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Singh K, Oladipupo SS. An overview of CCN4 (WISP1) role in human diseases. J Transl Med 2024; 22:601. [PMID: 38937782 PMCID: PMC11212430 DOI: 10.1186/s12967-024-05364-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 06/01/2024] [Indexed: 06/29/2024] Open
Abstract
CCN4 (cellular communication network factor 4), a highly conserved, secreted cysteine-rich matricellular protein is emerging as a key player in the development and progression of numerous disease pathologies, including cancer, fibrosis, metabolic and inflammatory disorders. Over the past two decades, extensive research on CCN4 and its family members uncovered their diverse cellular mechanisms and biological functions, including but not limited to cell proliferation, migration, invasion, angiogenesis, wound healing, repair, and apoptosis. Recent studies have demonstrated that aberrant CCN4 expression and/or associated downstream signaling is key to a vast array of pathophysiological etiology, suggesting that CCN4 could be utilized not only as a non-invasive diagnostic or prognostic marker, but also as a promising therapeutic target. The cognate receptor of CCN4 remains elusive till date, which limits understanding of the mechanistic insights on CCN4 driven disease pathologies. However, as therapeutic agents directed against CCN4 begin to make their way into the clinic, that may start to change. Also, the pathophysiological significance of CCN4 remains underexplored, hence further research is needed to shed more light on its disease and/or tissue specific functions to better understand its clinical translational benefit. This review highlights the compelling evidence of overlapping and/or diverse functional and mechanisms regulated by CCN4, in addition to addressing the challenges, study limitations and knowledge gaps on CCN4 biology and its therapeutic potential.
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Affiliation(s)
- Kirti Singh
- Biotherapeutic Enabling Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA
| | - Sunday S Oladipupo
- Biotherapeutic Enabling Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA.
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2
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Xu H, Duan S, Hu Y, Ding X, Xu FJ. Rapid Regulation of Cardiomyocytes Adhesion on Substrates with Varied Modulus via Mechanical Cues. Biomacromolecules 2023; 24:5847-5858. [PMID: 37956199 DOI: 10.1021/acs.biomac.3c00871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
In-depth understanding of the mechanisms underlying the adhesion of myocardial cells holds significant importance for the development of effective therapeutic biomaterials aimed at repairing damaged or pathological myocardial tissues. Herein, we present evidence that myocardial cells (H9C2) exhibit integrin-based mechanosensing during the initial stage of adhesion (within the first 2 h), enabling them to recognize and respond to variations in substrate stiffnesses. Moreover, the bioinformatics analysis of RNA transcriptome sequencing (RNA-seq) reveals that the gene expressions associated with initial stage focal adhesion (Ctgf, Cyr61, Amotl2, Prickle1, Serpine1, Akap12, Hbegf, and Nedd9) are up-regulated on substrates with elevated Young's modulus. The fluorescent immunostaining results also suggest that increased substrate stiffness enhances the expression of Y397-phosphorylated focal adhesion kinase (FAK Y397), talin, and vinculin and the assembly of F-actin in H9C2 cells, thereby facilitating the adhesion of myocardial cells on the substrate. Next, we utilize fluidic force microscopy (FluidFM)-based single-cell force spectroscopy (SCFS) to quantitatively evaluate the impact of substrate stiffness on the cell adhesion force and adhesion work, thus providing novel insights into the biomechanical regulation of initial cell adhesion. Our findings demonstrate that the maximum adhesion forces of myocardial cells exhibit a rise from 23.6 to 248.0 nN when exposed to substrates with different moduli. It is worth noting that once the αvβ3 integrins are blocked, the disparities in the adhesion forces of myocardial cells on these substrates become negligible. These results exhibit remarkable sensitivity of myocardial cells to mechanical cues of the substrate, highlighting the role of αvβ3 integrin as a biomechanical sensor for the regulation of cell adhesion. Overall, this work offers a prospective approach for the regulation of cell adhesion via integrin mechanosensing with potential practical applications in the areas of tissue engineering and regenerative medicine.
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Affiliation(s)
- Haifeng Xu
- College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China
| | - Shun Duan
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing 100029, P. R. China
- College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China
| | - Yang Hu
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing 100029, P. R. China
- College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China
| | - Xiaokang Ding
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing 100029, P. R. China
- College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China
| | - Fu-Jian Xu
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing Laboratory of Biomedical Materials, Beijing 100029, P. R. China
- College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China
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3
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Fayed HS, Bakleh MZ, Ashraf JV, Howarth A, Ebner D, Al Haj Zen A. Selective ROCK Inhibitor Enhances Blood Flow Recovery after Hindlimb Ischemia. Int J Mol Sci 2023; 24:14410. [PMID: 37833857 PMCID: PMC10572734 DOI: 10.3390/ijms241914410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/15/2023] [Accepted: 09/18/2023] [Indexed: 10/15/2023] Open
Abstract
The impairment in microvascular network formation could delay the restoration of blood flow after acute limb ischemia. A high-content screen of a GSK-published kinase inhibitor library identified a set of ROCK inhibitor hits enhancing endothelial network formation. Subsequent kinase activity profiling against a panel of 224 protein kinases showed that two indazole-based ROCK inhibitor hits exhibited high selectivity for ROCK1 and ROCK2 isoforms compared to other ROCK inhibitors. One of the chemical entities, GSK429286, was selected for follow-up studies. We found that GSK429286 was ten times more potent in enhancing endothelial tube formation than Fasudil, a classic ROCK inhibitor. ROCK1 inhibition by RNAi phenocopied the angiogenic phenotype of the GSK429286 compound. Using an organotypic angiogenesis co-culture assay, we showed that GSK429286 formed a dense vascular network with thicker endothelial tubes. Next, mice received either vehicle or GSK429286 (10 mg/kg i.p.) for seven days after hindlimb ischemia induction. As assessed by laser speckle contrast imaging, GSK429286 potentiated blood flow recovery after ischemia induction. At the histological level, we found that GSK429286 significantly increased the size of new microvessels in the regenerating areas of ischemic muscles compared with vehicle-treated ones. Our findings reveal that selective ROCK inhibitors have in vitro pro-angiogenic properties and therapeutic potential to restore blood flow in limb ischemia.
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Affiliation(s)
- Hend Salah Fayed
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar
| | - Mouayad Zuheir Bakleh
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar
| | | | - Alison Howarth
- Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK
| | - Daniel Ebner
- Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK
| | - Ayman Al Haj Zen
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
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4
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Zhang J, Shu J, Sun H, Zhai T, Li H, Li H, Sun Y, Huo R, Shen B, Sheng H. CCN1 upregulates IL-36 via AKT/NF-κB and ERK/CEBP β-mediated signaling pathways in psoriasis-like models. J Dermatol 2023; 50:337-348. [PMID: 36376243 DOI: 10.1111/1346-8138.16611] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/26/2022] [Accepted: 09/25/2022] [Indexed: 11/16/2022]
Abstract
Psoriasis is a chronic skin disorder characterized by epidermal keratinocyte hyperproliferation and inflammatory infiltration. CCN1 (also termed CYR61 or cysteine-rich angiogenic inducer 61) is an extracellular matrix-associated protein that is involved in multiple physiological functions. In psoriasis, we recently demonstrated that the overexpression of CCN1 promoted keratinocyte proliferation and activation. Furthermore, CCN1 was highly expressed in psoriatic skin lesions from psoriasis vulgaris patients. Here, we dissect the underlying molecular mechanism in imiquimod (IMQ) and interleukin (IL)-23-induced psoriasis-like models. Our results demonstrate that CCN1 can significantly upregulate IL-36 production in the murine skin of IMQ and IL-23-induced psoriasis-like models. Injection of CCN1-neutralizing antibody improved epidermal acanthosis and significantly reduced IL-36 production in vivo. These results suggest that CCN1 can be a critical upstream pro-inflammatory factor in psoriasis. In primary normal human epidermal keratinocytes, we demonstrated that CCN1 can selectively induced the production of IL-36α and IL-36γ through the activation of the protein kinase B (AKT)/nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and extracellular-regulated kinase (ERK)/CCAAT/enhancer binding protein β (CEBPβ) signaling pathways via integrin receptor α6β1 in vitro. Our results suggest that targeting CCN1 can be a potential therapeutic strategy for psoriasis.
