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Gao Y, Zandieh K, Zhao K, Khizanishvili N, Fazio PD, Yu X, Schulte L, Aillaud M, Chung HR, Ball Z, Meixner M, Bauer UM, Bartsch DK, Buchholz M, Lauth M, Nimsky C, Cook L, Bartsch JW. The long non-coding RNA NEAT1 contributes to aberrant STAT3 signaling in pancreatic cancer and is regulated by a metalloprotease-disintegrin ADAM8/miR-181a-5p axis. Cell Oncol (Dordr) 2025; 48:391-409. [PMID: 39412616 PMCID: PMC11996950 DOI: 10.1007/s13402-024-01001-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2024] [Indexed: 12/05/2024] Open
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and several studies demonstrate that STAT3 has critical roles throughout the course of PDAC pathogenesis. METHODS TCGA, microarray, and immunohistochemistry data from a PDAC cohort were used for clinical analyses. Panc89 cells with ADAM8 knockout, re-expression of ADAM8 mutants, and Panc1 cells overexpressing ADAM8 were generated. Gene expression analyses of ADAM8, STAT3, long non-coding (lnc) RNA NEAT1, miR-181a-5p and ICAM1 were performed by quantitative PCR. Subcellular fractionation quantified NEAT1 expression in cytoplasm and nucleus of PDAC cell lines. Cell proliferation, scratch, and invasion assays were performed to detect growth rate, migration and invasion capabilities of cells. Gain and loss of function experiments were carried out to investigate the biological effects of lncRNA NEAT1 and miR-181a-5p on PDAC cells and downstream genes. Dual-luciferase reporter gene assay determined interaction and binding sites of miR-181a-5p in lncRNA NEAT1. Pull down assays, RNA binding protein immunoprecipitation (RIP), and ubiquitination assays explored the molecular interaction between lncRNA NEAT1 and STAT3. RESULTS High ADAM8 expression causes aberrant STAT3 signaling in PDAC cells and is positively correlated with NEAT1 expression. NEAT1 binding to STAT3 was confirmed and prevents STAT3 degradation in the proteasome as increased degradation of STAT3 was observed in ADAM8 knockout cells and cells treated with bortezomib. Furthermore, miRNA-181a-5p regulates NEAT1 expression by direct binding to the NEAT1 promoter. CONCLUSION ADAM8 regulates intracellular STAT3 levels via miR-181a-5p and NEAT1 in pancreatic cancer.
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Affiliation(s)
- Yutong Gao
- Department of Neurosurgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Kimia Zandieh
- Department of Neurosurgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Kai Zhao
- Department of Neurosurgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Natalia Khizanishvili
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35033, Marburg, Germany
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35033, Marburg, Germany
| | - Xiangdi Yu
- Department of Anesthesiology, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou University, Guiyang, Guizhou, 550000, China
| | - Leon Schulte
- Institute for Lung Research, Philipps-University Marburg, Hans-Meerwein-Strasse 2, 35043, Marburg, Germany
| | - Michelle Aillaud
- Institute for Lung Research, Philipps-University Marburg, Hans-Meerwein-Strasse 2, 35043, Marburg, Germany
| | - Ho-Ryun Chung
- Institute for Medical Bioinformatics and Biostatistics, Philipps-University Marburg, 35033, Marburg, Germany
| | - Zachary Ball
- Department of Chemistry, Rice University, Houston, TX, USA
| | - Marion Meixner
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Marburg, Germany
| | - Uta-Maria Bauer
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Marburg, Germany
| | - Detlef Klaus Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35033, Marburg, Germany
| | - Malte Buchholz
- Department of Gastroenterology, Endocrinology, Metabolism and Infection, Center for Tumor and Immunology (ZTI), Philipps-University Marburg, Marburg, Germany
| | - Matthias Lauth
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Marburg, Germany
| | - Christopher Nimsky
- Department of Neurosurgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Lena Cook
- Department of Neurosurgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Jörg W Bartsch
- Department of Neurosurgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany.
