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Okuyama T, Tsuno T, Inoue R, Fukushima S, Kyohara M, Matsumura A, Miyashita D, Nishiyama K, Takano Y, Togashi Y, Meguro-Horike M, Horike SI, Kin T, Shapiro AJ, Yanagisawa H, Terauchi Y, Shirakawa J. The matricellular protein Fibulin-5 regulates β-cell proliferation in an autocrine/paracrine manner. iScience 2025; 28:111856. [PMID: 39995864 PMCID: PMC11848788 DOI: 10.1016/j.isci.2025.111856] [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: 02/22/2024] [Revised: 11/20/2024] [Accepted: 01/17/2025] [Indexed: 02/26/2025] Open
Abstract
The matricellular protein Fibulin-5 (Fbln5) is a secreted protein that is essential for elastic fiber formation, and pancreatic islets are usually surrounded by the extracellular matrix (ECM), which includes elastic fibers. However, much uncertainty remains regarding the function of the ECM and its components in β-cells. Here, we describe the role of Fbln5 in β-cell replication. Fbln5 expression was increased upon glucose stimulation in β-cells of mouse and human islets. β-Cell-specific Fbln5-knockout (βFbln5KO) mice exhibit significantly reduced β-cell proliferation in vivo but not in vitro. Secreted extracellular Fbln5 enhances β-cell replication. Fbln5-deficient β-cells exhibit the downregulated expression of the gene encoding Polo-like kinase 1 (PLK1), which is accompanied by ERK-mediated FoxM1 nuclear export. These data suggest that Fbln5 is secreted from β-cells in response to glucose and plays important roles in the appropriate maintenance of β-cell functions in an autocrine or paracrine manner.
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Affiliation(s)
- Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Takahiro Tsuno
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Ryota Inoue
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Setsuko Fukushima
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Anzu Matsumura
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Daisuke Miyashita
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Kuniyuki Nishiyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Yusuke Takano
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Makiko Meguro-Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Shin-ichi Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Tatsuya Kin
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - A.M. James Shapiro
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Hiromi Yanagisawa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Jun Shirakawa
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
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2
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Hao S, Cai D, Gou S, Li Y, Liu L, Tang X, Chen Y, Zhao Y, Shen J, Wu X, Li M, Chen M, Li X, Sun Y, Gu L, Li W, Wang F, Cho CH, Xiao Z, Du F. Does each Component of Reactive Oxygen Species have a Dual Role in the Tumor Microenvironment? Curr Med Chem 2024; 31:4958-4986. [PMID: 37469162 PMCID: PMC11340293 DOI: 10.2174/0929867331666230719142202] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/14/2023] [Accepted: 06/02/2023] [Indexed: 07/21/2023]
Abstract
Reactive oxygen species (ROS) are a class of highly reactive oxidizing molecules, including superoxide anion (O2 •-) and hydrogen peroxide (H2O2), among others. Moderate levels of ROS play a crucial role in regulating cellular signaling and maintaining cellular functions. However, abnormal ROS levels or persistent oxidative stress can lead to changes in the tumor microenvironment (TME) that favor cancer development. This review provides an overview of ROS generation, structure, and properties, as well as their effects on various components of the TME. Contrary to previous studies, our findings reveal a dual effect of ROS on different components of the TME, whereby ROS can either enhance or inhibit certain factors, ultimately leading to the promotion or suppression of the TME. For example, H2O2 has dual effects on immune cells and non-- cellular components within the TME, while O2 •- has dual effects on T cells and fibroblasts. Furthermore, each component demonstrates distinct mechanisms of action and ranges of influence. In the final section of the article, we summarize the current clinical applications of ROS in cancer treatment and identify certain limitations associated with existing therapeutic approaches. Therefore, this review aims to provide a comprehensive understanding of ROS, highlighting their dual effects on different components of the TME, and exploring the potential clinical applications that may pave the way for future treatment and prevention strategies.
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Affiliation(s)
- Siyu Hao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
| | - Dan Cai
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Shuang Gou
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
| | - Yan Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Lin Liu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Xiaolong Tang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
| | - Meijuan Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Yuhong Sun
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Li Gu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Wanping Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Fang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Sichuan Luzhou 646600, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646600, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646600, China
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Chen T, Li D, Wang Y, Shen X, Dong A, Dong C, Duan K, Ren J, Li W, Shu G, Yang J, Xie Y, Qian F, Zhou J. Loss of NDUFS1 promotes gastric cancer progression by activating the mitochondrial ROS-HIF1α-FBLN5 signaling pathway. Br J Cancer 2023; 129:1261-1273. [PMID: 37644092 PMCID: PMC10575981 DOI: 10.1038/s41416-023-02409-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 08/09/2023] [Accepted: 08/17/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Recent studies suggested that NDUFS1 has an important role in human cancers; however, the effects of NDUFS1 on gastric cancer (GC) are still not fully understood. METHODS We confirmed that NDUFS1 is downregulated in GC cells through western blot immunohistochemistry and bioinformation analysis. The effect of NDUFS1 on GC was studied by CCK-8, colony formation, transwell assay in vitro and Mouse xenograft assay in vivo. Expression and subcellular localization of NDUFS1 and the content of mitochondrial reactive oxygen species (mROS) was observed by confocal reflectance microscopy. RESULTS Reduced expression of NDUFS1 was found in GC tissues and cell lines. Also, NDUFS1 overexpression inhibited GC cell proliferation, migration, and invasion in vitro as well as growth and metastasis in vivo. Mechanistically, NDUFS1 reduction led to the activation of the mROS-hypoxia-inducible factor 1α (HIF1α) signaling pathway. We further clarified that NDUFS1 reduction upregulated the expression of fibulin 5 (FBLN5), a transcriptional target of HIF1α, through activation of mROS-HIF1α signaling in GC cells. CONCLUSIONS The results of this study indicate that NDUFS1 downregulation promotes GC progression by activating an mROS-HIF1α-FBLN5 signaling pathway.
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Affiliation(s)
- Tao Chen
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Dongbao Li
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Yunliang Wang
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Xiaochun Shen
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Anqi Dong
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Chao Dong
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Kaipeng Duan
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Jiayu Ren
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Weikang Li
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Gege Shu
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Jiaoyang Yang
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Yufeng Xie
- Department of Thoracic Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China.
| | - Fuliang Qian
- Center for Systems Biology, Suzhou Medical College of Soochow University, 215123, Suzhou, China.
- Medical Center of Soochow University, 215123, Suzhou, China.
- Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, 215123, Suzhou, China.
| | - Jin Zhou
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China.
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Benesch MGK, Wu R, Menon G, Takabe K. High beta integrin expression is differentially associated with worsened pancreatic ductal adenocarcinoma outcomes. Am J Cancer Res 2022; 12:5403-5424. [PMID: 36628277 PMCID: PMC9827087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 11/27/2022] [Indexed: 01/12/2023] Open
Abstract
Outcomes in pancreatic ductal adenocarcinoma (PDAC) are known to be worse in tumors with high integrin β1 expression, but targeted monotherapy against this integrin has not been effective. Seven other beta integrins are expressed in mammalian biology and they are known to have overlapping and compensatory signaling in biological systems. However, their roles in PDAC are poorly understood and have not been systematically compared to integrin β1 biology. In this study, we analyzed the clinical outcomes against beta integrin 1-8 (ITGB1-8) expression in PDAC samples from two large independent cohorts, The Cancer Genome Atlas (TCGA) and GSE21501. Biological function and tumor microenvironment composition were studied using Gene Set Enrichment Analysis and xCell. Expression of all eight beta integrins is significantly increased in PDACs relative to normal pancreatic tissues (all P<0.001). ITGB1, 2, 5, and 6 have similarly enriched gene patterns related to transforming growth factor (TGF)-β, epithelial mesenchymal transition, inflammation, stemness, and angiogenesis pathways. Homologous recombination defects and neoantigens are increased in high-ITGB4, 5, and 6 tumors, with decreased overall survival in high-ITGB1, 5, and 6 tumors compared to low expression tumors (hazard ratios 1.5-2.0). High-ITGB1, 2, and 5 tumors have increased fibroblast infiltration (all P<0.01) while endothelial cells are increased in high-ITGB2 and 3 tumors (all P<0.05). Overall, beta integrin expression does not correlate to immune cell populations in PDACs. Therefore, while all beta integrins are overexpressed in PDACs, they exert differential effects on PDAC biology. ITGB2, 5, and 6 have a similar profile to ITGB1, suggesting that future research in PDAC integrin therapy needs to consider the complementary signaling profiles mediated by these integrins.
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Affiliation(s)
- Matthew GK Benesch
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA,Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
| | - Gopal Menon
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA,Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan,Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8520, Japan,Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan,Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York 14263, USA
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Fakhri S, Moradi SZ, Nouri Z, Cao H, Wang H, Khan H, Xiao J. Modulation of integrin receptor by polyphenols: Downstream Nrf2-Keap1/ARE and associated cross-talk mediators in cardiovascular diseases. Crit Rev Food Sci Nutr 2022; 64:1592-1616. [PMID: 36073725 DOI: 10.1080/10408398.2022.2118226] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
As a group of heterodimeric and transmembrane glycoproteins, integrin receptors are widely expressed in various cell types overall the body. During cardiovascular dysfunction, integrin receptors apply inhibitory effects on the antioxidative pathways, including nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch like ECH Associated Protein 1 (Keap1)/antioxidant response element (ARE) and interconnected mediators. As such, dysregulation in integrin signaling pathways influences several aspects of cardiovascular diseases (CVDs) such as heart failure, arrhythmia, angina, hypertension, hyperlipidemia, platelet aggregation and coagulation. So, modulation of integrin pathway could trigger the downstream antioxidant pathways toward cardioprotection. Regarding the involvement of multiple aforementioned mediators in the pathogenesis of CVDs, as well as the side effects of conventional drugs, seeking for novel alternative drugs is of great importance. Accordingly, the plant kingdom could pave the road in the treatment of CVDs. Of natural entities, polyphenols are multi-target and accessible phytochemicals with promising potency and low levels of toxicity. The present study aims at providing the cardioprotective roles of integrin receptors and downstream antioxidant pathways in heart failure, arrhythmia, angina, hypertension, hyperlipidemia, platelet aggregation and coagulation. The potential role of polyphenols has been also revealed in targeting the aforementioned dysregulated signaling mediators in those CVDs.
