CirCHIPK3, miR‐193a, and HMGB1 was examined using bioinformatics, FISH, RIP, RNA‐pull down and luciferase reporter assays. Western blot analysis was performed to examine the expression of HMGB1, p‐PI3K, total PI3K, p‐AKT, and AKT after si‐CirCHIPK3 transfection. Results Upregulation of CirCHIPK3 was identified in BC, which predicted a worse prognosis in BC patients. Furthermore, it was found that CirCHIPK3 facilitated cell proliferation, migration, and invasion in BC by regulating miR‐193a/HMGB1/PI3K/AKT signaling. CirCHIPK3 acted as a sponge for miR‐193a to facilitate HMGB1 expression. si‐CirCHIPK3 also inhibited tumor growth of BC in nude mice. si‐CircCHIPK3 decreased HMGB1/PI3K/AKT signal expression in MDA‐MB‐231 cells, whereas overexpression of CircCHIPK3 enhanced HMGB1/PI3K/AKT signal. Conclusions CirCHIPK3 regulated miR‐193a/HMGB1/PI3K/AKT signaling to facilitate BC development and progression, providing a novel therapeutic target for BC.
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Affiliation(s)
- Zhen-Gang Chen
- Deapartment of Oncology, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, China
| | - Hong-Jie Zhao
- Deapartment of Oncology, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, China
| | - Ling Lin
- Deapartment of Oncology, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, China
| | - Jin-Bo Liu
- Deapartment of Oncology, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, China
| | - Jing-Zhen Bai
- Deapartment of General Surgery, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, China
| | - Guang-Shun Wang
- Deapartment of Oncology, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, China
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Rapoport BL, Steel HC, Theron AJ, Heyman L, Smit T, Ramdas Y, Anderson R. High Mobility Group Box 1 in Human Cancer. Cells 2020; 9:E1664. [PMID: 32664328 PMCID: PMC7407638 DOI: 10.3390/cells9071664] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 12/12/2022] Open
Abstract
High mobility group box 1 (HMGB1) is an extremely versatile protein that is located predominantly in the nucleus of quiescent eukaryotic cells, where it is critically involved in maintaining genomic structure and function. During cellular stress, however, this multifaceted, cytokine-like protein undergoes posttranslational modifications that promote its translocation to the cytosol, from where it is released extracellularly, either actively or passively, according to cell type and stressor. In the extracellular milieu, HMGB1 triggers innate inflammatory responses that may be beneficial or harmful, depending on the magnitude and duration of release of this pro-inflammatory protein at sites of tissue injury. Heightened awareness of the potentially harmful activities of HMGB1, together with a considerable body of innovative, recent research, have revealed that excessive production of HMGB1, resulting from misdirected, chronic inflammatory responses, appears to contribute to all the stages of tumorigenesis. In the setting of established cancers, the production of HMGB1 by tumor cells per se may also exacerbate inflammation-related immunosuppression. These pro-inflammatory mechanisms of HMGB1-orchestrated tumorigenesis, as well as the prognostic potential of detection of elevated expression of this protein in the tumor microenvironment, represent the major thrusts of this review.
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Affiliation(s)
- Bernardo L. Rapoport
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (H.C.S.); (A.J.T.); (R.A.)
- The Medical Oncology Centre of Rosebank, Johannesburg 2196, South Africa; (L.H.); (T.S.)
| | - Helen C. Steel
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (H.C.S.); (A.J.T.); (R.A.)
| | - Annette J. Theron
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (H.C.S.); (A.J.T.); (R.A.)
| | - Liezl Heyman
- The Medical Oncology Centre of Rosebank, Johannesburg 2196, South Africa; (L.H.); (T.S.)
| | - Teresa Smit
- The Medical Oncology Centre of Rosebank, Johannesburg 2196, South Africa; (L.H.); (T.S.)
| | - Yastira Ramdas
- The Breast Care Centre, Netcare Milpark, 9 Guild Road, Parktown, Johannesburg 2193, South Africa;
| | - Ronald Anderson
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (H.C.S.); (A.J.T.); (R.A.)