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Shen K, Shan Z, Li Y, Ji Z, Zhou L, Lv Z. TFAP2A Activates ADAM8 to Promote Lung Adenocarcinoma Angiogenesis Through the JAK/STAT Signaling Pathway. J Biochem Mol Toxicol 2025; 39:e70097. [PMID: 39812116 DOI: 10.1002/jbt.70097] [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: 07/16/2024] [Revised: 09/10/2024] [Accepted: 12/08/2024] [Indexed: 01/16/2025]
Abstract
As the most prevalent subtype of lung cancer, lung adenocarcinoma (LUAD) is closely associated with angiogenesis, which is fundamental to its progression. ADAM8 (A disintegrin and metalloproteinase 8) is an enzyme associated with tumor invasion, while its implications in LUAD angiogenesis are a field that awaits exploration. A thorough investigation into the impacts of ADAM8 on LUAD angiogenesis could contribute to the development of therapeutic drugs for LUAD. Bioinformatics delineated the expression profiles of TFAP2A and ADAM8 in LUAD tissues, focusing on ADAM8-enriched pathways. qRT-PCR confirmed their expression in LUAD cells. The CCK-8 assay was applied to gauge cell viability, and Western blot detected the presence of JAK2/STAT3 pathway proteins and VEGFR-2 and VEGF. Angiogenesis assays quantified the length of angiogenesis, and dual-luciferase and Chromatin immunoprecipitation assays verified the TFAP2A-ADAM8 binding. ADAM8 exhibited high expression in LUAD tissues and cells, with notable enrichment in the VEGF and JAK/STAT pathways. Cellular assays revealed that elevated ADAM8 expression enhanced cell viability, promoted the phosphorylation of JAK2 and STAT3, and boosted angiogenic capacity. The JAK inhibitor Peficitinib reversed the proangiogenic effects induced by ADAM8 overexpression. We also discovered overexpression of TFAP2A, an upstream transcription factor of ADAM8, in LUAD. Rescue experiments indicated that ADAM8 overexpression could counteract the inhibitory effects of TFAP2A knockdown on LUAD angiogenesis. This study reveals for the first time the critical role of ADAM8 in LUAD angiogenesis, demonstrating that TFAP2A promotes JAK/STAT pathway conduction by activating ADAM8. This finding not only provides a new perspective for understanding the pathogenesis of LUAD but also lays the foundation for the development of new therapies targeting ADAM8.
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Affiliation(s)
- Kai Shen
- Department of Two Branches Outside, The First People's Hospital of Yongkang, Yongkang, China
| | - Zhidong Shan
- Department of Two Branches Outside, The First People's Hospital of Yongkang, Yongkang, China
| | - Yingjie Li
- Department of Two Branches Outside, The First People's Hospital of Yongkang, Yongkang, China
| | - Zeyi Ji
- Department of Two Branches Outside, The First People's Hospital of Yongkang, Yongkang, China
| | - Luyao Zhou
- Department of Two Branches Outside, The First People's Hospital of Yongkang, Yongkang, China
| | - Zhiliang Lv
- Department of Two Branches Outside, The First People's Hospital of Yongkang, Yongkang, China
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Yang M, Li S, Luo R, Zhao Y, Sun Y, Li H, Cui Q, Wu J, Mao L. ADAM8 promotes alcoholic liver fibrosis through the MAPK signaling pathway. J Physiol Sci 2024; 74:52. [PMID: 39407108 PMCID: PMC11481351 DOI: 10.1186/s12576-024-00943-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 09/22/2024] [Indexed: 10/19/2024]
Abstract
The effect and molecular regulatory mechanism of A Disintegrin and Metalloproteinase 8 (ADAM8) were explored in alcoholic liver fibrosis (ALF). C57BL/6N male mice were randomly divided into control, alcohol, and ADAM8-sgRNA3 plasmid groups. The control group received control liquid diet, while the alcohol and ADAM8-sgRNA3 plasmid groups were given alcohol liquid feed diet combined with ethanol gavage treatment for 8 weeks to induce ALF modeling. In addition, the ADAM8-sgRNA3 plasmid group was injected with the effective ADAM8-sgRNA3 plasmid, while the alcohol and control group mice were injected with an equivalent amount of physiological saline. LX-2 human hepatic stellate cells were divided into control, alcohol, si-ADAM8-2, and si-ADAM8-NC groups and induced for 48 h for model establishment in vitro. Serological detection, pathological staining, Western blotting, qRT-PCR and CCK8 assay were performed for experiments. Compared with the alcohol group, ADAM8 mRNA, protein and, positive area rate, serological indicators, pathological changes, and the expression of liver fibrosis marker and MAPK signaling pathway-related factors in the ADAM8-sgRNA3 plasmid group significantly decreased in vivo. Compared with the alcohol group, ADAM8 mRNA and protein expression, cell viability, and the expression of liver fibrosis markers and MAPK signaling pathway-related factors (p-ERK1/2, PCNA, Bcl-2, p-c-Jun, TGFβ1, p-p38 MAPK and HSP27) reduced significantly in the si-ADAM8-2 group. Therefore, ADAM8 promotes ALF through the MAPK signaling pathway, a promising target for treating ALF.
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Affiliation(s)
- Mengli Yang
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Sanqiang Li
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China.
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China.
| | - Renli Luo
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Yadi Zhao
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Yue Sun
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Haoyuan Li
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Qinyi Cui
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Junfei Wu
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China
| | - Longfei Mao
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China.
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang, 471000, Henan, China.