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Affiliation(s)
- Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed Zachariah Moradi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zeinab Nouri
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hui Cao
- Department of Analytical and Food Chemistry, Faculty of Sciences, Universidade de Vigo, Nutrition and Bromatology Group, Ourense, Spain
| | - Hui Wang
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang, China
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Jianbo Xiao
- Department of Analytical and Food Chemistry, Faculty of Sciences, Universidade de Vigo, Nutrition and Bromatology Group, Ourense, Spain
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang, China
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6
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Tang Z, Wu S, Zhao P, Wang H, Ni D, Li H, Jiang X, Wu Y, Meng Y, Yao Z, Cai W, Bu W. Chemical Factory-Guaranteed Enhanced Chemodynamic Therapy for Orthotopic Liver Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201232. [PMID: 35712774 PMCID: PMC9376848 DOI: 10.1002/advs.202201232] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/09/2022] [Indexed: 05/05/2023]
Abstract
In the field of nanomedicine, there is a tendency of matching designed nanomaterials with a suitable type of orthotopic cancer model, not just a casual subcutaneous one. Under this condition, knowing the specific features of the chosen cancer model is the priority, then introducing a proper therapy strategy using designed nanomaterials. Here, the Fenton chemistry is combined with zinc peroxide nanoparticles in the treatment of orthotopic liver cancer which has a "chemical factory" including that liver is the main place for iron storage, metabolism, and also the main metabolic sites for the majority of ingested substances, guaranteeing customized and enhanced chemodynamic therapy and normal liver cells protection as well. The good results in vitro and in vivo can set an inspiring example for exploring and utilizing suitable nanomaterials in corresponding cancer models, ensuring well-fitness of nanomaterials for disease and satisfactory therapeutic effect.
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Affiliation(s)
- Zhongmin Tang
- Tongji University Cancer CenterShanghai Tenth People's HospitalTongji University School of MedicineShanghai200072P. R. China
- Departments of Radiology, Medical Physics, Materials Science & EngineeringPharmaceutical SciencesUniversity of Wisconsin − MadisonMadisonWI53705USA
| | - Shiman Wu
- Department of RadiologyHuashan HospitalFudan UniversityShanghai200040P. R. China
| | - Peiran Zhao
- Department of Materials Science and State Key Laboratory of Molecular Engineering of PolymersFudan University220 Handan RoadShanghai200438P. R. China
| | - Han Wang
- Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai200240P. R. China
| | - Dalong Ni
- Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai200240P. R. China
| | - Huiyan Li
- Department of Materials Science and State Key Laboratory of Molecular Engineering of PolymersFudan University220 Handan RoadShanghai200438P. R. China
| | - Xingwu Jiang
- Department of Materials Science and State Key Laboratory of Molecular Engineering of PolymersFudan University220 Handan RoadShanghai200438P. R. China
| | - Yelin Wu
- Tongji University Cancer CenterShanghai Tenth People's HospitalTongji University School of MedicineShanghai200072P. R. China
| | - Yun Meng
- Tongji University Cancer CenterShanghai Tenth People's HospitalTongji University School of MedicineShanghai200072P. R. China
| | - Zhenwei Yao
- Department of RadiologyHuashan HospitalFudan UniversityShanghai200040P. R. China
| | - Weibo Cai
- Departments of Radiology, Medical Physics, Materials Science & EngineeringPharmaceutical SciencesUniversity of Wisconsin − MadisonMadisonWI53705USA
| | - Wenbo Bu
- Tongji University Cancer CenterShanghai Tenth People's HospitalTongji University School of MedicineShanghai200072P. R. China
- Department of Materials Science and State Key Laboratory of Molecular Engineering of PolymersFudan University220 Handan RoadShanghai200438P. R. China
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7
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Li J, Peng L, Chen Q, Ye Z, Zhao T, Hou S, Gu J, Hang Q. Integrin β1 in Pancreatic Cancer: Expressions, Functions, and Clinical Implications. Cancers (Basel) 2022; 14:cancers14143377. [PMID: 35884437 PMCID: PMC9318555 DOI: 10.3390/cancers14143377] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/02/2022] [Accepted: 07/07/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Pancreatic cancer (PC) is a highly aggressive malignant tumor with an extremely poor prognosis. Early diagnosis and treatment are key to improving the survival rate of PC patients. Emerging studies show that integrins might contribute to the pathogenesis of PC. This review presents the various signaling pathways that are mediated by integrins in PC and emphasizes the multiple functions of integrin β1 in malignant behaviors of PC. It also discusses the clinical significance of integrin β1 as well as integrin β1-based therapy in PC patients. Abstract Pancreatic cancer (PC) is characterized by rapid progression and a high mortality rate. The current treatment is still based on surgical treatment, supplemented by radiotherapy and chemotherapy, and new methods of combining immune and molecular biological treatments are being explored. Despite this, the survival rate of PC patients is still very disappointing. Therefore, clarifying the molecular mechanism of PC pathogenesis and developing precisely targeted drugs are key to improving PC prognosis. As the most common β subunit of the integrin family, integrin β1 has been proved to be closely related to the vascular invasion, distant metastasis, and survival of PC patients, and treatment targeting integrin β1 in PC has gained initial success in animal models. In this review, we summarize the various signaling pathways by which integrins are involved in PC, focusing on the roles of integrin β1 in the malignant behaviors of PC. Additionally, recent studies regarding the feasibility of integrin β1 as a diagnostic and prognostic biomarker in PC are also discussed. Finally, we present the progress of several integrin β1-based clinical trials to highlight the potential of integrin β1 as a target for personalized therapy in PC.
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Affiliation(s)
- Jiajia Li
- Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou 225009, China; (J.L.); (S.H.)
| | - Liyao Peng
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, China;
| | - Qun Chen
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China;
| | - Ziping Ye
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China;
| | - Tiantian Zhao
- Department of Clinical Medicine, Medical College, Yangzhou University, Yangzhou 225001, China;
| | - Sicong Hou
- Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou 225009, China; (J.L.); (S.H.)
- Department of Clinical Medicine, Medical College, Yangzhou University, Yangzhou 225001, China;
| | - Jianguo Gu
- Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai 81-8558, Japan
- Correspondence: (J.G.); (Q.H.); Tel.: +86-13-8145-8885 (Q.H.)
| | - Qinglei Hang
- Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai 81-8558, Japan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence: (J.G.); (Q.H.); Tel.: +86-13-8145-8885 (Q.H.)
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8
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PCNA inhibition enhances the cytotoxicity of β-lapachone in NQO1-Positive cancer cells by augmentation of oxidative stress-induced DNA damage. Cancer Lett 2021; 519:304-314. [PMID: 34329742 DOI: 10.1016/j.canlet.2021.07.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/20/2021] [Accepted: 07/25/2021] [Indexed: 12/25/2022]
Abstract
β-Lapachone is a classic quinone-containing antitumor NQO1-bioactivatable drug that directly kills NQO1-overexpressing cancer cells. However, the clinical applications of β-lapachone are primarily limited by its high toxicity and modest lethality. To overcome this side effect and expand the therapeutic utility of β-lapachone, we demonstrate the effects of a novel combination therapy including β-lapachone and the proliferating cell nuclear antigen (PCNA) inhibitor T2 amino alcohol (T2AA) on various NQO1+ cancer cells. PCNA has DNA clamp processivity activity mediated by encircling double-stranded DNA to recruit proteins involved in DNA replication and DNA repair. In this study, we found that compared to monotherapy, a nontoxic dose of the T2AA synergized with a sublethal dose of β-lapachone in an NQO1-dependent manner and that combination therapy prevented DNA repair, increased double-strand break (DSB) formation and promoted programmed necrosis and G1 phase cell cycle arrest. We further determined that combination therapy enhanced antitumor efficacy and prolonged survival in Lewis lung carcinoma (LLC) xenografts model. Our findings show novel evidence for a new therapeutic approach that combines of β-lapachone treatment with PCNA inhibition that is highly effective in treating NQO1+ solid tumor cells.
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9
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Sun B, Tomita B, Salinger A, Tilvawala RR, Li L, Hakami H, Liu T, Tsoyi K, Rosas IO, Reinhardt DP, Thompson PR, Ho IC. PAD2-mediated citrullination of Fibulin-5 promotes elastogenesis. Matrix Biol 2021; 102:70-84. [PMID: 34274450 DOI: 10.1016/j.matbio.2021.07.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 07/03/2021] [Accepted: 07/05/2021] [Indexed: 12/14/2022]
Abstract
The formation of elastic fibers is active only in the perinatal period. How elastogenesis is developmentally regulated is not fully understood. Citrullination is a unique form of post-translational modification catalyzed by peptidylarginine deiminases (PADs), including PAD1-4. Its physiological role is largely unknown. By using an unbiased proteomic approach of lung tissues, we discovered that FBLN5 and LTBP4, two key elastogenic proteins, were temporally modified in mouse and human lungs. We further demonstrated that PAD2 citrullinated FBLN5 preferentially in young lungs compared to adult lungs. Genetic ablation of PAD2 resulted in attenuated elastogenesis in vitro and age-dependent emphysema in vivo. Mechanistically, citrullination protected FBLN5 from proteolysis and subsequent inactivation of its elastogenic activity. Furthermore, citrullinated but not native FBLN5 partially rescued in vitro elastogenesis in the absence of PAD activity. Our data uncover a novel function of citrullination, namely promoting elastogenesis, and provide additional insights to how elastogenesis is regulated.
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Affiliation(s)
- Bo Sun
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Beverly Tomita
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Ari Salinger
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Ronak R Tilvawala
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Ling Li
- Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada
| | - Hana Hakami
- Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada
| | - Tao Liu
- Harvard Medical School, Boston, MA 02115, USA; Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Konstantin Tsoyi
- Pulmonary, Critical Care and Sleep Medicine Section, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ivan O Rosas
- Pulmonary, Critical Care and Sleep Medicine Section, Baylor College of Medicine, Houston, TX 77030, USA
| | - Dieter P Reinhardt
- Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada
| | - Paul R Thompson
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - I-Cheng Ho
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
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10
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Yan Y, Liu X, Li X, Zhou X, Yang C, Tian J, Pu J, Niu X. Effect of fibulin-5 on aldosterone-induced apoptosis in human ascending aortic smooth muscle cells. Exp Ther Med 2021; 22:896. [PMID: 34257709 PMCID: PMC8243313 DOI: 10.3892/etm.2021.10328] [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: 09/09/2017] [Accepted: 12/01/2017] [Indexed: 11/06/2022] Open
Abstract
The aim of the current study was to investigate the effect of aldosterone on apoptosis in human aortic smooth muscle cells (HA-VSMC) and to determine the role of fibulin-5 in the aldosterone-induced apoptosis of HA-VSMC cells. Through the construction of a fibulin-5 eukaryotic overexpression vector and a short hairpin RNA interference plasmid, fibulin-5 was overexpressed and silenced, respectively. The role of fibulin-5 in the aldosterone-induced apoptosis of HA-VSMC was subsequently determined. The overexpression of fibulin-5 inhibited the apoptosis of cells, particularly at low concentrations of aldosterone; a smaller effect on apoptosis was induced by high concentrations of aldosterone. fibulin-5 knockdown promoted the apoptosis of cells induced by high concentrations of aldosterone but had a smaller effect on the apoptosis of cells induced by low concentrations of aldosterone. Therefore, the results of the current study indicate that fibulin-5 inhibits the aldosterone-induced apoptosis of HA-VSMC cells and that this effect may be altered by changing the aldosterone concentration.