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Affiliation(s)
- Jie Zhang
- Department of Clinical Laboratory of Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Shu
- Department of Clinical Laboratory of Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hanxiao Sun
- Department of Clinical Laboratory of Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Tianhang Zhai
- Shanghai Institute of Immunology & Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huidan Li
- Shanghai Institute of Immunology & Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haichuan Li
- Shanghai Institute of Immunology & Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Sun
- Shanghai Institute of Immunology & Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rongfen Huo
- Shanghai Institute of Immunology & Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Baihua Shen
- Shanghai Institute of Immunology & Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huiming Sheng
- Department of Clinical Laboratory of Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Chang Z, Dang T, Meng X, Chai J. The Role of CCN1 in Esophageal Adenocarcinoma: What We Have Learned From the Lab. Cancer Control 2022; 29:10732748221074734. [PMID: 35291889 PMCID: PMC8935545 DOI: 10.1177/10732748221074734] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background: Esophageal cancer is one of the most common and deadliest cancers in the world, particularly esophageal adenocarcinoma. There has never been a special drug to treat it.Purpose: This article summarizes the work that we have done in our laboratory about the role of CCN1 in esophageal cancer and gives a new perspective of CCN1 biology.Research Design: This is a review article. Study Sample: The work was done using validated cell lines and fixed human tissue slides.Data Collection and Analysis: This is a review article, therefore, no data collection or analysis was involved.Results: CCN1 is a matricellular protein supporting adhesion, migration, and survival in normal cells, but in the esophageal cancer cells, it induces TRAIL-mediated apoptosis. CCN1 promotes TRAIL and its death receptor expression but downregulates the decoy receptors and survivin in a p53-dependant manner. It was thought that CCN1 relies on TNF to induce apoptosis, but our study found that these two molecules antagonize each other. CCN1 promotes TNFR1 cleavage and uses the soluble product to block TNF signaling, while TNF upregulates PGLYRP1 to overcome this obstacle because PGLYRP1 is a secreted protein that competes with TNF for TNFR1 binding. As a result, when CCN1 and TNF are present together in the vicinity of esophageal tumors, they cancel each other out.Conclusions: Based on our laboratory study, CCN1 has much potential to be a candidate for the treatment of esophageal cancer.
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Affiliation(s)
- Zhiheng Chang
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Tong Dang
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Xianmei Meng
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Jianyuan Chai
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China.,Laboratory of Gastrointestinal Injury and Cancer, VA Long Beach Healthcare System, Long Beach, CA, USA.,College of Medicine, University of California, Irvine, CA, USA
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6
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Ac Kar L, Casjens S, Andreas A, Raiko I, Brüning T, Geffken M, Peine S, Kollmeier J, Johnen G, Bartkowiak K, Weber DG, Pantel K. Blood-based detection of lung cancer using cysteine-rich angiogenic inducer 61 (CYR61) as a circulating protein biomarker: a pilot study. Mol Oncol 2021; 15:2877-2890. [PMID: 34510714 PMCID: PMC8564649 DOI: 10.1002/1878-0261.13099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/27/2021] [Accepted: 09/09/2021] [Indexed: 12/11/2022] Open
Abstract
Lung cancer is the most often diagnosed cancer and the main cause of cancer deaths in the world compared with other tumor entities. To date, the only screening method for high‐risk lung cancer patients is low‐dosed computed tomography which still suffers from high false‐positive rates and overdiagnosis. Therefore, there is an obvious need to identify biomarkers for the detection of lung cancer that could be used to guide the use of low‐dosed computed tomography or other imaging procedures. We aimed to assess the performance of the protein cysteine‐rich angiogenic inducer 61 (CYR61) as a circulating biomarker for the detection of lung cancer. CYR61 concentrations in plasma were significantly elevated in 87 lung cancer patients (13.7 ± 18.6 ng·mL−1) compared with 150 healthy controls (0.29 ± 0.22 ng·mL−1). Subset analysis stratified by sex revealed increased CYR61 concentrations for adenocarcinoma and squamous cell carcinoma in men compared with women. For male lung cancer patients versus male healthy controls, the sensitivity was 84% at a specificity of 100%, whereas for females, the sensitivity was 27% at a specificity of 99%. The determination of circulating CYR61 protein in plasma might improve the detection of lung cancer in men. The findings of this pilot study support further verification of CYR61 as a biomarker for lung cancer detection in men. Additionally, CYR61 is significantly elevated in women but sensitivity and specificity for CYR61 are too low for the improvement of the detection of lung cancer in women.
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Affiliation(s)
- Lucija Ac Kar
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Germany
| | - Swaantje Casjens
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Germany
| | - Antje Andreas
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Germany
| | - Irina Raiko
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Germany
| | - Thomas Brüning
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Germany
| | - Maria Geffken
- Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Germany
| | - Sven Peine
- Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Germany
| | - Jens Kollmeier
- Lungenklinik Heckeshorn, Helios Klinikum Emil von Behring, Berlin, Germany
| | - Georg Johnen
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Germany
| | - Kai Bartkowiak
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Germany
| | - Daniel Gilbert Weber
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Germany
| | - Klaus Pantel
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Germany
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7
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Zhang K, Zhang H, Gao YH, Wang JQ, Li Y, Cao H, Hu Y, Wang L. A Monotargeting Peptidic Network Antibody Inhibits More Receptors for Anti-Angiogenesis. ACS NANO 2021; 15:13065-13076. [PMID: 34323463 DOI: 10.1021/acsnano.1c02194] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
The overexpression of growth factors and receptors on neovascular endothelial cells (ECs) and their binding may promote the abnormal growth of new blood vessels, leading to corneal neovascularization (CNV). Normally, monoclonal antibodies may bind and block only one growth factor or receptor, such as bevacizumab binding and blocking vascular endothelial growth factor (VEGF). Herein, we develop a monotargeting peptidic network antibody (pepnetibody) that blocks multiple receptors on the membrane of ECs through forming a fibrous network and ultimately achieves high-efficient treatment of CNV. The pepnetibody could bind to integrin αvβ3 in particulate formulation and in situ fibrillogenesis on ECs, mimicking the process of fibronectin fibrillogenesis on the cell membrane. The in situ formed peptidic network could firmly block integrin and cover other angiogenesis-related receptors, such as VEGF receptor-2 and neuropilin-1, exhibiting competitive efficacy of antiangiogenesis compared with traditional monoclonal antibody bevacizumab with 97.7 times lower dose.
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Affiliation(s)
- Kuo Zhang
- Department of Materials Physics and Chemistry, School of Materials Science and Engineering, University of Science and Technology Beijing, No. 30 Xueyuan Road, Beijing, 100083, China
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Hui Zhang
- Shanghai Jiao Tong University School of Medicine, 227 Chongqing South Road, Shanghai, 200025, China
| | - Yong-Hong Gao
- Department of Materials Physics and Chemistry, School of Materials Science and Engineering, University of Science and Technology Beijing, No. 30 Xueyuan Road, Beijing, 100083, China
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Jia-Qi Wang
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Yuan Li
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Hui Cao
- Department of Materials Physics and Chemistry, School of Materials Science and Engineering, University of Science and Technology Beijing, No. 30 Xueyuan Road, Beijing, 100083, China
| | - Ying Hu
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600, Yishan Road, Shanghai, 200233, China
| | - Lei Wang
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
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8
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Heng JW, Yazid MD, Abdul Rahman MR, Sulaiman N. Coatings in Decellularized Vascular Scaffolds for the Establishment of a Functional Endothelium: A Scoping Review of Vascular Graft Refinement. Front Cardiovasc Med 2021; 8:677588. [PMID: 34395554 PMCID: PMC8358320 DOI: 10.3389/fcvm.2021.677588] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022] Open
Abstract
Developments in tissue engineering techniques have allowed for the creation of biocompatible, non-immunogenic alternative vascular grafts through the decellularization of existing tissues. With an ever-growing number of patients requiring life-saving vascular bypass grafting surgeries, the production of functional small diameter decellularized vascular scaffolds has never been more important. However, current implementations of small diameter decellularized vascular grafts face numerous clinical challenges attributed to premature graft failure as a consequence of common failure mechanisms such as acute thrombogenesis and intimal hyperplasia resulting from insufficient endothelial coverage on the graft lumen. This review summarizes some of the surface modifying coating agents currently used to improve the re-endothelialization efficiency and endothelial cell persistence in decellularized vascular scaffolds that could be applied in producing a better patency small diameter vascular graft. A comprehensive search yielding 192 publications was conducted in the PubMed, Scopus, Web of Science, and Ovid electronic databases. Careful screening and removal of unrelated publications and duplicate entries resulted in a total of 16 publications, which were discussed in this review. Selected publications demonstrate that the utilization of surface coating agents can induce endothelial cell adhesion, migration, and proliferation therefore leads to increased re-endothelialization efficiency. Unfortunately, the large variance in methodologies complicates comparison of coating effects between studies. Thus far, coating decellularized tissue gave encouraging results. These developments in re-endothelialization could be incorporated in the fabrication of functional, off-the-shelf alternative small diameter vascular scaffolds.