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Evers M, Stühmer T, Schreder M, Steinbrunn T, Rudelius M, Jundt F, Ebert R, Hartmann TN, Bargou RC, Rosenwald A, Leich E. Association of ADAM family members with proliferation signaling and disease progression in multiple myeloma. Blood Cancer J 2024; 14:156. [PMID: 39261477 PMCID: PMC11390935 DOI: 10.1038/s41408-024-01133-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/26/2024] [Accepted: 08/28/2024] [Indexed: 09/13/2024] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy whose curability is greatly challenged by recurrent patient relapses and therapy resistance. We have previously proposed the high expression of ADAM8, ADAM9 and ADAM15 (A Disintegrin And Metalloproteinase 8/9/15) as adverse prognostic markers in MM. This study focused on the so far scarcely researched role of ADAM8/9/15 in MM using two patient cohorts and seven human MM cell lines (HMCL). High ADAM8/9/15 expression was associated with high-risk cytogenetic abnormalities and extramedullary disease. Furthermore, ADAM8/15 expression increased with MM progression and in relapsed/refractory MM compared to untreated patient samples. RNA sequencing and gene set enrichment analysis comparing ADAM8/9/15high/low patient samples revealed an upregulation of proliferation markers and proliferation-associated gene sets in ADAM8/9/15high patient samples. High ADAM8/9/15 expression correlated with high Ki67 and high ADAM8/15 expression with high MYC protein expression in immunohistochemical stainings of patient tissue. Conversely, siRNA-mediated knockdown of ADAM8/9/15 in HMCL downregulated proliferation-related gene sets. Western blotting revealed that ADAM8 knockdown regulated IGF1R/AKT signaling and ADAM9 knockdown decreased mTOR activation. Lastly, high ADAM8/9/15 expression levels were verified as prognostic markers independent of Ki67/MYC expression and/or high-risk abnormalities. Overall, these findings suggest that ADAM8/9/15 play a role in MM progression and proliferation signaling.
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Affiliation(s)
| | - Thorsten Stühmer
- Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Würzburg, Germany
| | - Martin Schreder
- First Department of Medicine, Klinik Ottakring, Vienna, Austria
| | - Torsten Steinbrunn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany
| | - Martina Rudelius
- Institute of Pathology, Ludwig-Maximilians-University München, München, Germany
| | - Franziska Jundt
- Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Würzburg, Germany
- Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany
| | - Regina Ebert
- Department of Musculoskeletal Tissue Regeneration, University of Würzburg, Würzburg, Germany
| | - Tanja Nicole Hartmann
- Department of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg, Breisgau, Germany
| | - Ralf Christian Bargou
- Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Würzburg, Germany
| | | | - Ellen Leich
- Institute of Pathology, University of Würzburg, Würzburg, Germany.
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Cook L, Gharzia FG, Bartsch JW, Yildiz D. A jack of all trades - ADAM8 as a signaling hub in inflammation and cancer. FEBS J 2024; 291:3989-4008. [PMID: 38097912 DOI: 10.1111/febs.17034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/23/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023]
Abstract
As a member of the family of A Disintegrin And Metalloproteinases (ADAM) ADAM8 is preferentially expressed in lymphatic organs, immune cells, and tumor cells. The substrate spectrum for ADAM8 proteolytic activity is not exclusive but is related to effectors of inflammation and signaling in the tumor microenvironment. In addition, complexes of ADAM8 with extracellular binding partners such as integrin β-1 cause an extensive intracellular signaling in tumor cells, thereby activating kinase pathways with STAT3, ERK1/2, and Akt signaling, which causes increased cell survival and enhanced motility. The cytoplasmic domain of ADAM8 harbors five SRC homology-3 (SH3) domains that can potentially interact with several proteins involved in actin dynamics and cell motility, including Myosin 1F (MYO1F), which is essential for neutrophil motility. The concept of ADAM8 thus involves immune cell recruitment, in most cases leading to an enhancement of inflammatory (asthma, COPD) and tumor (including pancreatic and breast cancers) pathologies. In this review, we report on available studies that qualify ADAM8 as a therapeutic target in different pathologies. As a signaling hub, ADAM8 controls extracellular, intracellular, and intercellular communication, the latter one mainly mediated by the release of extracellular vesicles with ADAM8 as cargo. Here, we will dissect the contribution of different domains to these distinct ways of communication in several pathologies. We conclude that therapeutic targeting attempts for ADAM8 should consider blocking more than a single domain and that this requires a thorough evaluation of potent molecules targeting ADAM8 in an in vivo setting.