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Sun S, Ma J, Xie P, Wu Z, Tian X. Hypoxia-responsive miR-141-3p is involved in the progression of breast cancer via mediating the HMGB1/HIF-1α signaling pathway. J Gene Med 2020; 22:e3230. [PMID: 32436353 PMCID: PMC7685107 DOI: 10.1002/jgm.3230] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/09/2020] [Accepted: 05/11/2020] [Indexed: 12/24/2022] Open
Abstract
Background Hypoxia‐responsive miRs have been frequently reported in the growth of various malignant tumors. The present study aimed to investigate whether hypoxia‐responsive miR‐141–3p was implicated in the pathogenesis of breast cancer via mediating the high‐mobility group box protein 1 (HMGB1)/hypoxia‐inducible factor (HIF)‐1α signaling pathway. Materials and methods miRs expression profiling was filtrated by miR microarray assays. Gene and protein expression levels, respectively, were examined by a quantitative reverse transcriptase‐polymerase chaion reaction and western blotting. Cell migration and invasion were analyzed using a transwell assay. Cell growth was determined using nude‐mouse transplanted tumor experiments. Results miR‐141–3p was observed as a hypoxia‐responsive miR in breast cancer. miR‐141–3p was down‐regulated in breast cancer specimens and could serve as an independent prognostic factor for predicting overall survival in breast cancer patients. In addition, the overexpression of miR‐141–3p could inhibit hypoxia‐induced cell migration and impede human breast cancer MDA‐MB‐231 cell growth in vivo. Mechanistically, the hypoxia‐related HMGB1/HIF‐1α signaling pathway might be a possible target of miR‐141–3p with respect to preventing the development of breast cancer. Conclusions Our finding provides a new mechanism by which miR‐141–3p could prevent hypoxia‐induced breast tumorigenesis via post‐transcriptional repression of the HMGB1/HIF‐1α signaling pathway.
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Affiliation(s)
- Shanping Sun
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Department of Breast and Thyroid Surgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, China
| | - Jinglin Ma
- Department of Breast and Thyroid Surgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, China
| | - Panpan Xie
- Department of Breast and Thyroid Surgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, China
| | - Zhen Wu
- Department of Breast and Thyroid Surgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, China
| | - Xingsong Tian
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong Province, China
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Liu Y, Chen TY, Yang ZY, Fang W, Wu Q, Zhang C. Identification of hub genes in papillary thyroid carcinoma: robust rank aggregation and weighted gene co-expression network analysis. J Transl Med 2020; 18:170. [PMID: 32299435 PMCID: PMC7161219 DOI: 10.1186/s12967-020-02327-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 04/02/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Papillary thyroid carcinoma (PTC), which is the most common endocrine malignancy, has been steadily increasing worldwide in incidence over the years, while mechanisms underlying the pathogenesis and diagnostic for PTC are incomplete. The purpose of this study is to identify potential biomarkers for diagnosis of PTC, and provide new insights into pathogenesis of PTC. METHODS Based on weighted gene co-expression network analysis, Robust Rank Aggregation, functional annotation, GSEA and DNA methylation, were employed for investigating potential biomarkers for diagnosis of PTC. RESULTS Black and turquoise modules were identified in the gene co-expression network constructed by 1807 DEGs that from 6 eligible gene expression profiles of Gene Expression Omnibus database based on Robust Rank Aggregation and weighted gene co-expression network analysis. Hub genes were significantly down-regulated and the expression levels of the hub genes were different in different stages in hub gene verification. ROC curves indicated all hub genes had good diagnostic value for PTC (except for ABCA6 AUC = 89.5%, the 15 genes with AUC > 90%). Methylation analysis showed that hub gene verification ABCA6, ACACB, RMDN1 and TFPI were identified as differentially methylated genes, and the decreased expression level of these genes may relate to abnormal DNA methylation. Moreover, the expression levels of 8 top hub genes were correlated with tumor purity and tumor-infiltrating immune cells. These findings, including functional annotations and GSEA provide new insights into pathogenesis of PTC. CONCLUSIONS The hub genes and methylation of hub genes may as potential biomarkers provide new insights for diagnosis of PTC, and all these findings may be the direction to study the mechanisms underlying of PTC in the future.