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Affiliation(s)
- Yongji Yan
- Department of Urology, Beijing University of Chinese Medicine Dongzhimen Hospital, Beijing 100700, P.R. China
| | - Xujie Liu
- Department of Neurosurgery, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Xuanchen Li
- Department of Neurosurgery, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Xuan Zhou
- Department of Neurosurgery, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Chaozhi Yang
- Department of Neurosurgery, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Jintao Tian
- Department of Neurosurgery, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Jun Pu
- Department of Neurosurgery, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China.,Department of Pneumology, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Xiaoqun Niu
- Department of Pneumology, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
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11
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Yuan R, Li Y, Yang B, Jin Z, Xu J, Shao Z, Miao H, Ren T, Yang Y, Li G, Song X, Hu Y, Wang X, Huang Y, Liu Y. LOXL1 exerts oncogenesis and stimulates angiogenesis through the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis in ICC. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 23:797-810. [PMID: 33614230 PMCID: PMC7868718 DOI: 10.1016/j.omtn.2021.01.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/05/2021] [Indexed: 02/07/2023]
Abstract
Aberrant expression of lysyl oxidase-like 1 (LOXL1) reportedly leads to fibrous diseases. Recent studies have revealed its role in cancers. In this study, we observed an elevated level of LOXL1 in the tissues and sera of patients with intrahepatic cholangiocarcinoma (ICC) compared with levels in nontumor tissues and sera of unaffected individuals. Overexpression of LOXL1 in RBE and 9810 cell lines promoted cell proliferation, colony formation, and metastasis in vivo and in vitro and induced angiogenesis. In contrast, depletion of LOXL1 showed the opposite effects. We further showed that LOXL1 interacted with fibulin 5 (FBLN5), which regulates angiogenesis, through binding to the αvβ3 integrin in an arginine-glycine-aspartic (Arg-Gly-Asp) domain-dependent mechanism and enhanced the focal adhesion kinase (FAK)-mitogen-activated protein kinase (MAPK) signaling pathway inside vascular endothelial cells. Our findings shed light on the molecular mechanism underlying LOXL1 regulation of angiogenesis in ICC development and indicate that the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis might be the critical pathological link leading to angiogenesis in ICC.
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Affiliation(s)
- Ruiyan Yuan
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yang Li
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Bo Yang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Department of Surgery, First Affiliated Hospital of Wenzhou Medical University, Baixiang Road, Wenzhou 325000, China
| | - Zhaohui Jin
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jiacheng Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China
| | - Ziyu Shao
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Huijie Miao
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Tai Ren
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yang Yang
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Guoqiang Li
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiaoling Song
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yunping Hu
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xu'an Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Ying Huang
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
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12
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Diversity of Mechanisms Underlying Latent TGF-β Activation in Recessive Dystrophic Epidermolysis Bullosa. J Invest Dermatol 2020; 141:1450-1460.e9. [PMID: 33333127 DOI: 10.1016/j.jid.2020.10.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 09/22/2020] [Accepted: 10/27/2020] [Indexed: 12/13/2022]
Abstract
Injury- and inflammation-driven progressive dermal fibrosis is a severe manifestation of recessive dystrophic epidermolysis bullosa-a genetic skin blistering disease caused by mutations in COL7A1. TGF-β activation plays a prominent part in progressing dermal fibrosis. However, the underlying mechanisms are not fully elucidated. TGF-β is secreted in a latent form, which has to be activated for its biological functions. In this study, we determined that recessive dystrophic epidermolysis bullosa fibroblasts have an enhanced capacity to activate the latent form. Mechanistic and functional assessment demonstrated that this process depends on multiple latent TGF-β activators, including TSP-1, RGD-binding integrins, matrix metalloproteinases, and ROS, which act in concert, in a self-perpetuating feedback loop to progress fibrosis. Importantly, our study also disclosed keratinocytes as prominent facilitators of fibrosis in recessive dystrophic epidermolysis bullosa. They stimulate microenvironmental latent TGF-β activation through enhanced production of the above mediators. Collectively, our study provides data on the molecular mechanism behind dysregulated TGF-β signaling in recessive dystrophic epidermolysis bullosa, which are much needed for the development of evidence-based fibrosis-delaying treatments.
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13
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Xu F, Zhang P, Yuan M, Yang X, Chong T. Bioinformatic screening and identification of downregulated hub genes in adrenocortical carcinoma. Exp Ther Med 2020; 20:2730-2742. [PMID: 32765768 PMCID: PMC7401943 DOI: 10.3892/etm.2020.8987] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 04/17/2020] [Indexed: 12/11/2022] Open
Abstract
The molecular mechanisms of adrenocortical carcinoma (ACC) carcinogenesis and progression remain unclear. In the present study, three microarray datasets from the Gene Expression Omnibus database were screened, which identified a total of 96 differentially expressed genes (DEGs). A protein-protein interaction network (PPI) was established for these DEGs and module analysis was performed using STRING and Cytoscape. A total of eight hub genes were identified from the most significant module; namely, calponin 1 (CNN1), myosin light chain kinase (MYLK), cysteine and glycine rich protein 1 (CSRP1), myosin heavy chain 11 (MYH11), fibulin extracellular matrix protein 2 (EFEMP2), fibulin 1 (FBLN1), microfibril associated protein 4 (MFAP4) and fibulin 5 (FBLN5). The biological functions of these hub genes were analyzed using the DAVID online tool. Changes in the expression of hub genes did not affect overall survival; however, downregulated EFEMP2 decreased disease-free survival. CSRP1 and MFAP4 expression levels were associated with adverse clinicopathological features. In conclusion, although all eight hub genes were downregulated in ACC, they appeared to have important functions in ACC carcinogenesis and progression. Identification of these genes complements the genetic expression profile of ACC and provides insight for the diagnosis, treatment and prognosis of ACC.
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Affiliation(s)
- Fangshi Xu
- Department of Urology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710000, P.R. China.,Department of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Peng Zhang
- Department of Urology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710000, P.R. China
| | - Miao Yuan
- Department of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaojie Yang
- Department of Urology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710000, P.R. China
| | - Tie Chong
- Department of Urology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710000, P.R. China
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14
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Yang Q, Li K, Huang X, Zhao C, Mei Y, Li X, Jiao L, Yang H. lncRNA SLC7A11-AS1 Promotes Chemoresistance by Blocking SCF β-TRCP-Mediated Degradation of NRF2 in Pancreatic Cancer. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 19:974-985. [PMID: 32036249 PMCID: PMC7013141 DOI: 10.1016/j.omtn.2019.11.035] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 11/05/2019] [Indexed: 12/18/2022]
Abstract
Drug resistance is the major obstacle of gemcitabine-based chemotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC). Many long non-coding RNAs (lncRNAs) are reported to play vital roles in cancer initiation and progression. Here, we report that lncRNA SLC7A11-AS1 is involved in gemcitabine resistance of PDAC. SLC7A11-AS1 is overexpressed in PDAC tissues and gemcitabine-resistant cell lines. Knockdown of SLC7A11-AS1 weakens the PDAC stemness and potentiates the sensitivity of resistant PDAC cells toward gemcitabine in vitro and in vivo. SLC7A11-AS1 promotes chemoresistance through reducing intracellular reactive oxygen species (ROS) by stabilizing nuclear factor erythroid-2-related factor 2 (NRF2), the key regulator in antioxidant defense. Mechanically, SLC7A11-AS1 is co-localized with β-TRCP1 in the nucleus. The exon 3 of SLC7A11-AS1 interacts with the F-box motif of β-TRCP1, the critical domain that recruits β-TRCP1 to the SCFβ-TRCP E3 complex. This interaction prevents the consequent ubiquitination and proteasomal degradation of NRF2 in the nucleus. Our results demonstrate that the overexpression of SLC7A11-AS1 in gemcitabine-resistant PDAC cells can scavenge ROS by blocking SCFβ-TRCP-mediated ubiquitination and degradation of NRF2, leading to a low level of intracellular ROS, which is required for the maintenance of cancer stemness. These findings suggest SLC7A11-AS1 as a therapeutic target to overcome gemcitabine resistance for PDAC treatment.
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Affiliation(s)
- Qingzhu Yang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Kai Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Xuemei Huang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Chen Zhao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Yu Mei
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Xinyuan Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Lin Jiao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Huanjie Yang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China.
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15
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De novo variants in an extracellular matrix protein coding gene, fibulin-5 (FBLN5) are associated with pseudoexfoliation. Eur J Hum Genet 2019; 27:1858-1866. [PMID: 31358954 DOI: 10.1038/s41431-019-0482-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 07/05/2019] [Accepted: 07/16/2019] [Indexed: 02/08/2023] Open
Abstract
Fibulin-5 (FBLN5), an extracellular scaffold protein, plays a crucial role in the activation of Lysyl oxidase like-1 (LOXL1), a tropoelastin crosslinking enzyme, and subsequent deposition of elastin in the extracellular matrix. Following study identifies polymorphisms within FBLN5 gene as risk factors and its aberrant expression in the pathogenesis of an ocular disorder, pseudoexfoliation (PEX). Exons and exon-intron boundaries within FBLN5 gene were scanned through fluorescence-based capillary electrophoresis for polymorphisms as risk factors for PEX pathogenesis in recruited study subjects with Indian ethnicity. mRNA and protein expression of FBLN5 was checked in lens capsule of study subjects through qRT-PCR and western blotting, respectively. In vitro functional analysis of risk variants was done through luciferase reporter assays. Thirty study subjects from control and PEX affected groups were scanned for potential risk variants. Putative polymorphisms identified by scanning were further evaluated for genetic association in a larger sample size comprising of 338 control and 375 PEX affected subjects. Two noncoding polymorphisms, hg38 chr14:g.91947643G>A (rs7149187:G>A) and hg38 chr14:g.91870431T>C (rs929608:T>C) within FBLN5 gene are found to be significantly associated with PEX as risk factors with a p-value of 0.005 and 0.004, respectively. Molecular assays showed a decreased expression of FBLN5 at both mRNA and protein level in lens capsule of pseudoexfoliation syndrome (PEXS) affected subjects than control. This study unravels two novel risk variants within FBLN5 gene in the pathogenesis of PEX. Further, a decreased expression of FBLN5 in PEXS affected lens capsules implicates a pathogenic link between extracellular matrix maintenance and onset of PEX.
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16
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Chen Y, Li J, Jin L, Lei K, Liu H, Yang Y. Fibulin-5 contributes to colorectal cancer cell apoptosis via the ROS/MAPK and Akt signal pathways by downregulating transient receptor potential cation channel subfamily V member 1. J Cell Biochem 2019; 120:17838-17846. [PMID: 31148262 DOI: 10.1002/jcb.29051] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 03/17/2019] [Accepted: 04/30/2019] [Indexed: 02/03/2023]
Abstract
Fibulin-5, a multifunctional extracellular matrix (ECM) protein, is secreted into the ECM, regulating metastasis and invasion in many malignant tumors. However, its role in colorectal cancer (CRC) has not been reported. In this study, we detected the expression of fibulin-5 in 56 CRC patients and eight CRC cell lines, revealing that fibulin-5 was expressed lower in CRC tumor tissues than in peritumor tissues. Furthermore, our study verified that fibulin-5 promoted cell apoptosis and reactive oxygen species (ROS) production by inhibiting transient receptor potential cation channel subfamily V member 1 (TRPV1) in CRC cells. Moreover, NAC (the scavenger of ROS), SB203580 (the inhibitor of p38), PD98059 (the inhibitor of ERK), and SC79 (the activator of Akt) were used to uncover that fibulin-5 induced apoptosis through the ROS/mitogen-activated protein kinase and Akt signal pathways by downregulating TRPV1. Together, these results suggest that fibulin-5 might serve as a novel drug target for the treatment of CRC patients.