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Affiliation(s)
- Lena Cook
- Department of Neurosurgery, Philipps University Marburg, Germany
| | - Federico Guillermo Gharzia
- Experimental and Clinical Pharmacology and Toxicology Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany
| | - Jörg W Bartsch
- Department of Neurosurgery, Philipps University Marburg, Germany
| | - Daniela Yildiz
- Experimental and Clinical Pharmacology and Toxicology Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany
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Qian Z, Li R, Zhao T, Xie K, Li P, Li G, Shen N, Gong J, Hong X, Yang L, Li H. Blockade of the ADAM8-Fra-1 complex attenuates neuroinflammation by suppressing the Map3k4/MAPKs axis after spinal cord injury. Cell Mol Biol Lett 2024; 29:75. [PMID: 38755530 PMCID: PMC11100242 DOI: 10.1186/s11658-024-00589-3] [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: 02/05/2024] [Accepted: 05/06/2024] [Indexed: 05/18/2024] Open
Abstract
BACKGROUND Mechanical spinal cord injury (SCI) is a deteriorative neurological disorder, causing secondary neuroinflammation and neuropathy. ADAM8 is thought to be an extracellular metalloproteinase, which regulates proteolysis and cell adherence, but whether its intracellular region is involved in regulating neuroinflammation in microglia after SCI is unclear. METHODS Using animal tissue RNA-Seq and clinical blood sample examinations, we found that a specific up-regulation of ADAM8 in microglia was associated with inflammation after SCI. In vitro, microglia stimulated by HMGB1, the tail region of ADAM8, promoted microglial inflammation, migration and proliferation by directly interacting with ERKs and Fra-1 to promote activation, then further activated Map3k4/JNKs/p38. Using SCI mice, we used BK-1361, a specific inhibitor of ADAM8, to treat these mice. RESULTS The results showed that administration of BK-1361 attenuated the level of neuroinflammation and reduced microglial activation and recruitment by inhibiting the ADAM8/Fra-1 axis. Furthermore, treatment with BK-1361 alleviated glial scar formation, and also preserved myelin and axonal structures. The locomotor recovery of SCI mice treated with BK-1361 was therefore better than those without treatment. CONCLUSIONS Taken together, the results showed that ADAM8 was a critical molecule, which positively regulated neuroinflammatory development and secondary pathogenesis by promoting microglial activation and migration. Mechanically, ADAM8 formed a complex with ERK and Fra-1 to further activate the Map3k4/JNK/p38 axis in microglia. Inhibition of ADAM8 by treatment with BK-1361 decreased the levels of neuroinflammation, glial formation, and neurohistological loss, leading to favorable improvement in locomotor functional recovery in SCI mice.
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Affiliation(s)
- Zhanyang Qian
- Department of Orthopedics, Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
- Department of Orthopedics, Zhongda Hospital of Southeast University, Nanjing, China
| | - Rulin Li
- Department of Orthopedics, Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
- School of Postgraduate, Dalian Medical University, Dalian, China
| | - Tianyu Zhao
- Department of Orthopedics, Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
- School of Postgraduate, Dalian Medical University, Dalian, China
| | - Kunxin Xie
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - PengFei Li
- Department of Orthopedics, Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
- School of Postgraduate, Nanjing University of Chinese Medicine, Nanjing, China
| | - Guangshen Li
- Department of Orthopedics, Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
| | - Na Shen
- School of Basic Medicine, Nanjing Medical University, Nanjing, China
| | - Jiamin Gong
- School of Basic Medicine, Nanjing Medical University, Nanjing, China
| | - Xin Hong
- Department of Orthopedics, Zhongda Hospital of Southeast University, Nanjing, China
| | - Lei Yang
- Department of Orthopedics, Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China.
| | - Haijun Li
- Department of Orthopedics, Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China.
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Chen K, Tao H, Zhu P, Chu M, Li X, Shi Y, Zhang L, Xu Y, Lv S, Huang L, Huang W, Geng D. ADAM8 silencing suppresses the migration and invasion of fibroblast-like synoviocytes via FSCN1/MAPK cascade in osteoarthritis. Arthritis Res Ther 2024; 26:20. [PMID: 38218854 PMCID: PMC10787439 DOI: 10.1186/s13075-023-03238-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 12/13/2023] [Indexed: 01/15/2024] Open
Abstract
OBJECTIVE Osteoarthritis (OA) is a degenerative joint disease that affects elderly populations worldwide, causing pain and disability. Alteration of the fibroblast-like synoviocytes (FLSs) phenotype leads to an imbalance in the synovial inflammatory microenvironment, which accelerates the progression of OA. Despite this knowledge, the specific molecular mechanisms of the synovium that affect OA are still unclear. METHODS Both in vitro and in vivo experiments were undertaken to explore the role of ADAM8 playing in the synovial inflammatory of OA. A small interfering RNA (siRNA) was targeting ADAM8 to intervene. High-throughput sequencing was also used. RESULTS Our sequencing analysis revealed significant upregulation of the MAPK signaling cascade and ADAM8 gene expression in IL-1β-induced FLSs. The in vitro results demonstrated that ADAM8 blockade inhibited the invasion and migration of IL-1β-induced FLSs, while also suppressing the expression of related matrix metallomatrix proteinases (MMPs). Furthermore, our study revealed that inhibiting ADAM8 weakened the inflammatory protein secretion and MAPK signaling networks in FLSs. Mechanically, it revealed that inhibiting ADAM8 had a significant effect on the expression of migration-related signaling proteins, specifically FSCN1. When siADAM8 was combined with BDP-13176, a FSCN1 inhibitor, the migration and invasion of FLSs was further inhibited. These results suggest that FSCN1 is a crucial downstream factor of ADAM8 in regulating the biological phenotypes of FLSs. The in vivo experiments demonstrated that ADAM8 inhibition effectively reduced synoviocytes inflammation and alleviated the progression of OA in rats. CONCLUSIONS ADAM8 could be a promising therapeutic target for treating OA by targeting synovial inflammation.