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Affiliation(s)
- Yang Liu
- Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, China
| | - Ting-Yu Chen
- Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, China
| | - Zhi-Yan Yang
- Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, China
| | - Wei Fang
- Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, China
| | - Qian Wu
- School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, People's Republic of China.
| | - Chao Zhang
- Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, China.
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Song Y, Zou X, Zhang D, Liu S, Duan Z, Liu L. Self-enforcing HMGB1/NF-κB/HIF-1α Feedback Loop Promotes Cisplatin Resistance in Hepatocellular Carcinoma Cells. J Cancer 2020; 11:3893-3902. [PMID: 32328193 PMCID: PMC7171489 DOI: 10.7150/jca.42944] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 03/27/2020] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is ranked the sixth most common cancer and the fourth leading cause of cancer-related death worldwide, and its incidence is expected to increase in the future. Cisplatin has been widely used in chemotherapy and transarterial chemoembolization in treatment for HCC. However, the main obstacle to the clinical use of cisplatin is the development of resistance, the mechanisms of which are poorly defined. Therefore, it is imperative to investigate the cellular mechanisms mediating cisplatin resistance in HCC. Here, we demonstrated that high mobility group box 1 (HMGB1) is upregulated in patients with cancer, and implicated in a tumor-supportive role. Further, we showed that HMGB1 has an important role in mediating cisplatin resistance via an HMGB1/ nuclear factor kappa-B (NF-κB)/ hypoxia inducible factor-1α (HIF-1α) feedback loop. The study findings reveal an unappreciated molecular mechanism of HMGB1-mediated cisplatin resistance and may provide a new clue in cancer therapy.
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Affiliation(s)
- Yang Song
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xuejing Zou
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Dongyan Zhang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Shanshan Liu
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhijiao Duan
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Li Liu
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Ye M, Hou H, Shen M, Dong S, Zhang T. Circular RNA circFOXM1 Plays a Role in Papillary Thyroid Carcinoma by Sponging miR-1179 and Regulating HMGB1 Expression. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 19:741-750. [PMID: 31951855 PMCID: PMC6965511 DOI: 10.1016/j.omtn.2019.12.014] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 12/07/2019] [Accepted: 12/12/2019] [Indexed: 12/31/2022]
Abstract
Circular RNAs (circRNAs) are a class of noncoding RNAs broadly expressed in cells of various species. However, the molecular mechanisms that link circRNAs with progression of papillary thyroid carcinoma (PTC) are not well understood. In the present study, we attempted to provide a novel basis for targeted therapy for PTC from the aspect of the circRNA-microRNA (miRNA)-mRNA interaction. We investigated the expression of circRNAs in five paired PTC tissues and normal tissues by microarray analysis. The circRNA microarray assay followed by qRT-PCR was used to verify the differential expression of circFOXM1 (hsa_circ_0025033), which is located at chr12: 2966846-2983691 and derived from FOXM1. The spliced length of circFOXM1 is 3410 nt. The qRT-PCR analysis was to investigate the expression pattern of circFOXM1 in PTC tissues and cell lines. Then, the effects of circFOXM1 on tumor growth were assessed in PTC in vitro and in vivo. Furthermore, bioinformatics online programs predicted, and the luciferase reporter assay was used to validate the association of circFOXM1 and miR-1179 in PTC cells. In this study, circFOXM1 was observed to be upregulated in PTC tissues and cell lines. circFOXM1 downregulation inhibited tumor growth of PTC in vitro and in vivo. Bioinformatics analysis predicted that there is a circFOXM1/miR-1179/high-mobility group box 1 (HMGB1) axis in PTC. A dual luciferase reporter system validated the direct interaction of circFOXM1, miR-1179, and HMGB1. In summary, our study demonstrated that circFOXM1 modulates cancer progression through the miR-1179/HMGB1 pathway in PTC. Our findings indicate that circFOXM1 may serve as a promising therapeutic target for the treatment of PTC patients.