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Affiliation(s)
- Yan Chen
- Department of General Surgery 2, The Ninth Hospital of Xi'an, Xi'an, Shaanxi, China
| | - Junzhi Li
- Department of Emergency Clinic, The Ninth Hospital of Xi'an, Xi'an, Shaanxi, China
| | - Lei Jin
- Department of General Surgery 2, The Ninth Hospital of Xi'an, Xi'an, Shaanxi, China
| | - Kai Lei
- Department of General Surgery 2, The Ninth Hospital of Xi'an, Xi'an, Shaanxi, China
| | - Haiwang Liu
- Department of General Surgery 2, The Ninth Hospital of Xi'an, Xi'an, Shaanxi, China
| | - Yong Yang
- Department of General Surgery 2, The Ninth Hospital of Xi'an, Xi'an, Shaanxi, China
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17
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Basu K, Maurya N, Kaur J, Saxena R, Gupta V, Sihota R, Ghosh I. Possible role of differentially expressing novel protein markers (ligatin and fibulin-7) in human aqueous humor and trabecular meshwork tissue in glaucoma progression. Cell Biol Int 2019; 43:820-834. [PMID: 30958601 DOI: 10.1002/cbin.11138] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 03/23/2019] [Indexed: 11/11/2022]
Abstract
The pathological mechanism underlying glaucoma has always been a complex aspect of this permanently blinding disease but proteomic studies have been helpful in elucidating it to a great extent in several studies. This study was designed to evaluate the expression and to get an idea about the function of two novel markers (ligatin and fibulin-7) identified in human aqueous humor (hAH) in relation to glaucomatous progression. A significant increase in the protein content of glaucomatous hAH compared to that of non-glaucomatous controls (NG-Ctrls) was observed. Ligatin, fibulin-7, and its proteolysis were revealed in hAH of primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG) and NG-Ctrls. Quantification confirmed no significant difference in expression of ligatin, whereas fibulin-7 was significantly (P < 0.05) low in hAH of PACG in comparison to NG-Ctrls and POAG. Importantly the immunohistochemical assay for both indicated their possible involvement in the maintenance of the appropriate structure of TM in vivo. Since oxidative stress is a major contributor to glaucomatous pathogenesis, in vitro analysis of nuclear and cytoplasmic fractions indicated intracellular changes in localization and expression of ligatin upon oxidative insult of human trabecular meshwork (TM) cells. While no such changes were found for fibulin-7 expression. This was also corroborated with the immunocytochemical assay. Though a study with a small sample size, this is the first report which confirms the presence of ligatin and fibulin-7 in hAH, quantified their differential expression, and indicated the possibility of their involvement in the maintenance of the TM structure.
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Affiliation(s)
- Kaustuv Basu
- Biochemistry and Environmental Toxicology Division, Laboratory # 103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Nancy Maurya
- Biochemistry and Environmental Toxicology Division, Laboratory # 103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Jasbir Kaur
- Department of Ocular Biochemistry, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Rohit Saxena
- Glaucoma Research Facility & Clinical Services Division, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Viney Gupta
- Glaucoma Research Facility & Clinical Services Division, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Ramanjit Sihota
- Glaucoma Research Facility & Clinical Services Division, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Ilora Ghosh
- Biochemistry and Environmental Toxicology Division, Laboratory # 103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India
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18
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Abstract
One of the biggest challenges in the management of obesity is the prevention of weight regain after successful weight loss. Weight regain after weight loss has large interindividual variation. Although many factors probably contribute to this variation, we hypothesize that variability in biological responses associated with weight loss-induced shrinking of subcutaneous adipocytes has an important role. In this Review, we show that weight loss-induced variations in cellular stress, extracellular matrix remodelling, inflammatory responses, adipokine secretion and lipolysis seem to be associated with the amount of weight that is regained after successful weight loss. Weight regain could therefore, at least in part, depend on a combination of these factors. Further research on the causality of these associations could aid the development of effective strategies to prevent weight regain after successful weight loss.
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Affiliation(s)
- Marleen A van Baak
- NUTRIM School for Nutrition and Translational Research in Metabolism, Department of Human Biology, Maastricht University, Maastricht, Netherlands.
| | - Edwin C M Mariman
- NUTRIM School for Nutrition and Translational Research in Metabolism, Department of Human Biology, Maastricht University, Maastricht, Netherlands
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19
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Roles of short fibulins, a family of matricellular proteins, in lung matrix assembly and disease. Matrix Biol 2018; 73:21-33. [DOI: 10.1016/j.matbio.2018.02.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 12/26/2017] [Accepted: 02/01/2018] [Indexed: 12/19/2022]
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20
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Manders DB, Kishore HA, Gazdar AF, Keller PW, Tsunezumi J, Yanagisawa H, Lea J, Word RA. Dysregulation of fibulin-5 and matrix metalloproteases in epithelial ovarian cancer. Oncotarget 2018; 9:14251-14267. [PMID: 29581841 PMCID: PMC5865667 DOI: 10.18632/oncotarget.24484] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 02/01/2018] [Indexed: 12/20/2022] Open
Abstract
Fibulin 5 (FBLN5) is an extracellular matrix glycoprotein that suppresses matrix metalloprotease 9 (MMP-9), angiogenesis and epithelial cell motility. Here, we investigated the regulation and function of FBLN5 in epithelial ovarian cancer (EOC). FBLN5 mRNA was down-regulated 5-fold in EOC relative to benign ovary. Not surprisingly, MMP9 mRNA and enzyme activity were increased significantly, and inversely correlated with FBLN5 gene expression. FBLN5 degradation products of 52.8 and 41.3 kDa were increased substantially in EOC. We identified two candidate proteases (serine elastase and MMP-7, but not MMP-9) that cleave FBLN5. MMP-7, but not neutrophil elastase, gene expression was increased dramatically in EOC. Recombinant FBLN5 significantly inhibited adhesion of EOC cells to both laminin and collagen I. Finally, using immunohistochemistry, we found immunoreactive FBLN5 within tumor macrophages throughout human EOC tumors. This work indicates that FBLN5 is degraded in EOC most likely by proteases enriched in macrophages of the tumor microenvironment. Proteolysis of FBLN5 serves as a mechanism to promote cell adhesion and local metastasis of ovarian cancer cells. Promotion of a stable ECM with intact FBLN5 in the tumor matrix may serve as a novel therapeutic adjunct to prevent spread of ovarian cancer.
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Affiliation(s)
- Dustin B Manders
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Hari Annavarapu Kishore
- Department of Obstetrics and Gynecology, Green Center for Reproductive Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Adi F Gazdar
- Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Patrick W Keller
- Department of Obstetrics and Gynecology, Green Center for Reproductive Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Jun Tsunezumi
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Hiromi Yanagisawa
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Current address: Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Jayanthi Lea
- Department of Obstetrics and Gynecology, Green Center for Reproductive Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Ruth Ann Word
- Department of Obstetrics and Gynecology, Green Center for Reproductive Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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21
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Shen H, Sun T, Hoang HH, Burchfield JS, Hamilton GF, Mittendorf EA, Ferrari M. Enhancing cancer immunotherapy through nanotechnology-mediated tumor infiltration and activation of immune cells. Semin Immunol 2017; 34:114-122. [PMID: 28947107 PMCID: PMC5705528 DOI: 10.1016/j.smim.2017.09.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 09/10/2017] [Accepted: 09/11/2017] [Indexed: 12/11/2022]
Abstract
Cancer immunotherapy has become arguably the most promising advancement in cancer research and therapy in recent years. The efficacy of cancer immunotherapy is critically dependent on specific physiological and physical processes - collectively referred to as transport barriers - including the activation of T cells by antigen presenting cells, T cells migration to and penetration into the tumor microenvironment, and movement of nutrients and other immune cells through the tumor microenvironment. Nanotechnology-based approaches have great potential to help overcome these transport barriers. In this review, we discuss the ways that nanotechnology is being leveraged to improve the efficacy and potency of various cancer immunotherapies.
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Affiliation(s)
- Haifa Shen
- Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA
| | - Tong Sun
- Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA
| | - Hanh H Hoang
- Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA
| | - Jana S Burchfield
- Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA
| | - Gillian F Hamilton
- Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA
| | - Elizabeth A Mittendorf
- Department of Breast Surgical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mauro Ferrari
- Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
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22
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Labrousse-Arias D, Martínez-Ruiz A, Calzada MJ. Hypoxia and Redox Signaling on Extracellular Matrix Remodeling: From Mechanisms to Pathological Implications. Antioxid Redox Signal 2017; 27:802-822. [PMID: 28715969 DOI: 10.1089/ars.2017.7275] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
SIGNIFICANCE The extracellular matrix (ECM) is an essential modulator of cell behavior that influences tissue organization. It has a strong relevance in homeostasis and translational implications for human disease. In addition to ECM structural proteins, matricellular proteins are important regulators of the ECM that are involved in a myriad of different pathologies. Recent Advances: Biochemical studies, animal models, and study of human diseases have contributed to the knowledge of molecular mechanisms involved in remodeling of the ECM, both in homeostasis and disease. Some of them might help in the development of new therapeutic strategies. This review aims to review what is known about some of the most studied matricellular proteins and their regulation by hypoxia and redox signaling, as well as the pathological implications of such regulation. CRITICAL ISSUES Matricellular proteins have complex regulatory functions and are modulated by hypoxia and redox signaling through diverse mechanisms, in some cases with controversial effects that can be cell or tissue specific and context dependent. Therefore, a better understanding of these regulatory processes would be of great benefit and will open new avenues of considerable therapeutic potential. FUTURE DIRECTIONS Characterizing the specific molecular mechanisms that modulate matricellular proteins in pathological processes that involve hypoxia and redox signaling warrants additional consideration to harness the potential therapeutic value of these regulatory proteins. Antioxid. Redox Signal. 27, 802-822.