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Affiliation(s)
- Jun Wei Heng
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Muhammad Dain Yazid
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Mohd Ramzisham Abdul Rahman
- Department of Surgery, Hospital Canselor Tuanku Muhriz, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nadiah Sulaiman
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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9
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Mo FE. Shear-Regulated Extracellular Microenvironments and Endothelial Cell Surface Integrin Receptors Intertwine in Atherosclerosis. Front Cell Dev Biol 2021; 9:640781. [PMID: 33889574 PMCID: PMC8056009 DOI: 10.3389/fcell.2021.640781] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 03/18/2021] [Indexed: 01/22/2023] Open
Abstract
Mechanical forces imposed by blood flow shear stress directly modulate endothelial gene expression and functional phenotype. The production of extracellular matrix proteins and corresponding cell-surface integrin receptors in arterial endothelial cells is intricately regulated by blood flow patterns. Laminar blood flow promotes mature and atheroresistant endothelial phenotype, while disturbed flow induces dysfunctional and atheroprone endothelial responses. Here, we discuss how hemodynamic changes orchestrate the remodeling of extracellular microenvironments and the expression profile of the integrin receptors in endothelial cells leading to oxidative stress and inflammation. Targeting the interaction between matrix proteins and their corresponding integrins is a potential therapeutic approach for atherosclerosis.
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Affiliation(s)
- Fan-E Mo
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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10
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Duan H, He Z, Lin M, Wang Y, Yang F, Mitteer RA, Kim HJ, Yeo E, Han H, Qin L, Fan Y, Gong Y. Plasminogen regulates mesenchymal stem cell-mediated tissue repair after ischemia through Cyr61 activation. JCI Insight 2020; 5:131376. [PMID: 32759492 PMCID: PMC7455064 DOI: 10.1172/jci.insight.131376] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 07/02/2020] [Indexed: 12/12/2022] Open
Abstract
Stem cell transplantation has emerged as a promising strategy in regenerative medicine. However, the poor survival and persistence of the transplanted cells, including mesenchymal stem cells (MSCs), in the hostile ischemic microenvironments represents a major therapeutic barrier. Here we report that plasminogen (Plg) stimulated MSC functions and promoted MSC survival during tissue repair after ischemia. Genetic Plg ablation abolished MSC survival, migration, and proliferation in mouse ischemic limbs, and abrogated MSC-mediated blood reperfusion, neovascularization, and tissue repair after ischemia, suggesting a critical role for Plg in MSC-mediated tissue repair. Furthermore, multiplex cytokine array analysis identified that Plg cleaved and activated cysteine-rich protein 61 (Cyr61), an ECM-associated growth factor, to stimulate MSC survival and migration. Overexpression with truncated Cyr61 in MSCs rescued blood reperfusion after hind limb ischemia in Plg-deficient mice. Finally, Plg-mediated Cyr61 cleavage promoted endothelial cell migration and neovascularization in vitro and in vivo. Our study reveals that Plg promotes MSC survival, persistence, and paracrine effects and improves postischemic neovascularization and tissue repair through Cyr61 cleavage and activation. Thus, targeting Plg/Cyr61 may offer exciting therapeutic opportunities for strengthening MSC therapy in ischemic diseases. Plasminogen promotes mesenchymal stem cell function and improves post-ischemic neovascularization and tissue repair through cysteine-rich protein 61 activation.
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Affiliation(s)
- Hao Duan
- Division of Translational Medicine and Human Genetics, Department of Medicine, and.,Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Neurosurgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhenqiang He
- Division of Translational Medicine and Human Genetics, Department of Medicine, and.,Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Neurosurgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Maohuan Lin
- Division of Translational Medicine and Human Genetics, Department of Medicine, and.,Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yanling Wang
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Fan Yang
- Division of Translational Medicine and Human Genetics, Department of Medicine, and
| | - R Alan Mitteer
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hyun-Jun Kim
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Eujing Yeo
- Division of Translational Medicine and Human Genetics, Department of Medicine, and
| | - Hongyu Han
- Division of Translational Medicine and Human Genetics, Department of Medicine, and
| | - Ling Qin
- Department of Orthopaedics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Yi Fan
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Yanqing Gong
- Division of Translational Medicine and Human Genetics, Department of Medicine, and
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Yu S, Yan C, Wu W, He S, Liu M, Liu J, Yang X, Ma J, Lu Y, Jia L. RU486 Metabolite Inhibits CCN1/Cyr61 Secretion by MDA-MB-231-Endothelial Adhesion. Front Pharmacol 2019; 10:1296. [PMID: 31824306 PMCID: PMC6880622 DOI: 10.3389/fphar.2019.01296] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 10/10/2019] [Indexed: 12/26/2022] Open
Abstract
Successful adhesion of circulating tumor cells (CTCs) to microvascular endothelium of distant metastatic tissue is the key starting step of metastatic cascade that could be effectively chemoprevented as we demonstrated previously. Here, we hypothesize that the hetero-adhesion may produce secretory biomarkers that may be important for both premetastatic diagnosis and chemoprevention. We show that co-incubation of triple-negative breast cancer (TNBC) cell line MDA-MB-231 with human pulmonary microvascular endothelial monolayers (HPMEC) secretes Cyr61 (CCN1), primarily from MDA-MB-231. However, addition of metapristone (RU486 metabolite) to the co-incubation system inhibits Cyr61 secretion probably via the Cyr61/integrin αvβ1 signaling pathway without significant cytotoxicity on both MDA-MB-231 and HPMEC. Transfection of MDA-MB-231 with Cyr61-related recombinant plasmid or siRNA enhances or reduces Cyr61 expression, accordingly. The transfection significantly changes hetero-adhesion and migration of MDA-MB-231, and the changed bioactivities by overexpressed CYR61 could be antagonized by metapristone in vitro. Moreover, the circulating MDA-MB-231 develops lung metastasis in mice, which could be effectively prevented by oral metapristone without significant toxicity. The present study, for the first time, demonstrates that co-incubation of MDA-MB-231 with HPMEC secrets CYR61 probably via the CYR61/integrin αvβ1 signaling pathway to promote adhesion-invasion of TNBC (early metastatic step). Metapristone, by interfering the adhesion-invasion process, prevents metastasis from happening.
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Affiliation(s)
- Suhong Yu
- Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
| | - Cuicui Yan
- Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
| | - Wenjing Wu
- Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
| | - Sudan He
- Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
| | - Min Liu
- Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
| | - Jian Liu
- Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
| | - Xingtian Yang
- Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
| | - Ji Ma
- Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
| | - Yusheng Lu
- Institute of Oceanography, Minjiang University, Fuzhou, China
| | - Lee Jia
- Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China.,Institute of Oceanography, Minjiang University, Fuzhou, China
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12
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Park MH, Kim AK, Manandhar S, Oh SY, Jang GH, Kang L, Lee DW, Hyeon DY, Lee SH, Lee HE, Huh TL, Suh SH, Hwang D, Byun K, Park HC, Lee YM. CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity. eLife 2019; 8:46012. [PMID: 31429823 PMCID: PMC6726423 DOI: 10.7554/elife.46012] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 08/15/2019] [Indexed: 01/14/2023] Open
Abstract
CCN1 (CYR61) stimulates active angiogenesis in various tumours, although the mechanism is largely unknown. Here, we report that CCN1 is a key regulator of endothelial tip cell activity in angiogenesis. Microvessel networks and directional vascular cell migration patterns were deformed in ccn1-knockdown zebrafish embryos. CCN1 activated VEGFR2 and downstream MAPK/PI3K signalling pathways, YAP/TAZ, as well as Rho effector mDia1 to enhance tip cell activity and CCN1 itself. VEGFR2 interacted with integrin αvβ3 through CCN1. Integrin αvβ3 inhibitor repressed tip cell number and sprouting in postnatal retinas from endothelial cell-specific Ccn1 transgenic mice, and allograft tumours in Ccn1 transgenic mice showed hyperactive vascular sprouting. Cancer patients with high CCN1 expression have poor survival outcomes and positive correlation with ITGAV and ITGB3 and high YAP/WWTR1. Thus, our data underscore the positive feedback regulation of tip cells by CCN1 through integrin αvβ3/VEGFR2 and increased YAP/TAZ activity, suggesting a promising therapeutic intervention for pathological angiogenesis.