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Affiliation(s)
- Mao Ye
- Department of General Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
| | - Haitao Hou
- Department of Breast and Thyroid Surgery, Tengzhou Central People's Hospital, Tengzhou 277500, China
| | - Minghai Shen
- Department of General Surgery, Xixi Hospital of Hangzhou, 310023 Hangzhou, China
| | - Shu Dong
- Jiangsu Hengrui Medicine, Jiangsu 200245, China
| | - Tao Zhang
- Department of General Surgery, Taizhou Traditional Chinese Medicine Hospital, Taizhou 318000, China
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Yang X, Wang Z, Kai J, Wang F, Jia Y, Wang S, Tan S, Shen X, Chen A, Shao J, Zhang F, Zhang Z, Zheng S. Curcumol attenuates liver sinusoidal endothelial cell angiogenesis via regulating Glis-PROX1-HIF-1α in liver fibrosis. Cell Prolif 2020; 53:e12762. [PMID: 32119185 PMCID: PMC7106966 DOI: 10.1111/cpr.12762] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 12/13/2019] [Accepted: 12/21/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Hepatic sinusoidal angiogenesis owing to dysfunctional liver sinusoidal endothelial cells (LSECs) accompanied by an abnormal angioarchitecture is a symbol related to liver fibrogenesis, which indicates a potential target for therapeutic interventions. However, there are few researches connecting angiogenesis with liver fibrosis, and the deeper mechanism remains to be explored. MATERIALS AND METHODS Cell angiogenesis and angiogenic protein were examined in primary LSECs of rats, and multifarious cellular and molecular assays revealed the efficiency of curcumol intervention in fibrotic mice. RESULTS We found that curcumol inhibited angiogenic properties through regulating their upstream mediator hypoxia-inducible factor-1α (HIF-1α). The transcription activation of HIF-1α was regulated by hedgehog signalling on the one hand, and the protein stabilization of HIF-1α was under the control of Prospero-related homeobox 1 (PROX1) on the other. A deubiquitinase called USP19 could be recruited by PROX1 and involved in ubiquitin-dependent degradation of HIF-1α. Furthermore, our researches revealed that hedgehog signalling participated in the activation of PROX1 transcription probably in vitro. Besides, curcumol was found to ameliorate liver fibrosis and sinusoid angiogenesis via hedgehog pathway in carbon tetrachloride (CCl4 ) induced liver fibrotic mice. The protein expression of key regulatory factors, PROX1 and HIF-1α, was consistent with the Smo, the marker protein of Hh signalling pathway. CONCLUSIONS In this article, we evidenced that curcumol controlling LSEC-mediated angiogenesis could be a promising therapeutic approach for liver fibrosis.
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Affiliation(s)
- Xiang Yang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Zhimin Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Jun Kai
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Feixia Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Yan Jia
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Shijun Wang
- Shandong University of Traditional Chinese MedicineJinanChina
| | - Shanzhong Tan
- Nanjing Hospital Affiliated to Nanjing University of Chinese MedicineNanjingChina
| | - Xikun Shen
- Suzhou Hospital of Traditional Chinese MedicineSuzhouChina
| | - Anping Chen
- Department of PathologySchool of MedicineSaint Louis UniversitySt. LouisMOUSA
| | - Jiangjuan Shao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
- Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
- Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
- Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
- Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
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