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Affiliation(s)
- David Labrousse-Arias
- 1 Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) , Madrid, Spain
| | - Antonio Martínez-Ruiz
- 1 Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) , Madrid, Spain .,2 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) , Madrid, Spain
| | - María J Calzada
- 1 Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) , Madrid, Spain .,3 Departmento de Medicina, Universidad Autónoma de Madrid , Madrid, Spain
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23
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Huang H, Du W, Brekken RA. Extracellular Matrix Induction of Intracellular Reactive Oxygen Species. Antioxid Redox Signal 2017; 27:774-784. [PMID: 28791881 DOI: 10.1089/ars.2017.7305] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
SIGNIFICANCE The extracellular matrix (ECM) is the noncellular component secreted by cells and is present within all tissues and organs. The ECM provides the structural support required for tissue integrity and also contributes to diseases, including cancer. Many diseases rich in ECM are characterized by changes in reactive oxygen species (ROS) levels that have been shown to have important context-dependent functions. Recent Advances: Many studies have found that the ECM affects ROS production through integrins. The activation of integrins by ECM ligands results in stimulation of multiple pathways that can generate ROS. Furthermore, control of ECM-integrin interaction by matricellular proteins is an underappreciated pathway that functions as an ROS rheostat in remodeling tissues. CRITICAL ISSUES A better understanding of how the ECM affects the generation of intracellular ROS is required for advances in the development of therapeutic strategies that affect or exploit oxidative stress. FUTURE DIRECTIONS Targeting ROS generation can be therapeutic or can promote disease progression in a context-dependent manner. Many ECM proteins can impact ROS generation. However, given the breadth of different proteins that constitute the ECM and the cell surface receptors that interact with ECM proteins, there are likely many tissue and microenvironmental-specific ROS-generating pathways that have yet to be investigated in depth. Identifying canonical pathways of ECM-induced ROS generation should be a priority for the field. Antioxid. Redox Signal. 27, 774-784.
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Affiliation(s)
- Huocong Huang
- 1 Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research , Dallas, Texas
| | - Wenting Du
- 1 Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research , Dallas, Texas
| | - Rolf A Brekken
- 1 Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research , Dallas, Texas.,2 Department of Pharmacology, UT Southwestern, Dallas, Texas
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24
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Fibulin-5 promotes airway smooth muscle cell proliferation and migration via modulating Hippo-YAP/TAZ pathway. Biochem Biophys Res Commun 2017; 493:985-991. [PMID: 28942149 DOI: 10.1016/j.bbrc.2017.09.105] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 09/19/2017] [Indexed: 01/27/2023]
Abstract
Asthma is a common chronic disease mainly occurs from childhood. Increased airway smooth muscle mass is involved in the pathogenesis of asthma. Fibulin-5 was upregulated in the lung tissues of patients with COPD and idiopathic pulmonary fibrosis. This study aimed to investigate Fibulin-5 expression in asthmatic patients and the effect and mechanism of Fibulin-5 on the proliferation and migration of airway smooth muscle cells (ASMCs). The expression of Fibulin-5, YAP, and TAZ in the induced sputum of 38 asthmatic children (19 mild and 19 moderate asthmatics) and 19 healthy controls was determined. The effects and mechanisms of Fibulin-5 on the proliferation and migration of ASMCs were analyzed through upregulating Fibulin-5. We found compared with healthy controls, the expression of Fibulin-5, YAP, and TAZ was increased in the induced sputum of asthmatic children and much higher in moderate asthmatics. Fibulin-5 overexpression promoted the proliferation and migration of ASMCs, upregulated the expression of YAP and TAZ, and reduced the levels of p-YAP and p-TAZ. YAP inhibitor (Peptide 17) abrogated the proliferation and migration of ASMCs induced by Fibulin-5 overexpression in a dose-dependent manner. Additionally, Fibulin-5 overexpression enhanced its binding capacity of β1 integrin, and β1 integrin blocking antibody partly reversed the effect of Fibulin-5 overexpression on the levels of YAP and TAZ. In conclusion, Fibulin-5 expression is correlated with the pathogenesis of childhood asthma. It may function at least partly through binding to β1 integrin and modulating Hippo-YAP/TAZ pathway to promote the proliferation and migration of ASMCs.
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25
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Okuyama T, Shirakawa J, Yanagisawa H, Kyohara M, Yamazaki S, Tajima K, Togashi Y, Terauchi Y. Identification of the matricellular protein Fibulin-5 as a target molecule of glucokinase-mediated calcineurin/NFAT signaling in pancreatic islets. Sci Rep 2017; 7:2364. [PMID: 28539593 PMCID: PMC5443834 DOI: 10.1038/s41598-017-02535-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 04/12/2017] [Indexed: 12/12/2022] Open
Abstract
Glucokinase-mediated glucose signaling induces insulin secretion, proliferation, and apoptosis in pancreatic β-cells. However, the precise molecular mechanisms underlying these processes are not clearly understood. Here, we demonstrated that glucokinase activation using a glucokinase activator (GKA) significantly upregulated the expression of Fibulin-5 (Fbln5), a matricellular protein involved in matrix-cell signaling, in isolated mouse islets. The islet Fbln5 expression was induced by ambient glucose in a time- and dose-dependent manner and further enhanced by high-fat diet or the deletion of insulin receptor substrate 2 (IRS-2), whereas the GKA-induced increase in Fbln5 expression was diminished in Irs-2-deficient islets. GKA-induced Fbln5 upregulation in the islets was blunted by a glucokinase inhibitor, KATP channel opener, Ca2+ channel blocker and calcineurin inhibitor, while it was augmented by harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1 A inhibitor. Although deletion of Fbln5 in mice had no significant effects on the glucose tolerance or β-cell functions, adenovirus-mediated Fbln5 overexpression increased glucose-stimulated insulin secretion in INS-1 rat insulinoma cells. Since the islet Fbln5 expression is regulated through a glucokinase/KATP channel/calcineurin/nuclear factor of activated T cells (NFAT) pathway crucial for the maintenance of β-cell functions, further investigation of Fbln5 functions in the islets is warranted.
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Affiliation(s)
- Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Jun Shirakawa
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan.
| | - Hiromi Yanagisawa
- Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Shunsuke Yamazaki
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Kazuki Tajima
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan.
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26
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Adult-onset demyelinating neuropathy associated with FBLN5 gene mutation. Clin Neuropathol 2017; 36:171-177. [PMID: 28332470 PMCID: PMC5541264 DOI: 10.5414/np301011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2017] [Indexed: 11/18/2022] Open
Abstract
Rare forms of autosomal-dominant Charcot-Marie-Tooth disease (AD-CMT) may be associated with mutations in Fibulin-5 (FBLN5) as AD-CMT is genetically heterogeneous. Here, we report the first pathological study of an Asian family. The proband was a 46-year-old man with slowly progressive distal numbness and weakness for 12 years. He had a history of diabetes mellitus for 12 years. His mother was 81 years old and had mild polyneuropathy. His 16-year-old daughter was asymptomatic. The nerve conduction velocities (NCVs) and compound muscular action potential (CMAP) amplitudes were moderately to severely reduced in the proband, and moderately reduced in his daughter and mother. A sensory response could not be elicited in the proband and was moderately to severely decreased in the daughter and mother. Nerve ultrasound indicated a general enlargement of the peripheral nerves in the proband, daughter, and mother. A sural nerve biopsy from the proband demonstrated a pronounced depletion of myelinated fibers, thin myelinated fibers, and onion-bulb formations. A reported heterozygous mutation of c.1117C>T in FBLN5 was identified in the proband, mother, and daughter. These findings confirm a novel subtype of AD-CMT 1 due to a mutation in the FBLN5 gene.
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27
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Zhang D, Wang S, Chen J, Liu H, Lu J, Jiang H, Huang A, Chen Y. Fibulin-4 promotes osteosarcoma invasion and metastasis by inducing epithelial to mesenchymal transition via the PI3K/Akt/mTOR pathway. Int J Oncol 2017; 50:1513-1530. [PMID: 28339091 PMCID: PMC5403358 DOI: 10.3892/ijo.2017.3921] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 03/13/2017] [Indexed: 01/01/2023] Open
Abstract
This study explored the role of fibulin-4 in osteosarcoma progression and the possible signaling pathway involved. Fibulin-4 mRNA and protein expression in normal tissue, benign fibrous dysplasia, osteosarcoma, osteosarcoma cell lines, the normal osteoblastic cell line hFOB, and different invasive subclones were evaluated by immunohistochemistry (IHC) or immunocytochemistry (ICC) and real-time reverse transcriptase-polymerase chain reaction (real-time qRT-PCR). Using in vitro functional assays, we analyzed the invasive and proliferative abilities of different osteosarcoma cell lines and subclones with differing invasive potential. To assess the role of fibulin-4 in the invasion and metastasis of osteosarcoma cells, lentiviral vectors with fibulin-4 small hairpin RNA (shRNA) and pLVX-fibulin-4 were constructed and used to infect the highly invasive and low invasive subclones and osteosarcoma cell lines. The effects of fibulin-4 knockdown and upregulation on the biological behavior of osteosarcoma cells were investigated by functional in vitro and in vivo assays. The results revealed that fibulin-4 expression was upregulated in osteosarcoma, and was positively correlated with low differentiation, lymph node metastasis, and poor prognosis. Fibulin-4 was also found to be over-expressed in highly invasive cell lines and in the highly invasive subclones. Fibulin-4 could promote osteosarcoma cell invasion and metastasis by inducing EMT via the PI3K/AKT/mTOR pathway. Collectively, our findings demonstrate that fibulin-4 is a promoter of osteosarcoma development and progression, and suggest a novel therapeutic target for future studies.
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Affiliation(s)
- Dong Zhang
- Department of Orthopedics, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Songgang Wang
- Department of Orthopedics, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jie Chen
- Department of Maternal and Child Health, School of Public Health, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Haitao Liu
- Department of Orthopedics, Xiangcheng No. 2 People's Hospital, Suzhou, Jiangsu 215143, P.R. China
| | - Jinfa Lu
- Department of Orthopedics, Xiangcheng No. 2 People's Hospital, Suzhou, Jiangsu 215143, P.R. China
| | - Hua Jiang
- Department of Orthopedics, Xiangcheng No. 2 People's Hospital, Suzhou, Jiangsu 215143, P.R. China
| | - Aimin Huang
- Department of Orthopedics, Xiangcheng No. 2 People's Hospital, Suzhou, Jiangsu 215143, P.R. China
| | - Yunzhen Chen
- Department of Orthopedics, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
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28
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Ventura JLM. [Fibulin-5, a new potential therapeutic target in AAA]. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ARTERIOSCLEROSIS 2016; 28:281-282. [PMID: 27890284 DOI: 10.1016/j.arteri.2016.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
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Topalovski M, Hagopian M, Wang M, Brekken RA. Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer. J Biol Chem 2016; 291:22244-22252. [PMID: 27531748 DOI: 10.1074/jbc.m116.730945] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Indexed: 12/17/2022] Open
Abstract
The deposition of extracellular matrix (ECM) is a defining feature of pancreatic ductal adenocarcinoma (PDA), where ECM signaling can promote cancer cell survival and epithelial plasticity programs. However, ECM signaling can also limit PDA tumor growth by producing cytotoxic levels of reactive oxygen species. For example, excess fibronectin stimulation of α5β1 integrin on stromal cells in PDA results in reduced angiogenesis and increased tumor cell apoptosis because of oxidative stress. Fibulin-5 (Fbln5) is a matricellular protein that blocks fibronectin-integrin interaction and thus directly limits ECM-driven reactive oxygen species production and supports PDA progression. Compared with normal pancreatic tissue, Fbln5 is expressed abundantly in the stroma of PDA; however, the mechanisms underlying the stimulation of Fbln5 expression in PDA are undefined. Using in vitro and in vivo approaches, we report that hypoxia triggers Fbln5 expression in a TGF-β- and PI3K-dependent manner. Pharmacologic inhibition of TGF-β receptor, PI3K, or protein kinase B (AKT) was found to block hypoxia-induced Fbln5 expression in mouse embryonic fibroblasts and 3T3 fibroblasts. Moreover, tumor-associated fibroblasts from mouse PDA were also responsive to TGF-β receptor and PI3K/AKT inhibition with regard to suppression of Fbln5. In genetically engineered mouse models of PDA, therapy-induced hypoxia elevated Fbln5 expression, whereas pharmacologic inhibition of TGF-β signaling reduced Fbln5 expression. These findings offer insight into the signaling axis that induces Fbln5 expression in PDA and a potential strategy to block its production.