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Affiliation(s)
- Myo-Hyeon Park
- BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Ae Kyung Kim
- BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea.,School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Sarala Manandhar
- BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Su-Young Oh
- BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Gun-Hyuk Jang
- BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea.,School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Li Kang
- BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Dong-Won Lee
- Department of Biomedical Sciences, Korea University, Ansan Hospital, Ansan, Republic of Korea
| | - Do Young Hyeon
- School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Republic of Korea
| | - Sun-Hee Lee
- BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Hye Eun Lee
- BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Tae-Lin Huh
- School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Sang Heon Suh
- Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Korea
| | - Daehee Hwang
- Department of New Biology and Center for Plant Aging Research, DGIST, Daegu, Republic of Korea
| | - Kyunghee Byun
- Gachon University, School of Medicine, Incheon, Republic of Korea
| | - Hae-Chul Park
- Department of Biomedical Sciences, Korea University, Ansan Hospital, Ansan, Republic of Korea
| | - You Mie Lee
- BK21 Plus KNU Multi-Omics Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea.,School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
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13
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Li Z, Yan G, Diao Q, Yu F, Li X, Sheng X, Liu Y, Dai Y, Zhou H, Zhen X, Hu Y, Péault B, Ding L, Sun H, Li H. Transplantation of human endometrial perivascular cells with elevated CYR61 expression induces angiogenesis and promotes repair of a full-thickness uterine injury in rat. Stem Cell Res Ther 2019; 10:179. [PMID: 31215503 PMCID: PMC6582612 DOI: 10.1186/s13287-019-1272-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 04/25/2019] [Accepted: 05/21/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Disruptions of angiogenesis can have a significant effect on the healing of uterine scars. Human endometrial perivascular cells (CD146+PDGFRβ+) function as stem cells in the endometrium. Cysteine-rich angiogenic inducer 61 (CYR61) plays an important role in vascular development. The purpose of this study was to observe the effects of the transplantation of human endometrial perivascular cells (En-PSCs) overexpressing CYR61 on structural and functional regeneration in rat models of partial full-thickness uterine excision. METHODS We first sorted human En-PSCs from endometrial single-cell suspensions by flow cytometry. Human En-PSCs expressing low or high levels of CYR61 were then generated via transfection with a CYR61-specific small interfering ribonucleic acid (si-CYR61) construct or overexpression plasmid. To establish a rat model of uterine injury, a subset of uterine wall was then resected from each uterine horn in experimental animals. Female rats were randomly assigned to five groups, including a sham-operated group and four repair groups that received either PBS loaded on a collagen scaffold (collagen/PBS), En-PSCs loaded on a collagen scaffold (collagen/En-PSCs), En-PSCs with low CYR61 expression loaded on a collagen scaffold (collagen/si-CYR61 En-PSCs), and En-PSCs overexpressing CYR61 loaded on a collagen scaffold (collagen/ov-CYR61 En-PSCs). These indicated constructs were sutured in the injured uterine area to replace the excised segment. On days 30 and 90 after transplantation, a subset of rats in each group was sacrificed, and uterine tissue was recovered and serially sectioned. Hematoxylin and eosin staining and immunohistochemical staining were then performed. Finally, the remaining rats of each group were mated with fertile male rats on day 90 for a 2-week period. RESULTS Sorted En-PSCs expressed all recognized markers of mesenchymal stem cells (MSCs), including CD10, CD13, CD44, CD73, CD90, and CD105, and exhibited differentiation potential toward adipocytes, osteoblasts, and neuron-like cells. Compared with En-PSCs and En-PSCs with low CYR61 expression, En-PSCs with elevated CYR61 expression enhanced angiogenesis by in vitro co-culture assays. At day 90 after transplantation, blood vessel density in the collagen/ov-CYR61 En-PSCs group (11.667 ± 1.287) was greater than that in the collagen/En-PSCs group (7.167 ± 0.672) (P < 0.05) and the collagen/si-CYR61 En-PSCs group (3.750 ± 0.906) (P < 0.0001). Pregnancy rates differed among groups, from 40% in the collagen/PBS group to 80% in the collagen/En-PSCs group, 12.5% in the collagen/si-CYR61 En-PSCs group, and 80% in the collagen/ov-CYR61 En-PSCs group. In addition, four embryos were evident in the injured uterine horns of the collagen/ov-CYR61 En-PSCs group, while no embryos were identified in the injured uterine horns of the collagen/PBS group. CONCLUSIONS The results showed that CYR61 plays an important role in angiogenesis. Collagen/ov-CYR61 En-PSCs promoted endometrial and myometrial regeneration and induced neovascular regeneration in injured rat uteri. The pregnancy rate of rats treated with transplantation of collagen/En-PSCs or collagen/ov-CYR61 En-PSCs was improved. Moreover, the number of embryos implantation on the injured area in uterus was increased after transplantation of collagen/ov-CYR61 En-PSCs.
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Affiliation(s)
- Zhongxun Li
- Department of Histology and Embryology of Shanxi Medical University, Taiyuan, 030001 China
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
| | - Guijun Yan
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
| | - Qiang Diao
- Department of Medical Imaging, Jinling Hospital, Nanjing University Medical School, Nanjing, 210002 China
| | - Fei Yu
- Center for Experimental Animal, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
| | - Xin’an Li
- Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
| | - Xiaoqiang Sheng
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
| | - Yong Liu
- Department of Experimental Medicine, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
| | - Yimin Dai
- Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
| | - Huaijun Zhou
- Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
| | - Xin Zhen
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
| | - Yali Hu
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
| | - Bruno Péault
- UKMRC Center for Regenerative Medicine and Center for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, UK
| | - Lijun Ding
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
- UKMRC Center for Regenerative Medicine and Center for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, UK
- Clinical Center for Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
| | - Haixiang Sun
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 China
- Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China
| | - Hairong Li
- Department of Histology and Embryology of Shanxi Medical University, Taiyuan, 030001 China
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14
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Boopathy GTK, Hong W. Role of Hippo Pathway-YAP/TAZ Signaling in Angiogenesis. Front Cell Dev Biol 2019; 7:49. [PMID: 31024911 PMCID: PMC6468149 DOI: 10.3389/fcell.2019.00049] [Citation(s) in RCA: 246] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 03/19/2019] [Indexed: 12/12/2022] Open
Abstract
Angiogenesis is a highly coordinated process of formation of new blood vessels from pre-existing blood vessels. The process of development of the proper vascular network is a complex process that is crucial for the vertebrate development. Several studies have defined essential roles of Hippo pathway-YAP/TAZ in organ size control, tissue regeneration, and self-renewal. Thus Hippo pathway is one of the central components in tissue homeostasis. There are mounting evidences on the eminence of Hippo pathway-YAP/TAZ in angiogenesis in multiple model organisms. Hippo pathway-YAP/TAZ is now demonstrated to regulate endothelial cell proliferation, migration and survival; subsequently regulating vascular sprouting, vascular barrier formation, and vascular remodeling. Major intracellular signaling programs that regulate angiogenesis concomitantly activate YAP/TAZ to regulate key events in angiogenesis. In this review, we provide a brief overview of the recent findings in the Hippo pathway and YAP/TAZ signaling in angiogenesis.