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Affiliation(s)
- Kai Chen
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, Jiangsu, China
- Department of Orthopedics, Hai'an People's Hospital, Zhongba Road 17, Hai'an, Jiangsu, China
| | - Huaqiang Tao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, Jiangsu, China
| | - Pengfei Zhu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, Jiangsu, China
| | - Miao Chu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, Jiangsu, China
- Department of Orthopedics, Yixing Peoples's Hospital, Xincheng Road 1588, Yixing, Jiangsu, China
| | - Xueyan Li
- Anesthesiology department, Suzhou Municipal Hospital (North District), Nanjing Medical University Affiliated Suzhou Hospital, Guangjj Road 242, Suzhou, Jiangsu, China
| | - Yi Shi
- Anesthesiology department, Suzhou Municipal Hospital (North District), Nanjing Medical University Affiliated Suzhou Hospital, Guangjj Road 242, Suzhou, Jiangsu, China
| | - Liyuan Zhang
- Anesthesiology department, Suzhou Municipal Hospital (North District), Nanjing Medical University Affiliated Suzhou Hospital, Guangjj Road 242, Suzhou, Jiangsu, China
| | - Yaozeng Xu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, Jiangsu, China
| | - Shujun Lv
- Department of Orthopedics, Hai'an People's Hospital, Zhongba Road 17, Hai'an, Jiangsu, China.
| | - Lixin Huang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, Jiangsu, China.
| | - Wei Huang
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Lujiang Road 17, Hefei, An'hui, China.
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, Jiangsu, China.
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Kalita A, Sikora-Skrabaka M, Nowakowska-Zajdel E. Role of Some microRNA/ADAM Proteins Axes in Gastrointestinal Cancers as a Novel Biomarkers and Potential Therapeutic Targets—A Review. Curr Issues Mol Biol 2023; 45:2917-2936. [PMID: 37185715 PMCID: PMC10136553 DOI: 10.3390/cimb45040191] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/16/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Gastrointestinal (GI) cancers are some of the most common cancers in the world and their number is increasing. Their etiology and pathogenesis are still unclear. ADAM proteins are a family of transmembrane and secreted metalloproteinases that play a role in cancerogenesis, metastasis and neoangiogenesis. MicroRNAs are small single-stranded non-coding RNAs that take part in the post-transcriptional regulation of gene expression. Some ADAM proteins can be targets for microRNAs. In this review, we analyze the impact of microRNA/ADAM protein axes in GI cancers.
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Affiliation(s)
- Agnieszka Kalita
- Department of Nutrition-Related Disease Prevention, Department of Metabolic Disease Prevention, Faculty of Health Sciences in Bytom, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
- Department of Clinical Oncology, No. 4 Provincial Specialist Hospital, 41-902 Bytom, Poland
| | - Magdalena Sikora-Skrabaka
- Department of Nutrition-Related Disease Prevention, Department of Metabolic Disease Prevention, Faculty of Health Sciences in Bytom, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
- Department of Clinical Oncology, No. 4 Provincial Specialist Hospital, 41-902 Bytom, Poland
| | - Ewa Nowakowska-Zajdel
- Department of Nutrition-Related Disease Prevention, Department of Metabolic Disease Prevention, Faculty of Health Sciences in Bytom, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
- Department of Clinical Oncology, No. 4 Provincial Specialist Hospital, 41-902 Bytom, Poland
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9
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Mierke CT. The versatile roles of ADAM8 in cancer cell migration, mechanics, and extracellular matrix remodeling. Front Cell Dev Biol 2023; 11:1130823. [PMID: 36910158 PMCID: PMC9995898 DOI: 10.3389/fcell.2023.1130823] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/15/2023] [Indexed: 02/25/2023] Open
Abstract
The posttranslational proteolytic cleavage is a unique and irreversible process that governs the function and half-life of numerous proteins. Thereby the role of the family of A disintegrin and metalloproteases (ADAMs) plays a leading part. A member of this family, ADAM8, has gained attention in regulating disorders, such as neurogenerative diseases, immune function and cancer, by attenuating the function of proteins nearby the extracellular membrane leaflet. This process of "ectodomain shedding" can alter the turnover rate of a number of transmembrane proteins that function in cell adhesion and receptor signal transduction. In the past, the major focus of research about ADAMs have been on neurogenerative diseases, such as Alzheimer, however, there seems to be evidence for a connection between ADAM8 and cancer. The role of ADAMs in the field of cancer research has gained recent attention, but it has been not yet been extensively addressed. Thus, this review article highlights the various roles of ADAM8 with particular emphasis on pathological conditions, such as cancer and malignant cancer progression. Here, the shedding function, direct and indirect matrix degradation, effects on cancer cell mobility and transmigration, and the interplay of ADAM8 with matrix-embedded neighboring cells are presented and discussed. Moreover, the most probable mechanical impact of ADAM8 on cancer cells and their matrix environment is addressed and debated. In summary, this review presents recent advances in substrates/ligands and functions of ADAM8 in its new role in cancer and its potential link to cell mechanical properties and discusses matrix mechanics modifying properties. A deeper comprehension of the regulatory mechanisms governing the expression, subcellular localization, and activity of ADAM8 is expected to reveal appropriate drug targets that will permit a more tailored and fine-tuned modification of its proteolytic activity in cancer development and metastasis.