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Affiliation(s)
- Mary Topalovski
- From the Hamon Center for Therapeutic Oncology Research, Cancer Biology Graduate Program
| | | | - Miao Wang
- From the Hamon Center for Therapeutic Oncology Research
| | - Rolf A Brekken
- From the Hamon Center for Therapeutic Oncology Research, Cancer Biology Graduate Program, Division of Surgical Oncology, Department of Surgery, and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593
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30
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Mohamedi Y, Fontanil T, Solares L, Garcia-Suárez O, García-Piqueras J, Vega JA, Cal S, Obaya AJ. Fibulin-5 downregulates Ki-67 and inhibits proliferation and invasion of breast cancer cells. Int J Oncol 2016; 48:1447-56. [PMID: 26891749 DOI: 10.3892/ijo.2016.3394] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 12/08/2015] [Indexed: 11/06/2022] Open
Abstract
Fibulins not only function as molecular bridges within the cellular microenvironment but also influence cell behavior. Thus, fibulins may contribute to create a permissive microenvironment for tumor growth but can also stimulate different mechanisms that may impede tumor progression. This is the case with Fibulin-5, which has been shown to display both tumor-promoting and tumor-protective functions by mechanisms that are not totally defined. We show new evidence on the tumor-protective functions displayed by Fibulin-5 in MCF-7, T47D and MDA-MB-231 breast cancer cells including the inhibition of invasion and proliferation capacity and hampering the ability to form mammospheres. Reduction in the level of phosphorylation of Ser residues involved in the nuclear translocation of β-catenin may underlie these antitumor effects. We also found that Fibulin-5 reduces the level of expression of Ki-67, a nuclear protein associated with cell proliferation. Moreover, reduction in Fibulin-5 expression corresponds to an increase of Ki-67 detection in breast tissue samples. Overall, our data provide new insights into the influence of Fibulin-5 to modify breast cancer cell behavior and contribute to better understand the connections between fibulins and cancer.
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Affiliation(s)
- Yamina Mohamedi
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
| | - Tania Fontanil
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
| | - Laura Solares
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
| | - Olivia Garcia-Suárez
- Department of Morphology and Cellular Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
| | - Jorge García-Piqueras
- Department of Morphology and Cellular Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
| | - Jose A Vega
- Department of Morphology and Cellular Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
| | - Santiago Cal
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
| | - Alvaro J Obaya
- Department of Functional Biology-Physiology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
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31
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Variation in extracellular matrix genes is associated with weight regain after weight loss in a sex-specific manner. GENES AND NUTRITION 2015; 10:56. [PMID: 26584808 PMCID: PMC4653119 DOI: 10.1007/s12263-015-0506-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 11/04/2015] [Indexed: 11/04/2022]
Abstract
The extracellular matrix (ECM) of adipocytes is important for body weight regulation. Here, we investigated whether genetic variation in ECM-related genes is associated with weight regain among participants of the European DiOGenes study. Overweight and obese subjects (n = 469, 310 females, 159 males) were on an 8-week low-calorie diet with a 6-month follow-up. Body weight was measured before and after the diet, and after follow-up. Weight maintenance scores (WMS, regained weight as percentage of lost weight) were calculated based on the weight data. Genotype data were retrieved for 2903 SNPs corresponding to 124 ECM-related genes. Regression analyses provided us with six significant SNPs associated with the WMS in males: 3 SNPs in the POSTN gene and a SNP in the LAMB1, COL23A1, and FBLN5 genes. For females, 1 SNP was found in the FN1 gene. The risk of weight regain was increased by: the C/C genotype for POSTN in a co-dominant model (OR 8.25, 95 % CI 2.85–23.88) and the T/C–C/C genotype in a dominant model (OR 4.88, 95 % CI 2.35–10.16); the A/A genotype for LAMB1 both in a co-dominant model (OR 18.43, 95 % CI 2.35–144.63) and in a recessive model (OR 16.36, 95 % CI 2.14–124.9); the G/A genotype for COL23A1 in a co-dominant model (OR 3.94, 95 % CI 1.28–12.10), or the A-allele in a dominant model (OR 2.86, 95 % CI 1.10–7.49); the A/A genotype for FBLN5 in a co-dominant model (OR 13.00, 95 % CI 1.61–104.81); and the A/A genotype for FN1 in a recessive model (OR 2.81, 95 % CI 1.40–5.63). Concluding, variants of ECM genes are associated with weight regain after weight loss in a sex-specific manner.
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32
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Wang M, Topalovski M, Toombs JE, Wright CM, Moore ZR, Boothman DA, Yanagisawa H, Wang H, Witkiewicz A, Castrillon DH, Brekken RA. Fibulin-5 Blocks Microenvironmental ROS in Pancreatic Cancer. Cancer Res 2015; 75:5058-69. [PMID: 26577699 DOI: 10.1158/0008-5472.can-15-0744] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 08/15/2015] [Indexed: 12/16/2022]
Abstract
Elevated oxidative stress is an aberration seen in many solid tumors, and exploiting this biochemical difference has the potential to enhance the efficacy of anticancer agents. Homeostasis of reactive oxygen species (ROS) is important for normal cell function, but excessive production of ROS can result in cellular toxicity, and therefore ROS levels must be balanced finely. Here, we highlight the relationship between the extracellular matrix and ROS production by reporting a novel function of the matricellular protein Fibulin-5 (Fbln5). We used genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC) and found that mutation of the integrin-binding domain of Fbln5 led to decreased tumor growth, increased survival, and enhanced chemoresponse to standard PDAC therapies. Through mechanistic investigations, we found that improved survival was due to increased levels of oxidative stress in Fbln5-mutant tumors. Furthermore, loss of the Fbln5-integrin interaction augmented fibronectin signaling, driving integrin-induced ROS production in a 5-lipooxygenase-dependent manner. These data indicate that Fbln5 promotes PDAC progression by functioning as a molecular rheostat that modulates cell-ECM interactions to reduce ROS production, and thus tip the balance in favor of tumor cell survival and treatment-refractory disease.
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Affiliation(s)
- Miao Wang
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas
| | - Mary Topalovski
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas
| | - Jason E Toombs
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas
| | - Christopher M Wright
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas
| | - Zachary R Moore
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - David A Boothman
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - Hiromi Yanagisawa
- Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas
| | - Huamin Wang
- Department of Pathology, UT MD Anderson Cancer Center, Houston, Texas
| | | | | | - Rolf A Brekken
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas. Department of Surgery, UT Southwestern Medical Center, Dallas, Texas. Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas.
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Tang JC, Liu JH, Liu XL, Liang X, Cai XJ. Effect of fibulin-5 on adhesion, migration and invasion of hepatocellular carcinoma cells via an integrin-dependent mechanism. World J Gastroenterol 2015; 21:11127-11140. [PMID: 26494967 PMCID: PMC4607910 DOI: 10.3748/wjg.v21.i39.11127] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 07/08/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To elucidate the role of fibulin-5 (FBLN-5) as a suppressor of hepatocellular carcinoma (HCC) cell metastasis via integrin.
METHODS: The expression of FBLN-5 was determined by immunohistochemistry in 140 HCC samples and matched normal tissues, and was further confirmed by RT-PCR and Western blot analyses in various cell lines. Recombinant FBLN-5 was expressed in Escherichia coli BL21(DE3), purified and used in cell attachment assays. Expression of a specific plasmid or a specific siRNA in HCC cells resulted in the overexpression or knockdown of FBLN-5, respectively. Further, the migration and invasion of HCC cells were investigated using the Boyden chamber and transwell assays. The concentration of secreted matrix metalloproteinase 7 (MMP-7) was determined using ELISA.
RESULTS: FBLN-5 expression was found to be downregulated in HCC. Its expression was significantly correlated with advanced tumor metastasis; this was indicative of poor 5-year overall survival. Recombinant full-length human FBLN-5 promoted the attachment of HCC cells via integrins: it inhibited HCC cell adhesion and migration to fibronectin in a concentration-dependent manner. It also inhibited HCC cell migration and invasion through an integrin-binding arginine-glycine-aspartic acid (RGD) motif by downregulating MMP-7.
CONCLUSION: These results suggest that lower FBLN-5 expression is an important indicator of poor survival and that FBLN-5 inhibits HCC motility via an integrin-dependent mechanism. RGD-dependent suppression of MMP-7 by FBLN-5 might contribute to the development of new therapeutic strategies for HCC.
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Shi XY, Wang L, Cao CH, Li ZY, Chen J, Li C. Effect of Fibulin-5 on cell proliferation and invasion in human gastric cancer patients. ASIAN PAC J TROP MED 2015; 7:787-91. [PMID: 25129461 DOI: 10.1016/s1995-7645(14)60137-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Revised: 07/15/2014] [Accepted: 09/15/2014] [Indexed: 10/24/2022] Open
Abstract
OBJECTIVES To explore the effect of Fibulin-5 expression on cell proliferation and invasion in human gastric cancer patients. METHODS Fibulin-5 expression was detected in 56 samples of surgically resected gastric cancer and paired noncancerous tissues using qRT-PCR and immunoblotting. Fibulin-5 was knocked down by Fibulin-5 shRNA in MGC-803 cells, then BrdU cell proliferation and transwell invasion assays were used to determine cell proliferation and invasion. RESULTS The level of Fibulin-5 mRNA in gastric cancer tissues was significantly higher as compared with that in normal tumor-adjacent tissues (P<0.05). Otherwise, the level of Fibulin-5 protein in cancer and noncancerous tissues was consistent with mRNA expression (P<0.05). Fibulin-5 protein expression in tumor tissues with poorly differentiated, lymph node metastasis and advanced TNM tumor stage was significantly higher (P<0.05, respectively). Fibulin-5 was obviously knocked down by Fibulin-5 shRNA (P<0.05), and Fibulin-5 knockdown significantly inhibited cell proliferation and invasion in MGC-803 cells (P<0.05, respectively). CONCLUSIONS The high-expression of Fibulin-5 is associated with the malignant clinicopathologic parameters in gastric cancer and Fibulin-5 knockdown inhibits cell proliferation and invasion in MGC-803 cells, suggesting Fibulin-5 may act as a key factor in the progression of gastric cancer.