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Affiliation(s)
- Gandhi T K Boopathy
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Wanjin Hong
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
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15
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Valdés A, Zhao H, Pettersson U, Lind SB. Time-resolved proteomics of adenovirus infected cells. PLoS One 2018; 13:e0204522. [PMID: 30252905 PMCID: PMC6155545 DOI: 10.1371/journal.pone.0204522] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/10/2018] [Indexed: 12/30/2022] Open
Abstract
Viral infections cause large problems in the world and deeper understanding of the disease mechanisms is needed. Here we present an analytical strategy to investigate the host cell protein changes during human adenovirus type 2 (HAdV-C2 or Ad2) infection of lung fibroblasts by stable isotope labelling of amino acids in cell culture (SILAC) and nanoLC-MS/MS. This work focuses on early phase of infection (6 and 12 h post-infection (hpi)) but the data is combined with previously published late phase (24 and 36 hpi) proteomics data to produce a time series covering the complete infection. As many as 2169 proteins were quantitatively monitored from 6 to 36 hpi, while some proteins were time-specific. After applying different filter criteria, 2027 and 2150 proteins were quantified at 6 and 12 hpi and among them, 431 and 544 were significantly altered at the two time points. Pathway analysis showed that the De novo purine and pyrimidine biosynthesis, Glycolysis and Cytoskeletal regulation by Rho GTPase pathways were activated early during infection while inactivation of the Integrin signalling pathway started between 6 and 12 hpi. Moreover, upstream regulator analysis predicted MYC to be activated with time of infection and protein and RNA data for genes controlled by this transcription factor showed good correlation, which validated the use of protein data for this prediction. Among the identified phosphorylation sites, a group related to glycolysis and cytoskeletal reorganization were up-regulated during infection. The results show specific aspects on how the host cell proteins, the final products in the genetic information flow, are influenced by Ad2 infection, which would be overlooked if only knowledge derived from mRNA data is considered.
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Affiliation(s)
- Alberto Valdés
- Department of Chemistry-BMC, Analytical Chemistry, Uppsala University, Uppsala, Sweden
| | - Hongxing Zhao
- The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
| | - Ulf Pettersson
- The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
| | - Sara Bergström Lind
- Department of Chemistry-BMC, Analytical Chemistry, Uppsala University, Uppsala, Sweden
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16
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CCN1/Cyr61 Stimulates Melanogenesis through Integrin α6β1, p38 MAPK, and ERK1/2 Signaling Pathways in Human Epidermal Melanocytes. J Invest Dermatol 2018; 138:1825-1833. [DOI: 10.1016/j.jid.2018.02.029] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 02/11/2018] [Accepted: 02/18/2018] [Indexed: 02/01/2023]
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17
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Imoto K, Hirakawa M, Okada M, Yamawaki H. Canstatin modulates L-type calcium channel activity in rat ventricular cardiomyocytes. Biochem Biophys Res Commun 2018; 499:954-959. [PMID: 29626474 DOI: 10.1016/j.bbrc.2018.04.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 04/03/2018] [Indexed: 12/24/2022]
Abstract
Excessive increase of cytosolic Ca2+ through the activation of L-type Ca2+ channels (LTCCs) via β adrenergic receptor induces apoptosis of cardiomyocytes. Canstatin, a cleaved fragment of collagen type IV α2 chain, is abundantly expressed in normal heart tissue. We previously reported that canstatin inhibits β adrenergic receptor-stimulated apoptosis in cardiomyoblasts. Here, we tested the hypothesis that canstatin regulates LTCCs activity in ventricular cardiomyocytes. Collagen type IV α2 chain (COL4A2) small interfering (si) RNA (for canstatin suppression) or control siRNA was injected via jugular vein in Wistar rats. Two days after the injection, electrocardiogram (ECG) was recorded and the left ventricular tissue was isolated using Langendorff apparatus. Immunofluorescence staining was performed to clarify the distribution of canstatin in cardiomyocytes. The knockdown efficiency was confirmed by Western blotting. The L-type Ca2+ channel current (ICaL) of ventricular cardiomyocyte was measured by a whole-cell patch clamp technique. In immunofluorescence staining, colocalization of canstatin and αv integrin was observed in the isolated ventricular cardiomyocytes. The ICaL of ventricular cardiomyocyte isolated from COL4A2 siRNA-injected rats was significantly enhanced compared with control siRNA-injected rats. Recombinant canstatin (250 ng/ml) significantly reversed it. ECG analysis showed that QT interval tended to be shortened and amplitude of T wave was significantly increased in the COL4A2 siRNA-injected rats. In summary, we for the first time clarified that suppressing canstatin expression increases the basal ICaL in ventricular cardiomyocytes. It is proposed that canstatin might play a role in the stabilization of cardiac function through the modulation of LTCC activity in cardiomyocytes.
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Affiliation(s)
- Keisuke Imoto
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
| | - Masaki Hirakawa
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
| | - Muneyoshi Okada
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan.
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
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18
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Huber MC, Falkenberg N, Hauck SM, Priller M, Braselmann H, Feuchtinger A, Walch A, Schmitt M, Aubele M. Cyr61 and YB-1 are novel interacting partners of uPAR and elevate the malignancy of triple-negative breast cancer. Oncotarget 2018; 7:44062-44075. [PMID: 27286449 PMCID: PMC5190079 DOI: 10.18632/oncotarget.9853] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/16/2016] [Indexed: 11/29/2022] Open
Abstract
The triple-negative breast cancer (TNBC) is a very aggressive tumor type often occurring in young women and is associated with a bad prognosis for the patients. TNBC lacks established targets for breast cancer therapy, such as the estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2). Therefore, novel therapeutic targets and strategies are needed for an improved treatment of this breast cancer subtype. TNBC and respective cell lines often overexpress proteins of the urokinase plasminogen activator system (uPAS) including uPA, its receptor uPAR and inhibitor PAI-1, which together with co-factors contribute to the malignancy of TNBC. Here, two novel interacting partners of uPAR, the cysteine-rich angiogenic inducer 61 (Cyr61) and the Y-box-binding protein 1 (YB-1) were identified and their differential expression demonstrated in TNBC cells as well as in tumors. In the TNBC cohort, both interactors significantly correlated with expression levels of cathepsin B, c-Met and the tumor grade. In addition, expression levels of Cyr61 significantly correlated with cathepsin D (p=0.03), insulin receptor (p≤0.001), insulin-like growth factor receptor 1 (IGF1R, p=0.015) and also with YB-1 (p=0.0004) levels. The interactions of uPAR with Cyr61 significantly correlated with expression levels of tumor-promoting biomarkers including plasminogen (p=0.0014), cathepsin B (p=0.032), c-Met (p=0.0192) as well as with the tumor grade (p=0.02). In multivariate survival analysis, YB-1 showed independent prognostic value (p=0.01). As the novel interacting partners, also together with uPAR, contribute to tumor progression and metastasis, both may be potential therapeutic targets in breast cancer.
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Affiliation(s)
- Michaela C Huber
- Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany
| | - Natalie Falkenberg
- Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany
| | - Stefanie M Hauck
- Research Unit of Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany
| | - Markus Priller
- Research Unit of Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany
| | - Herbert Braselmann
- Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany
| | - Annette Feuchtinger
- Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.,Research Unit of Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany
| | - Axel Walch
- Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.,Research Unit of Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany
| | - Manfred Schmitt
- Clinical Research Unit, Department of Obstetrics and Gynecology, Technische Universität München, München 81675, Germany
| | - Michaela Aubele
- Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany
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19
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Yang R, Chen Y, Chen D. Biological functions and role of CCN1/Cyr61 in embryogenesis and tumorigenesis in the female reproductive system (Review). Mol Med Rep 2017; 17:3-10. [PMID: 29115499 PMCID: PMC5780141 DOI: 10.3892/mmr.2017.7880] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 09/18/2017] [Indexed: 12/17/2022] Open
Abstract
Cysteine-rich angiogenic inducer 61 (CCN1/Cyr61) is a prompt response transcription product activated by growth factors. As a member of the CCN family, it mediates cell survival, proliferation, differentiation, migration, adhesion and synthesis of the extracellular matrix by binding directly to the integrins and heparin sulfate proteoglycans or activating multiple signaling transduction pathways. It has previously been demonstrated that CCN1/Cyr61 exhibits an important role in the female reproductive system during embryogenesis and tumorigenesis. However, the functions of CCN1/Cyr61 in the female reproductive system have not been systematically investigated, therefore, the primary aim of the present review is to introduce the role and function of CCN1/Cyr61 in the female reproductive system. The current review presents the molecular structure and biological function of CCN1/Cyr61 and provides detailed data on its expression pattern and contribution to the female reproductive system, including the role in embryogenesis and tumorigenesis.