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Affiliation(s)
- Claudia Tanja Mierke
- Faculty of Physics and Earth Science, Biological Physics Division, Peter Debye Institute of Soft Matter Physics, Leipzig University, Leipzig, Germany
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10
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Schäfer A, Evers L, Meier L, Schlomann U, Bopp MHA, Dreizner GL, Lassmann O, Ben Bacha A, Benescu AC, Pojskic M, Preußer C, von Strandmann EP, Carl B, Nimsky C, Bartsch JW. The Metalloprotease-Disintegrin ADAM8 Alters the Tumor Suppressor miR-181a-5p Expression Profile in Glioblastoma Thereby Contributing to Its Aggressiveness. Front Oncol 2022; 12:826273. [PMID: 35371977 PMCID: PMC8964949 DOI: 10.3389/fonc.2022.826273] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/16/2022] [Indexed: 01/08/2023] Open
Abstract
Glioblastoma (GBM) as the most common and aggressive brain tumor is characterized by genetic heterogeneity, invasiveness, radio-/chemoresistance, and occurrence of GBM stem-like cells. The metalloprotease-disintegrin ADAM8 is highly expressed in GBM tumor and immune cells and correlates with poor survival. In GBM, ADAM8 affects intracellular kinase signaling and increases expression levels of osteopontin/SPP1 and matrix metalloproteinase 9 (MMP9) by an unknown mechanism. Here we explored whether microRNA (miRNA) expression levels could be regulators of MMP9 expression in GBM cells expressing ADAM8. Initially, we identified several miRNAs as dysregulated in ADAM8-deficient U87 GBM cells. Among these, the tumor suppressor miR-181a-5p was significantly upregulated in ADAM8 knockout clones. By inhibiting kinase signaling, we found that ADAM8 downregulates expression of miR-181a-5p via activation of signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling suggesting an ADAM8-dependent silencing of miR-181a-5p. In turn, mimic miR-181a-5p transfection caused decreased cell proliferation and lower MMP9 expression in GBM cells. Furthermore, miR-181a-5p was detected in GBM cell-derived extracellular vesicles (EVs) as well as patient serum-derived EVs. We identified miR-181a-5p downregulating MMP9 expression via targeting the MAPK pathway. Analysis of patient tissue samples (n=22) revealed that in GBM, miR-181a-5p is strongly downregulated compared to ADAM8 and MMP9 mRNA expression, even in localized tumor areas. Taken together, we provide evidence for a functional axis involving ADAM8/miR-181a-5p/MAPK/MMP9 in GBM tumor cells.
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Affiliation(s)
- Agnes Schäfer
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Lara Evers
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Lara Meier
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Uwe Schlomann
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Miriam H A Bopp
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany.,Marburg Center for Mind, Brain and Behavior (MCMBB), Marburg, Germany
| | - Gian-Luca Dreizner
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Olivia Lassmann
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Aaron Ben Bacha
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | | | - Mirza Pojskic
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Christian Preußer
- Core Facility Extracellular Vesicles, Philipps University of Marburg - Medical Faculty, Marburg, Germany
| | - Elke Pogge von Strandmann
- Core Facility Extracellular Vesicles, Philipps University of Marburg - Medical Faculty, Marburg, Germany
| | - Barbara Carl
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Christopher Nimsky
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany.,Marburg Center for Mind, Brain and Behavior (MCMBB), Marburg, Germany
| | - Jörg W Bartsch
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany.,Marburg Center for Mind, Brain and Behavior (MCMBB), Marburg, Germany
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11
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Liu J, Li J, Du H, Xu L, Yang Z, Yuan M, Zhang K, Li J, Xing W, Wang S, Hu T, Wang J, Wang J, Gong Q. Three Potential Tumor Markers Promote Metastasis and Recurrence of Colorectal Cancer by Regulating the Inflammatory Response: ADAM8, LYN, and S100A9. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:3118046. [PMID: 35103068 PMCID: PMC8800630 DOI: 10.1155/2022/3118046] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/08/2021] [Indexed: 11/17/2022]
Abstract
Metastasis and recurrence are major causes of colorectal cancer (CRC) death, but their molecular mechanisms are unclear. In this study, genes associated with CRC metastasis and recurrence were identified by weighted gene coexpression network analysis, selecting the top 25% most variant genes in the dataset GSE33113. By average linkage hierarchical clustering, a total of 21 modules were generated. One key module was identified as the most relevant to the prognosis of CRC. Gene Ontology analysis indicated that genes associated with tumor metastasis and recurrence in this module were significantly enriched in inflammatory biological functions. Functional analysis was performed on the key module, and candidate hub genes (ADAM8, LYN, and S100A9) were screened out by expression and survival analysis. In summary, the three core genes identified in this study could greatly improve our understanding of CRC metastasis and recurrence. The results also provide a theoretical basis for the use of three core genes (ADAM8, LYN, and S100A9) as a combined marker for early diagnosis, which could benefit CRC patients.