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Affiliation(s)
- Xiao-Yu Shi
- Department of General Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Liang Wang
- Department of General Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Chun-Hui Cao
- Department of General Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Zhi-Yu Li
- Department of General Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Jian Chen
- Department of General Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Chen Li
- Department of General Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.
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Guo J, Cheng C, Chen CS, Xing X, Xu G, Feng J, Qin X. Overexpression of Fibulin-5 Attenuates Ischemia/Reperfusion Injury After Middle Cerebral Artery Occlusion in Rats. Mol Neurobiol 2015; 53:3154-3167. [DOI: 10.1007/s12035-015-9222-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Accepted: 05/21/2015] [Indexed: 02/07/2023]
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Chen J, Liu Z, Fang S, Fang R, Liu X, Zhao Y, Li X, Huang L, Zhang J. Fibulin-4 is associated with tumor progression and a poor prognosis in ovarian carcinomas. BMC Cancer 2015; 15:91. [PMID: 25885889 PMCID: PMC4359517 DOI: 10.1186/s12885-015-1100-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 02/20/2015] [Indexed: 12/16/2022] Open
Abstract
Background Fibulin-4, a member of the fibulin family of extracellular glycoproteins, is implicated in the progressions of some cancers. However, no information has been available to date regarding the function of fibulin-4 in ovarian carcinoma progression. Methods In this study, fibulin-4 mRNA and protein expression in normal ovarian tissue, ovarian tumor, high invasive subclones and low invasive subclones were evaluated by immunohistochemistry and real time reverse transcriptase-polymerase chain reaction (RT-PCR). The serum levels of fibulin-4, cancer antigen 125 (CA-125) and cerbohydrate antigen 199 (CA19-9) in patients with ovarian tumor were measured by enzyme-linked immunosorbent assay and electrochemiluminescent immunoassay. To assess the angiogenic properties of fibulin-4, vascular endothelial growth factor (VEGF) expression and tumor microvessel density were analyzed in ovarian carcinoma by immunohistochemistry. Results Fibulin-4 expression was upregulated in ovarian carcinoma, and positively correlated with MVD and VEGF expression. Fibulin-4 overexpression was significantly associated with advanced stage, low differentiation, lymph node metastasis and poor prognosis in patients with ovarian cancer. The serum levels of fibulin-4, CA-125 and CA19-9 in patients with ovarian carcinoma were much higher than those with benign ovarian tumors and normal controls. Compared to CA-125 and CA19-9, fibulin-4 had better diagnostic sensitivity and specificity. Conclusions Fibulin-4 is a novel gene that is found overexpressed in ovarian cancer and associated with poor prognostic clinicopathologic features. This study shows that fibulin-4 may serve as a new prognostic factor and as a potential therapeutic target for patients with ovarian cancer in the future.
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Affiliation(s)
- Jie Chen
- Department of Maternal and Child Health Care, School of Public Health, Shandong University, Jinan, 250012, China.
| | - Zhao Liu
- Hepatobiliary and Pancreatic Surgery, Jinan Central Hospital affiliated to Shandong University, Jinan, 250013, China.
| | - Shuang Fang
- Biochemistry & Molecular Biology, Georgetown University, Georgetown, Washington D.C, 20057, USA.
| | - Rui Fang
- Grade 2011, Clinical Medicine, School of Medicine, Shandong University, Jinan, 250012, China.
| | - Xi Liu
- Grade 2011, Clinical Medicine, School of Medicine, Shandong University, Jinan, 250012, China.
| | - Yueran Zhao
- Central Laboratory, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021, China.
| | - XiangXin Li
- Department of Haematology, QiLu Hospital of Shandong University, Jinan, 250012, China.
| | - Lei Huang
- Department of Pediatrics, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021, China.
| | - Jie Zhang
- Central Laboratory, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021, China.
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Chen J, Zhang J, Liu X, Fang R, Zhao Y, Ma D. Overexpression of fibulin-4 is associated with tumor progression and poor prognosis in patients with cervical carcinoma. Oncol Rep 2014; 31:2601-10. [PMID: 24737201 DOI: 10.3892/or.2014.3139] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 04/03/2014] [Indexed: 11/06/2022] Open
Abstract
Fibulin-4, a member of the fibulin family of extracellular glycoproteins, is implicated in the progression of a number of types of cancer. However, the function of fibulin-4 in cervical cancer progression remains unexplored. Fibulin-4 mRNA and protein expression levels in normal cervical tissue, cervical intraepithelial neoplasia (CIN), cervical carcinoma, highly invasive subclones and low-invasive subclones were evaluated by real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. Serum fibulin-4 levels in patients with CIN and cervical carcinoma were measured by enzyme-linked immunosorbent assay. To assess the angiogenic properties of fibulin-4, vascular endothelial growth factor (VEGF) expression and tumor microvessel density (MVD) were analyzed in the cervical carcinoma cases by immunohistochemistry. Fibulin-4 expression was upregulated in the cervical carcinoma cases, and was positively correlated with MVD and VEGF expression. Fibulin-4 overexpression and high serum levels were significantly associated with advanced stage, low differentiation, lymph node metastasis, and poor prognosis in patients with cervical cancer. Fibulin-4 expression was also found to be overexpressed in highly invasive subclones when compared with the low-invasive subclones. Fibulin-4 is a newly identified glycoprotein that is overexpressed in cervical carcinoma. Fibulin-4 promotes angiogenesis and is associated with poor prognostic clinicopathologic features. This study demonstrated that fibulin-4 may serve as a new prognostic factor and as a potential therapeutic target for patients with cervical carcinoma.
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Affiliation(s)
- Jie Chen
- Department of Maternal and Child Health Care, School of Public Health, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jie Zhang
- Central Laboratory, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xi Liu
- Clinical Medicine, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Rui Fang
- Clinical Medicine, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Yueran Zhao
- Central Laboratory, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Demei Ma
- Department of Obstetrics and Gynecology, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
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Papke CL, Yanagisawa H. Fibulin-4 and fibulin-5 in elastogenesis and beyond: Insights from mouse and human studies. Matrix Biol 2014; 37:142-9. [PMID: 24613575 DOI: 10.1016/j.matbio.2014.02.004] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Revised: 02/25/2014] [Accepted: 02/26/2014] [Indexed: 01/03/2023]
Abstract
The fibulin family of extracellular matrix/matricellular proteins is composed of long fibulins (fibulin-1, -2, -6) and short fibulins (fibulin-3, -4, -5, -7) and is involved in protein-protein interaction with the components of basement membrane and extracellular matrix proteins. Fibulin-1, -2, -3, -4, and -5 bind the monomeric form of elastin (tropoelastin) in vitro and fibulin-2, -3, -4, and -5 are shown to be involved in various aspects of elastic fiber development in vivo. In particular, fibulin-4 and -5 are critical molecules for elastic fiber assembly and play a non-redundant role during elastic fiber formation. Despite manifestation of systemic elastic fiber defects in all elastogenic tissues, fibulin-5 null (Fbln5(-/-)) mice have a normal lifespan. In contrast, fibulin-4 null (Fbln4(-/-)) mice die during the perinatal period due to rupture of aortic aneurysms, indicating differential functions of fibulin-4 and fibulin-5 in normal development. In this review, we will update biochemical characterization of fibulin-4 and fibulin-5 and discuss their roles in elastogenesis and outside of elastogenesis based on knowledge obtained from loss-of-function studies in mouse and in human patients with FBLN4 or FBLN5 mutations. Finally, we will evaluate therapeutic options for matrix-related diseases.
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Affiliation(s)
- Christina L Papke
- Department of Molecular Biology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9148, USA
| | - Hiromi Yanagisawa
- Department of Molecular Biology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9148, USA.
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Tkachuk VA. Role of multidomain structure of urokinase in regulation of growth and remodeling of vessels. UKRAINIAN BIOCHEMICAL JOURNAL 2013. [DOI: 10.15407/ubj85.06.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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Chen J, Wei D, Zhao Y, Liu X, Zhang J. Overexpression of EFEMP1 correlates with tumor progression and poor prognosis in human ovarian carcinoma. PLoS One 2013; 8:e78783. [PMID: 24236050 PMCID: PMC3827232 DOI: 10.1371/journal.pone.0078783] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Accepted: 09/21/2013] [Indexed: 11/25/2022] Open
Abstract
Objective This study was to explore the role of EFEMP1 in ovarian tumor progression and its relationship with prognosis of ovarian carcinoma. Methods EFEMP1 mRNA and protein expressions in normal ovarian tissue, ovarian tumor, high invasive subclones and low invasive subclones were evaluated by immunohistochemistry and real time RT-PCR. Serum EFEMP1 levels in patients with ovarian tumor were measured by ELISA assay. To assess the angiogenic properties of EFEMP1, VEGF and tumor microvessel density were analyzed in ovarian carcinoma by immunohistochemistry. Results EFEMP1 expression was up-regulated in ovarian carcinoma, positively correlated with MVD and VEGF, and its overexpression and high serum levels were significantly associated with high stage, low differentiation, lymph node metastasis and poor prognosis of ovarian cancer. EFEMP1 expression was also found to be over-expressed in the highly invasive subclones compared with the low invasive subclones. Conclusion EFEMP1 is a newly identified gene over-expressed in ovarian cancer, associated with poor clinicopathologic features and promotes angiogenesis. This study shows that EFEMP1 may serve as a new prognostic factor and a therapeutic target for patients with ovarian cancer in the future.
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Affiliation(s)
- Jie Chen
- Department of Maternal and Child Health Care, School of Public Health, Shandong University, Jinan, China
| | - Deying Wei
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
- * E-mail: (DW); (JZ)
| | - Yueran Zhao
- Central Laboratory, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Xiaoyan Liu
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China
| | - Jie Zhang
- Central Laboratory, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
- * E-mail: (DW); (JZ)
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Nikitovic D, Corsini E, Kouretas D, Tsatsakis A, Tzanakakis G. ROS-major mediators of extracellular matrix remodeling during tumor progression. Food Chem Toxicol 2013; 61:178-86. [DOI: 10.1016/j.fct.2013.06.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Revised: 05/22/2013] [Accepted: 06/10/2013] [Indexed: 12/30/2022]
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Urban Z, Davis EC. Cutis laxa: intersection of elastic fiber biogenesis, TGFβ signaling, the secretory pathway and metabolism. Matrix Biol 2013; 33:16-22. [PMID: 23954411 DOI: 10.1016/j.matbio.2013.07.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 07/08/2013] [Accepted: 07/09/2013] [Indexed: 12/11/2022]
Abstract
Cutis laxa (CL), a disease characterized by redundant and inelastic skin, displays extensive locus heterogeneity. Together with geroderma osteodysplasticum and arterial tortuosity syndrome, which show phenotypic overlap with CL, eleven CL-related genes have been identified to date, which encode proteins within 3 groups. Elastin, fibulin-4, fibulin-5 and latent transforming growth factor-β-binding protein 4 are secreted proteins which form elastic fibers and are involved in the sequestration and subsequent activation of transforming growth factor-β (TGFβ). Proteins within the second group, localized to the secretory pathway, perform transport and membrane trafficking functions necessary for the modification and secretion of elastic fiber components. Key proteins include a subunit of the vacuolar-type proton pump, which ensures the efficient secretion of tropoelastin, the precursor or elastin. A copper transporter is required for the activity of lysyl oxidases, which crosslink collagen and elastin. A Rab6-interacting goglin recruits kinesin motors to Golgi-vesicles facilitating the transport from the Golgi to the plasma membrane. The Rab and Ras interactor 2 regulates the activity of Rab5, a small guanosine triphosphatase essential for the endocytosis of various cell surface receptors, including integrins. Proteins of the third group related to CL perform metabolic functions within the mitochondria, inhibiting the accumulation of reactive oxygen species. Two of these proteins catalyze subsequent steps in the conversion of glutamate to proline. The third transports dehydroascorbate into mitochondria. Recent studies on CL-related proteins highlight the intricate connections among membrane trafficking, metabolism, extracellular matrix assembly, and TGFβ signaling.