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Affiliation(s)
- Rui Yang
- Wuxi Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214002, P.R. China
| | - Ying Chen
- Wuxi Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214002, P.R. China
| | - Daozhen Chen
- Wuxi Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214002, P.R. China
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Zhong C, Huo R, Hu K, Shen J, Li D, Li N, Ding J. Molecular basis for the recognition of CCN1 by monoclonal antibody 093G9. J Mol Recognit 2017; 30. [PMID: 28608634 DOI: 10.1002/jmr.2645] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 05/01/2017] [Accepted: 05/10/2017] [Indexed: 11/07/2022]
Abstract
CCN1, also named Cyr61 (cysteine-rich protein 61), is the first identified member of the CCN family that is composed of 6 secreted extracellular matrix-associated glycoproteins. CCN1 has been demonstrated to participate in pathogenesis of rheumatoid arthritis through various pathways. A monoclonal antibody, namely, 093G9, is effective to antagonize the effects of CCN1 and hence has potential therapeutic benefits against rheumatoid arthritis. Here, we show that the epitope recognized by 093G9 is mapped to residues 77 to 80 of CCN1, and a cyclic peptide encompassing residues 75 to 81 of CCN1 displays high binding affinity for 093G9. The crystal structure of the 093G9 Fab in complex with the cyclic peptide was determined at 2.7 Å resolution, which reveals the intensive interactions between CCN1 and 093G9. Particularly, residues Asn79 and Phe80 of CCN1 are inserted into cavities mainly formed by residues of complementarity-determining region loop L3 and framework region L2 and by residues of complementarity-determining region loops H2 and H3, respectively, which contribute most of the interactions and therefore are critical for the recognition by 093G9. Together, these findings not only identify the epitope of CCN1 for 093G9 but also reveal the molecular mechanism of recognition and binding of CCN1 by 093G9.
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Affiliation(s)
- Chen Zhong
- National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Rongfen Huo
- Shanghai Institute of Immunology and Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kuan Hu
- National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jinlong Shen
- National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Dangsheng Li
- National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ningli Li
- Shanghai Institute of Immunology and Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianping Ding
- National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, China.,Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, China
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21
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Haddad T, Qin R, Lupu R, Satele D, Eadens M, Goetz MP, Erlichman C, Molina J. A phase I study of cilengitide and paclitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 2017; 79:1221-1227. [PMID: 28477227 DOI: 10.1007/s00280-017-3322-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 04/23/2017] [Indexed: 01/16/2023]
Abstract
PURPOSE Cilengitide is a potent and selective inhibitor of the integrins αvβ3 and αvβ5. The primary objective of this phase I clinical trial was to establish the maximum tolerated dose and determine safety/tolerability of cilengitide in combination with paclitaxel in patients with advanced solid tumors. Secondary objectives included the evaluation of the preliminary clinical outcomes. PATIENTS AND METHODS Patients with advanced solid tumors experiencing disease progression on standard treatment were assigned to two different dose levels of cilengitide (2000 mg intravenously once or twice weekly) in combination with fixed-dose, weekly paclitaxel (90 mg/m2 intravenously). RESULTS Twelve evaluable patients were treated per protocol. A single dose limiting toxicity (DLT) of grade 4 neutropenia was observed at the starting dose level of once weekly cilengitide. There were no grade ≥3 adverse events that occurred with >10% frequency. One patient achieved a partial response to therapy. Five patients experienced stable disease as best response, 3 of which discontinued study participation due to progressive, peripheral neuropathy. CONCLUSIONS Cilengitide in combination with paclitaxel was well tolerated. Antitumor activity was observed. The recommended phase II dose is twice weekly cilengitide (2000 mg) with weekly paclitaxel (90 mg/m2). Further studies evaluating drugs that target this pathway are warranted.
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Affiliation(s)
- Tufia Haddad
- Division of Medical Oncology, Mayo Clinic, 200 First Street S.W., Rochester, MN, 55905, USA
| | - Rui Qin
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Ruth Lupu
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Daniel Satele
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Matthew Eadens
- Mayo School of Graduate Medical Education, Fellow Hematology/Oncology, Rochester, MN, USA
| | - Matthew P Goetz
- Division of Medical Oncology, Mayo Clinic, 200 First Street S.W., Rochester, MN, 55905, USA
| | - Charles Erlichman
- Division of Medical Oncology, Mayo Clinic, 200 First Street S.W., Rochester, MN, 55905, USA
| | - Julian Molina
- Division of Medical Oncology, Mayo Clinic, 200 First Street S.W., Rochester, MN, 55905, USA.
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22
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Kanazawa H, Imoto K, Okada M, Yamawaki H. Canstatin inhibits hypoxia-induced apoptosis through activation of integrin/focal adhesion kinase/Akt signaling pathway in H9c2 cardiomyoblasts. PLoS One 2017; 12:e0173051. [PMID: 28235037 PMCID: PMC5325616 DOI: 10.1371/journal.pone.0173051] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 02/14/2017] [Indexed: 12/19/2022] Open
Abstract
A hypoxic stress which causes apoptosis of cardiomyocytes is the main problem in the ischemic heart disease. Canstatin, a non-collagenous fragment of type IV collagen α2 chain, is an endogenous anti-angiogenic factor. We have previously reported that canstatin has a cytoprotective effect on cardiomyoblasts. In the present study, we examined the effects of canstatin on hypoxia-induced apoptosis in H9c2 cardiomyoblasts. Cell counting assay was performed to determine a cell viability. Western blotting was performed to detect expression of cleaved casepase-3 and phosphorylation of focal adhesion kinase (FAK) and Akt. Immunocytochemical staining was performed to observe a distribution of αv integrin. Hypoxia (1% O2, 48 h) significantly decreased cell viability and increased cleaved caspase-3 expression. Canstatin (10–250 ng/ml) significantly inhibited these changes in a concentration-dependent manner. Cilengitide (1 μM), an αvβ3 and αvβ5 integrin inhibitor, significantly prevented the protective effects of canstatin on cell viability. Canstatin significantly increased phosphorylation of FAK and Akt under hypoxic condition, which were inhibited by cilengitide. LY294002, an inhibitor of phosphatidylinositol-3 kinase/Akt pathway, suppressed the canstatin-induced Akt phosphorylation and reversed the protective effects of canstatin. It was observed that hypoxia caused a localization of αv integrin to focal adhesion. In summary, we for the first time clarified that canstatin inhibits hypoxia-induced apoptosis via FAK and Akt pathways through activating integrins in H9c2 cardiomyoblasts.
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Affiliation(s)
- Hiroki Kanazawa
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan
| | - Keisuke Imoto
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan
| | - Muneyoshi Okada
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan
- * E-mail:
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan
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23
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Zhu X, Song Y, Wu C, Pan C, Lu P, Wang M, Zheng P, Huo R, Zhang C, Li W, Lin Y, Cao Y, Li N. Cyr61 participates in the pathogenesis of acute lymphoblastic leukemia by enhancing cellular survival via the AKT/NF-κB signaling pathway. Sci Rep 2016; 6:34018. [PMID: 27725691 PMCID: PMC5057070 DOI: 10.1038/srep34018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 09/06/2016] [Indexed: 12/25/2022] Open
Abstract
Cyr61 (CCN1) is the product of a growth factor–inducible immediate early gene and is involved in cell adhesion, survival, proliferation, and differentiation. Cyr61 is overexpressed in human tumors and is involved in the development of tumors. However, the role that Cyr61 plays in acute lymphoblastic leukemia (ALL) cells remains undetermined. The aim of this study was to identify the role of Cyr61 in regulating ALL cell survival. Here, we found that the level of Cyr61 was increased in the plasma and bone marrow (BM) from ALL patients compared with samples from normal control patients. Furthermore, we observed that Cyr61 could effectively stimulate Jurkat (T ALL cell lines), Nalm-6 (B ALL cell lines), and primary ALL cell survival. Mechanistically, we showed that Cyr61 stimulated ALL cell survival via the AKT/NF-κB signaling pathways and the consequent up-regulation of Bcl-2. Taken together, our study is the first to reveal that Cyr61 is elevated in ALL and promotes cell survival through the AKT/NF-κB pathway by up-regulating Bcl-2. Our findings suggest that Cyr61 plays an important role in the pathogenesis of ALL.