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Affiliation(s)
- Jiawei Liu
- Department of Clinical Laboratory, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, China
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jing Li
- Department of Hepatobiliary Surgery, Kailuan General Hospital, Tangshan, Hebei 063210, China
| | - Haolin Du
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, China
- Department of Clinical Laboratory, Tianshui Hospital of Traditional Chinese Medicine, Tianshui 741000, China
| | - Liming Xu
- Department of Clinical Laboratory, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China
| | - Zhenbang Yang
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Mengjiao Yuan
- Department of Clinical Laboratory, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China
| | - Kaiyue Zhang
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Jialei Li
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Wenjun Xing
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Shoujie Wang
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Tingting Hu
- Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Jinjin Wang
- Department of Clinical Laboratory, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China
| | - Jin Wang
- Department of Clinical Laboratory, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China
| | - Qian Gong
- Department of Clinical Laboratory, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China
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12
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Cuffaro D, Camodeca C, Tuccinardi T, Ciccone L, Bartsch JW, Kellermann T, Cook L, Nuti E, Rossello A. Discovery of Dimeric Arylsulfonamides as Potent ADAM8 Inhibitors. ACS Med Chem Lett 2021; 12:1787-1793. [PMID: 35111280 PMCID: PMC8805605 DOI: 10.1021/acsmedchemlett.1c00411] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 10/05/2021] [Indexed: 11/30/2022] Open
Abstract
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The metalloproteinase
ADAM8 is upregulated in several cancers but
has a dispensable function under physiological conditions. In tumor
cells, ADAM8 is involved in invasion, migration, and angiogenesis.
The use of bivalent inhibitors could impair migration and invasion
through the double binding to a homodimeric form of ADAM8 located
on the cell surface of tumor cells. Herein we report the rational
design and synthesis of the first dimeric ADAM8 inhibitors selective
over ADAM10 and matrix metalloproteinases. Bivalent derivatives have
been obtained by dimerizing the structure of a previously described
ADAM17 inhibitor, JG26. In particular, derivative 2 was
shown to inhibit ADAM8 proteolytic activity in vitro and in cell-based assays at nanomolar concentration. Moreover, it
was more effective than the parent monomeric compound in blocking
invasiveness in the breast cancer MDA-MB-231 cell line, thus supporting
our hypothesis about the importance of inhibiting the active homodimer
of ADAM8.