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Affiliation(s)
- Zsolt Urban
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, United States.
| | - Elaine C Davis
- Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, H3A 0C7 Canada
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Kinseth MA, Jia Z, Rahmatpanah F, Sawyers A, Sutton M, Wang-Rodriguez J, Mercola D, McGuire KL. Expression differences between African American and Caucasian prostate cancer tissue reveals that stroma is the site of aggressive changes. Int J Cancer 2013; 134:81-91. [PMID: 23754304 DOI: 10.1002/ijc.28326] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 05/22/2013] [Indexed: 12/21/2022]
Abstract
In prostate cancer, race/ethnicity is the highest risk factor after adjusting for age. African Americans have more aggressive tumors at every clinical stage of the disease, resulting in poorer prognosis and increased mortality. A major barrier to identifying crucial gene activity differences is heterogeneity, including tissue composition variation intrinsic to the histology of prostate cancer. We hypothesized that differences in gene expression in specific tissue types would reveal mechanisms involved in the racial disparities of prostate cancer. We examined 17 pairs of arrays for AAs and Caucasians that were formed by closely matching the samples based on the known tissue type composition of the tumors. Using pair-wise t-test we found significantly altered gene expression between AAs and CAs. Independently, we performed multiple linear regression analyses to associate gene expression with race considering variation in percent tumor and stroma tissue. The majority of differentially expressed genes were associated with tumor-adjacent stroma rather than tumor tissue. Extracellular matrix, integrin family and signaling mediators of the epithelial-to-mesenchymal transition (EMT) pathways were all downregulated in stroma of AAs. Using MetaCore (GeneGo) analysis, we observed that 35% of significant (p < 10(-3)) pathways identified EMT and 25% identified immune response pathways especially for interleukins-2, -4, -5, -6, -7, -10, -13, -15 and -22 as the major changes. Our studies reveal that altered immune and EMT processes in tumor-adjacent stroma may be responsible for the aggressive nature of prostate cancer in AAs.
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Horiguchi M, Ota M, Rifkin DB. Matrix control of transforming growth factor-β function. J Biochem 2012; 152:321-9. [PMID: 22923731 DOI: 10.1093/jb/mvs089] [Citation(s) in RCA: 193] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The cytokine transforming growth factor-beta (TGF-β) has multiple effects in both physiological and pathological conditions. TGF-β is secreted as part of a tripartite complex from which it must be released in order to bind to its receptor. Sequestration of latent TGF-β in the extracellular matrix (ECM) is crucial for proper mobilization of the latent cytokine and its activation. However, contrary to expectation, loss-of-function mutations in genes encoding certain matrix proteins that bind TGF-β yield elevated, rather than decreased, TGF-β levels, posing a 'TGF-β paradox.' In this review, we discuss recent findings concerning the relationship of TGF-β, ECM molecules, and latent TGF-β activation and propose a model to resolve the 'TGF-β paradox.'
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Affiliation(s)
- Masahito Horiguchi
- Departments of Cell Biology and Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
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Obaya AJ, Rua S, Moncada-Pazos A, Cal S. The dual role of fibulins in tumorigenesis. Cancer Lett 2012; 325:132-8. [PMID: 22781395 DOI: 10.1016/j.canlet.2012.06.019] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2012] [Revised: 06/26/2012] [Accepted: 06/30/2012] [Indexed: 11/24/2022]
Abstract
The human fibulin family consists of seven complex extracellular glycoproteins originally characterized as components of elastic fibers in connective tissue. However, beyond its structural role, fibulins are involved in complex biological processes such as cell adhesion, migration or proliferation. Indeed, they have proved to be essential elements in normal physiology, as shown by mouse models lacking these proteins, that evidence several developmental abnormalities and pathological features. Their relevance is also apparent in tumorigenesis, an aspect that has started to be intensely studied. Distinct fibulins are expressed in both tumor and stromal cells and are subjected to multiple expression regulations with either anti or pro-tumor effects. The mechanistic insights that underlie these observations are now commencing to emerge, portraying these proteins as very versatile and active constituents of connective tissue. The aim of this review is to highlight the most relevant connections between fibulins and cancer.
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Affiliation(s)
- Alvaro J Obaya
- Departamento de Biología Funcional, Area de Fisiología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Spain
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Gupta SC, Hevia D, Patchva S, Park B, Koh W, Aggarwal BB. Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy. Antioxid Redox Signal 2012; 16:1295-322. [PMID: 22117137 PMCID: PMC3324815 DOI: 10.1089/ars.2011.4414] [Citation(s) in RCA: 526] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
SIGNIFICANCE Extensive research during the last quarter century has revealed that reactive oxygen species (ROS) produced in the body, primarily by the mitochondria, play a major role in various cell-signaling pathways. Most risk factors associated with chronic diseases (e.g., cancer), such as stress, tobacco, environmental pollutants, radiation, viral infection, diet, and bacterial infection, interact with cells through the generation of ROS. RECENT ADVANCES ROS, in turn, activate various transcription factors (e.g., nuclear factor kappa-light-chain-enhancer of activated B cells [NF-κB], activator protein-1, hypoxia-inducible factor-1α, and signal transducer and activator of transcription 3), resulting in the expression of proteins that control inflammation, cellular transformation, tumor cell survival, tumor cell proliferation and invasion, angiogenesis, and metastasis. Paradoxically, ROS also control the expression of various tumor suppressor genes (p53, Rb, and PTEN). Similarly, γ-radiation and various chemotherapeutic agents used to treat cancer mediate their effects through the production of ROS. Interestingly, ROS have also been implicated in the chemopreventive and anti-tumor action of nutraceuticals derived from fruits, vegetables, spices, and other natural products used in traditional medicine. CRITICAL ISSUES These statements suggest both "upside" (cancer-suppressing) and "downside" (cancer-promoting) actions of the ROS. Thus, similar to tumor necrosis factor-α, inflammation, and NF-κB, ROS act as a double-edged sword. This paradox provides a great challenge for researchers whose aim is to exploit ROS stress for the development of cancer therapies. FUTURE DIRECTIONS the various mechanisms by which ROS mediate paradoxical effects are discussed in this article. The outstanding questions and future directions raised by our current understanding are discussed.
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Affiliation(s)
- Subash C Gupta
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Fibulin-5 binds urokinase-type plasminogen activator and mediates urokinase-stimulated β1-integrin-dependent cell migration. Biochem J 2012; 443:491-503. [PMID: 22280367 DOI: 10.1042/bj20110348] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
uPA (urokinase-type plasminogen activator) stimulates cell migration through multiple pathways, including formation of plasmin and extracellular metalloproteinases, and binding to the uPAR (uPA receptor; also known as CD87), integrins and LRP1 (low-density lipoprotein receptor-related protein 1) which activate intracellular signalling pathways. In the present paper we report that uPA-mediated cell migration requires an interaction with fibulin-5. uPA stimulates migration of wild-type MEFs (mouse embryonic fibroblasts) (Fbln5+/+ MEFs), but has no effect on fibulin-5-deficient (Fbln5-/-) MEFs. Migration of MEFs in response to uPA requires an interaction of fibulin-5 with integrins, as MEFs expressing a mutant fibulin-5 incapable of binding integrins (Fbln(RGE/RGE) MEFs) do not migrate in response to uPA. Moreover, a blocking anti-(human β1-integrin) antibody inhibited the migration of PASMCs (pulmonary arterial smooth muscle cells) in response to uPA. Binding of uPA to fibulin-5 generates plasmin, which excises the integrin-binding N-terminal cbEGF (Ca2+-binding epidermal growth factor)-like domain, leading to loss of β1-integrin binding. We suggest that uPA promotes cell migration by binding to fibulin-5, initiating its cleavage by plasmin, which leads to its dissociation from β1-integrin and thereby unblocks the capacity of integrin to facilitate cell motility.
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Budatha M, Roshanravan S, Zheng Q, Weislander C, Chapman SL, Davis EC, Starcher B, Word RA, Yanagisawa H. Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans. J Clin Invest 2011; 121:2048-59. [PMID: 21519142 DOI: 10.1172/jci45636] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Accepted: 02/09/2011] [Indexed: 12/21/2022] Open
Abstract
Pelvic organ prolapse (POP) is a common condition affecting almost half of women over the age of 50. The molecular and cellular mechanisms underlying this condition, however, remain poorly understood. Here we have reported that fibulin-5, an integrin-binding matricellular protein that is essential for elastic fiber assembly, regulated the activity of MMP-9 to maintain integrity of the vaginal wall and prevented development of POP. In murine vaginal stromal cells, fibulin-5 inhibited the β1 integrin-dependent, fibronectin-mediated upregulation of MMP-9. Mice in which the integrin-binding motif was mutated to an integrin-disrupting motif (Fbln5RGE/RGE) exhibited upregulation of MMP-9 in vaginal tissues. In contrast to fibulin-5 knockouts (Fbln5-/-), Fbln5RGE/RGE mice were able to form intact elastic fibers and did not exhibit POP. However, treatment of mice with β-aminopropionitrile (BAPN), an inhibitor of matrix cross-linking enzymes, induced subclinical POP. Conversely, deletion of Mmp9 in Fbln5-/- mice significantly attenuated POP by increasing elastic fiber density and improving collagen fibrils. Vaginal tissue samples from pre- and postmenopausal women with POP also displayed significantly increased levels of MMP-9. These results suggest that POP is an acquired disorder of extracellular matrix and that therapies targeting matrix proteases may be successful for preventing or ameliorating POP in women.
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Affiliation(s)
- Madhusudhan Budatha
- Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas, USA
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Devitt Møller H, Ralfkjær U, Cremers N, Frankel M, Troelsgaard Pedersen R, Klingelhöfer J, Yanagisawa H, Grigorian M, Guldberg P, Sleeman J, Lukanidin E, Ambartsumian N. Role of Fibulin-5 in Metastatic Organ Colonization. Mol Cancer Res 2011; 9:553-63. [DOI: 10.1158/1541-7786.mcr-11-0093] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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