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Affiliation(s)
- Xianjin Zhu
- Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, China
| | - Yanfang Song
- Affiliated Renmin Hospital of Fujian University of Traditional Chinese Medicine, 602 Bayiqi Road, Fuzhou 350001, China
| | - Conglian Wu
- Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, China
| | - Chuxi Pan
- University of Toronto, 27 King's College Circle, Toronto M5S1A1, Canada
| | - Pingxia Lu
- Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, China
| | - Meihua Wang
- Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, China
| | - Peizheng Zheng
- Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, China
| | - Rongfen Huo
- Shanghai Institute of Immunology, Institute of medical sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China
| | - Chenqing Zhang
- Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, China
| | - Wanting Li
- Fujian Medical University, 88 Jiaotong Road, Fuzhou 350001, China
| | - Yulin Lin
- Fujian Medical University, 88 Jiaotong Road, Fuzhou 350001, China
| | - Yingping Cao
- Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, China
| | - Ningli Li
- Shanghai Institute of Immunology, Institute of medical sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China
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24
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Emerging roles of CCN proteins in vascular development and pathology. J Cell Commun Signal 2016; 10:251-257. [PMID: 27241177 DOI: 10.1007/s12079-016-0332-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 05/19/2016] [Indexed: 01/02/2023] Open
Abstract
The CCN family of proteins consists of 6 members (CCN1-CCN6) that share conserved functional domains. These matricellular proteins interact with growth factors, extracellular matrix (ECM) proteins, cell surface integrins and other receptors to promote ECM-intracellular signaling. This signaling leads to propagation of a variety of cellular actions, including adhesion, invasion, migration and proliferation within several cell types, including epithelial, endothelial and smooth muscle cells. Though CCNs share significant homology, the function of each is unique due to distinct and cell specific expression patterns. Thus, their correct spatial and temporal expressions are critical during embryonic development, wound healing, angiogenesis and fibrosis. Disruption of these patterns leads to severe development disorders and contributes to the pathological progression of cancers, vascular diseases and chronic inflammatory diseases such as colitis, rheumatoid arthritis and atherosclerosis. While the effects of CCNs are diverse, this review will focus on the role of CCNs within the vasculature during development and in vascular diseases.
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25
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Cell surface receptors for CCN proteins. J Cell Commun Signal 2016; 10:121-7. [PMID: 27098435 DOI: 10.1007/s12079-016-0324-z] [Citation(s) in RCA: 139] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 04/16/2016] [Indexed: 01/22/2023] Open
Abstract
The CCN family (CYR61; CTGF; NOV; CCN1-6; WISP1-3) of matricellular proteins in mammals is comprised of six homologous members that play important roles in development, inflammation, tissue repair, and a broad range of pathological processes including fibrosis and cancer. Despite considerable effort to search for a high affinity CCN-specific receptor akin to growth factor receptors, no such receptor has been found. Rather, CCNs bind several groups of multi-ligand receptors as characteristic of other matricellular proteins. The most extensively documented among CCN-binding receptors are integrins, including αvβ3, αvβ5, α5β1, α6β1, αIIbβ3, αMβ2, and αDβ2, which mediate diverse CCN functions in various cell types. CCNs also bind cell surface heparan sulfate proteoglycans (HSPGs), low density liproprotein receptor-related proteins (LRPs), and the cation-independent mannose-6-phosphate (M6P) receptor, which are endocytic receptors that may also serve as co-receptors in cooperation with other cell surface receptors. CCNs have also been reported to bind FGFR-2, Notch, RANK, and TrkA, potentially altering the affinities of these receptors for their ligands. The ability of CCNs to bind a multitude of receptors in various cell types may account for the remarkable versatility of their functions, and underscore the diverse signaling pathways that mediate their activities.
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26
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Adhesion molecules and the extracellular matrix as drug targets for glioma. Brain Tumor Pathol 2016; 33:97-106. [PMID: 26992378 DOI: 10.1007/s10014-016-0261-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 03/07/2016] [Indexed: 12/14/2022]
Abstract
The formation of tumor vasculature and cell invasion along white matter tracts have pivotal roles in the development and progression of glioma. A better understanding of the mechanisms of angiogenesis and invasion in glioma will aid the development of novel therapeutic strategies. The processes of angiogenesis and invasion cause the production of an array of adhesion molecules and extracellular matrix (ECM) components. This review focuses on the role of adhesion molecules and the ECM in malignant glioma. The results of clinical trials using drugs targeted against adhesion molecules and the ECM for glioma are also discussed.
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Kurundkar AR, Kurundkar D, Rangarajan S, Locy ML, Zhou Y, Liu RM, Zmijewski J, Thannickal VJ. The matricellular protein CCN1 enhances TGF-β1/SMAD3-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury. FASEB J 2016; 30:2135-50. [PMID: 26884454 DOI: 10.1096/fj.201500173] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 02/01/2016] [Indexed: 11/11/2022]
Abstract
Matricellular proteins mediate pleiotropic effects during tissue injury and repair. CCN1 is a matricellular protein that has been implicated in angiogenesis, inflammation, and wound repair. In this study, we identified CCN1 as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive idiopathic pulmonary fibrosis (IPF). Elevated levels of CCN1 mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and CCN1 protein was predominantly localized to fibroblastic foci. CCN1 expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen (Col)1a1, Col1a2, and fibronectin as well as the myofibroblast marker, α-smooth muscle actin. RNA interference (RNAi)-mediated knockdown of CCN1 down-regulated the constitutive expression of these profibrotic genes in IPF fibroblasts. TGF-β1, a known mediator of tissue fibrogenesis, induces gene and protein expression of CCN1 via a mothers against decapentaplegic homolog 3 (SMAD3)-dependent mechanism. Importantly, endogenous CCN1 potentiates TGF-β1-induced SMAD3 activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of CCN1 attenuates fibrogenic responses to bleomycin-induced lung injury. These studies support previously unrecognized, cooperative interaction between the CCN1 matricellular protein and canonical TGF-β1/SMAD3 signaling that promotes lung fibrosis.-Kurundkar, A. R., Kurundkar, D., Rangarajan, S., Locy, M. L., Zhou, Y., Liu, R.-M., Zmijewski, J., Thannickal, V. J. The matricellular protein CCN1 enhances TGF-β1/SMAD3-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury.
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Affiliation(s)
- Ashish R Kurundkar
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Deepali Kurundkar
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Sunad Rangarajan
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Morgan L Locy
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Yong Zhou
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rui-Ming Liu
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jaroslaw Zmijewski
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Victor J Thannickal
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Qin Z, Robichaud P, Quan T. Oxidative stress and CCN1 protein in human skin connective tissue aging. AIMS MOLECULAR SCIENCE 2016. [DOI: 10.3934/molsci.2016.2.269] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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29
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Hwang S, Lee HJ, Kim G, Won KJ, Park YS, Jo I. CCN1 acutely increases nitric oxide production via integrin αvβ3-Akt-S6K-phosphorylation of endothelial nitric oxide synthase at the serine 1177 signaling axis. Free Radic Biol Med 2015; 89:229-40. [PMID: 26393424 DOI: 10.1016/j.freeradbiomed.2015.08.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 07/14/2015] [Accepted: 08/05/2015] [Indexed: 11/30/2022]
Abstract
Although CCN1 (also known as cysteine-rich, angiogenic inducer 61, CYR61) has been reported to promote angiogenesis and neovascularization in endothelial cells (ECs), its effects on endothelial nitric oxide (NO) production have never been studied. Using human umbilical vein ECs, we investigated whether and how CCN1 regulates NO production. CCN1 acutely increased NO production in a time- and dose-dependent manner, which was accompanied by increased phosphorylation of endothelial NO synthase (eNOS) at serine 1177 (eNOS-Ser(1177)), but not that of eNOS-Thr(495) or eNOS-Ser(114). The level of total eNOS expression was unaltered. Treatment with either LY294002, a selective inhibitor of phosphoinositide 3-kinase known as an upstream kinase of Akt, or H-89, an inhibitor of protein kinase A, mitogen- and stress-activated protein kinase 1, Rho-associated protein kinase 2, and ribosomal protein S6 kinase (S6K), inhibited CCN1-stimulated eNOS-Ser(1177) phosphorylation and subsequent NO production. Ectopic expression of small interfering RNA against Akt and S6K significantly inhibited the effects of CCN1. Consistently, CCN1 increased the phosphorylation of Akt-Ser(473) and S6K-Thr(389). However, CCN1 did not alter the expression or secretion of VEGF, a known downstream factor of CCN1 and a potential upstream factor of Akt-mediated eNOS-Ser(1177) phosphorylation. Furthermore, neutralization of integrin αvβ3 with corresponding antibody completely reversed all of the observed effects of CCN1. Moreover, CCN1 increased acetylcholine-induced relaxation in the rat aortas. Finally, we also found that CCN1-stimulated eNOS-Ser(1177) phosphorylation and NO production are true for other types of EC tested. In conclusion, CCN1 acutely increases NO production via activation of a signaling axis in integrin αvβ3-Akt-S6K-eNOS-Ser(1177) phosphorylation, suggesting an important role for CCN1 in vasodilation.