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Affiliation(s)
- Doretta Cuffaro
- Department of Pharmacy, University of Pisa, via Bonanno 6, 56126 Pisa, Italy
| | - Caterina Camodeca
- Department of Pharmacy, University of Pisa, via Bonanno 6, 56126 Pisa, Italy
| | - Tiziano Tuccinardi
- Department of Pharmacy, University of Pisa, via Bonanno 6, 56126 Pisa, Italy
| | - Lidia Ciccone
- Department of Pharmacy, University of Pisa, via Bonanno 6, 56126 Pisa, Italy
| | - Jörg W Bartsch
- Department of Neurosurgery, Marburg University, Baldingerstrasse, 35033 Marburg, Germany
| | - Tanja Kellermann
- Department of Neurosurgery, Marburg University, Baldingerstrasse, 35033 Marburg, Germany
| | - Lena Cook
- Department of Neurosurgery, Marburg University, Baldingerstrasse, 35033 Marburg, Germany
| | - Elisa Nuti
- Department of Pharmacy, University of Pisa, via Bonanno 6, 56126 Pisa, Italy
| | - Armando Rossello
- Department of Pharmacy, University of Pisa, via Bonanno 6, 56126 Pisa, Italy
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13
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Expression of the Metalloproteinase ADAM8 Is Upregulated in Liver Inflammation Models and Enhances Cytokine Release In Vitro. Mediators Inflamm 2021; 2021:6665028. [PMID: 33814981 PMCID: PMC7987468 DOI: 10.1155/2021/6665028] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 02/22/2021] [Accepted: 03/02/2021] [Indexed: 11/17/2022] Open
Abstract
Acute and chronic liver inflammation is driven by cytokine and chemokine release from various cell types in the liver. Here, we report that the induction of inflammatory mediators is associated with a yet undescribed upregulation of the metalloproteinase ADAM8 in different murine hepatitis models. We further show the importance of ADAM8 expression for the production of inflammatory mediators in cultured liver cells. As a model of acute inflammation, we investigated liver tissue from lipopolysaccharide- (LPS-) treated mice in which ADAM8 expression was markedly upregulated compared to control mice. In vitro, stimulation with LPS enhanced ADAM8 expression in murine and human endothelial and hepatoma cell lines as well as in primary murine hepatocytes. The enhanced ADAM8 expression was associated with an upregulation of TNF-α and IL-6 expression and release. Inhibition studies indicate that the cytokine response of hepatoma cells to LPS depends on the activity of ADAM8 and that signalling by TNF-α can contribute to these ADAM8-dependent effects. The role of ADAM8 was further confirmed with primary hepatocytes from ADAM8 knockout mice in which TNF-α and IL-6 induction and release were considerably attenuated. As a model of chronic liver injury, we studied liver tissue from mice undergoing high-fat diet-induced steatohepatitis and again observed upregulation of ADAM8 mRNA expression compared to healthy controls. In vitro, ADAM8 expression was upregulated in hepatoma, endothelial, and stellate cell lines by various mediators of steatohepatitis including fatty acid (linoleic-oleic acid), IL-1β, TNF-α, IFN-γ, and TGF-β. Upregulation of ADAM8 was associated with the induction and release of proinflammatory cytokines (TNF-α and IL-6) and chemokines (CX3CL1). Finally, knockdown of ADAM8 expression in all tested cell types attenuated the release of these mediators. Thus, ADAM8 is upregulated in acute and chronic liver inflammation and is able to promote inflammation by enhancing expression and release of inflammatory mediators.
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14
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Awan T, Babendreyer A, Mahmood Alvi A, Düsterhöft S, Lambertz D, Bartsch JW, Liedtke C, Ludwig A. Expression levels of the metalloproteinase ADAM8 critically regulate proliferation, migration and malignant signalling events in hepatoma cells. J Cell Mol Med 2021; 25:1982-1999. [PMID: 33314720 PMCID: PMC7882935 DOI: 10.1111/jcmm.16015] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 10/01/2020] [Accepted: 10/05/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common metastatic tumours. Tumour growth and metastasis depend on the induction of cell proliferation and migration by various mediators. Here, we report that the A Disintegrin and Metalloproteinase (ADAM) 8 is highly expressed in murine HCC tissues as well as in murine and human hepatoma cell lines Hepa1-6 and HepG2, respectively. To establish a dose-dependent role of different ADAM8 expression levels for HCC progression, ADAM8 expression was either reduced via shRNA- or siRNA-mediated knockdown or increased by using a retroviral overexpression vector. These two complementary approaches revealed that ADAM8 expression levels correlated positively with proliferation, clonogenicity, migration and matrix invasion and negatively with apoptosis of hepatoma cells. Furthermore, the analysis of pro-migratory and proliferative signalling pathways revealed that ADAM8 expression level was positively associated with expression of β1 integrin as well as with the activation of focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK), Src kinase and Rho A GTPase. Finally, up-regulation of promigatory signalling and cell migration was also seen with a proteolytically inactive ADAM8 mutant. These findings reveal that ADAM8 is critically up-regulated in hepatoma cells contributes to cell proliferation and survival and furthermore induces pro-migratory signalling pathways independently of its proteolytic activity. By this, ADAM8 can promote cell functions most relevant for HCC growth and metastasis.
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Affiliation(s)
- Tanzeela Awan
- Institute of Molecular PharmacologyRWTH Aachen UniversityAachenGermany
| | - Aaron Babendreyer
- Institute of Molecular PharmacologyRWTH Aachen UniversityAachenGermany
| | - Abid Mahmood Alvi
- Institute of Molecular PharmacologyRWTH Aachen UniversityAachenGermany
| | - Stefan Düsterhöft
- Institute of Molecular PharmacologyRWTH Aachen UniversityAachenGermany
| | - Daniela Lambertz
- Department of Medicine IIIUniversity Hospital RWTH Aachen UniversityAachenGermany
| | - Jörg W. Bartsch
- Department of NeurosurgeryPhilipps University MarburgUniversity Hospital MarburgMarburgGermany
| | - Christian Liedtke
- Department of Medicine IIIUniversity Hospital RWTH Aachen UniversityAachenGermany
| | - Andreas Ludwig
- Institute of Molecular PharmacologyRWTH Aachen UniversityAachenGermany
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