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Affiliation(s)
- Soojin Hwang
- Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea
| | - Hyeon-Ju Lee
- Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea
| | - Gyungah Kim
- Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea
| | - Kyung-Jong Won
- Department of Medical Science, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea
| | - Yoon Shin Park
- Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea
| | - Inho Jo
- Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea.
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Krupska I, Bruford EA, Chaqour B. Eyeing the Cyr61/CTGF/NOV (CCN) group of genes in development and diseases: highlights of their structural likenesses and functional dissimilarities. Hum Genomics 2015; 9:24. [PMID: 26395334 PMCID: PMC4579636 DOI: 10.1186/s40246-015-0046-y] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 09/16/2015] [Indexed: 01/03/2023] Open
Abstract
“CCN” is an acronym referring to the first letter of each of the first three members of this original group of mammalian functionally and phylogenetically distinct extracellular matrix (ECM) proteins [i.e., cysteine-rich 61 (CYR61), connective tissue growth factor (CTGF), and nephroblastoma-overexpressed (NOV)]. Although “CCN” genes are unlikely to have arisen from a common ancestral gene, their encoded proteins share multimodular structures in which most cysteine residues are strictly conserved in their positions within several structural motifs. The CCN genes can be subdivided into members developmentally indispensable for embryonic viability (e.g., CCN1, 2 and 5), each assuming unique tissue-specific functions, and members not essential for embryonic development (e.g., CCN3, 4 and 6), probably due to a balance of functional redundancy and specialization during evolution. The temporo-spatial regulation of the CCN genes and the structural information contained within the sequences of their encoded proteins reflect diversity in their context and tissue-specific functions. Genetic association studies and experimental anomalies, replicated in various animal models, have shown that altered CCN gene structure or expression is associated with “injury” stimuli—whether mechanical (e.g., trauma, shear stress) or chemical (e.g., ischemia, hyperglycemia, hyperlipidemia, inflammation). Consequently, increased organ-specific susceptibility to structural damages ensues. These data underscore the critical functions of CCN proteins in the dynamics of tissue repair and regeneration and in the compensatory responses preceding organ failure. A better understanding of the regulation and mode of action of each CCN member will be useful in developing specific gain- or loss-of-function strategies for therapeutic purposes.
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Affiliation(s)
- Izabela Krupska
- Department of Cell Biology, Downstate Medical Center, Brooklyn, NY, 11203, USA.,Department of Ophthalmology, Downstate Medical Center, Brooklyn, NY, 11203, USA
| | - Elspeth A Bruford
- HUGO Gene Nomenclature Committee, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
| | - Brahim Chaqour
- Department of Cell Biology, Downstate Medical Center, Brooklyn, NY, 11203, USA. .,Department of Ophthalmology, Downstate Medical Center, Brooklyn, NY, 11203, USA. .,State University of New York (SUNY) Eye Institute Downstate Medical Center, 450 Clarkson Avenue, MSC 5, Brooklyn, NY, 11203, USA.
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31
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Raissadati A, Nykänen AI, Tuuminen R, Syrjälä SO, Krebs R, Arnaudova R, Rouvinen E, Wang X, Poller W, Lemström KB. Systemic overexpression of matricellular protein CCN1 exacerbates obliterative bronchiolitis in mouse tracheal allografts. Transpl Int 2015; 28:1416-25. [DOI: 10.1111/tri.12639] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Revised: 05/25/2015] [Accepted: 07/08/2015] [Indexed: 02/05/2023]
Affiliation(s)
- Alireza Raissadati
- University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center; Helsinki Finland
| | - Antti I. Nykänen
- University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center; Helsinki Finland
| | - Raimo Tuuminen
- University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center; Helsinki Finland
| | - Simo O. Syrjälä
- University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center; Helsinki Finland
| | - Rainer Krebs
- University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center; Helsinki Finland
| | - Ralica Arnaudova
- University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center; Helsinki Finland
| | - Eeva Rouvinen
- University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center; Helsinki Finland
| | - Xiaomin Wang
- Department of Cardiology and Pneumology; Charité - Universitätsmedizin Berlin; Berlin Germany
| | - Wolfgang Poller
- Department of Cardiology and Pneumology; Charité - Universitätsmedizin Berlin; Berlin Germany
- Berlin Center for Regenerative Therapies (BCRT); Charité - Universitätsmedizin Berlin; Berlin Germany
| | - Karl B. Lemström
- University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center; Helsinki Finland
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32
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Sharma AK, Cheng EY. Growth factor and small molecule influence on urological tissue regeneration utilizing cell seeded scaffolds. Adv Drug Deliv Rev 2015; 82-83:86-92. [PMID: 25446138 DOI: 10.1016/j.addr.2014.11.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2014] [Revised: 08/25/2014] [Accepted: 11/08/2014] [Indexed: 12/24/2022]
Abstract
Regenerative medicine strategies combine various attributes from multiple disciplines including stem cell biology, chemistry, materials science and medicine. The junction at which these disciplines intersect provides a means to address unmet medical needs in an assortment of pathologies with the goal of creating sustainable, functional replacement tissues. Tissue damage caused by trauma for example, requires rapid responses in order to mitigate further tissue deterioration. Cell/scaffold composites have been utilized to initiate and stabilize regenerative responses in vivo with the hope that functional tissue can be attained. Along with the gross reconfiguration of regenerating tissues, small molecules and growth factors also play a pivotal role in tissue regeneration. Several regenerative studies targeting a variety of urological tissues demonstrate the utility of these small molecules or growth factors in an in vivo setting.
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Joki Y, Ohashi K, Yuasa D, Shibata R, Kataoka Y, Kambara T, Uemura Y, Matsuo K, Hayakawa S, Hiramatsu-Ito M, Kanemura N, Ito M, Ogawa H, Daida H, Murohara T, Ouchi N. Neuron-derived neurotrophic factor ameliorates adverse cardiac remodeling after experimental myocardial infarction. Circ Heart Fail 2015; 8:342-51. [PMID: 25654972 DOI: 10.1161/circheartfailure.114.001647] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Myocardial infarction (MI) is one of the major causes of death worldwide. Chronic heart failure is a serious complication of MI that leads to poor prognosis. We recently found that neuron-derived neurotrophic factor (NDNF) is a proangiogenic secretory protein that is upregulated in ischemic skeletal muscle. Here, we examined whether NDNF modulates cardiac remodeling in response to chronic ischemia. METHODS AND RESULTS C57BL/6J wild-type mice were subjected to the permanent ligation of the left anterior descending coronary artery to create MI. Adenoviral vectors expressing NDNF or β-galactosidase (control) were intramuscularly injected into mice 3 days before permanent left anterior descending coronary artery ligation. Intramuscular administration of adenoviral vectors expressing NDNF to mice resulted in increased levels of circulating NDNF. Adenoviral vectors expressing NDNF administration improved left ventricular systolic dysfunction and dilatation after MI surgery. Moreover, adenoviral vectors expressing NDNF enhanced capillary formation and reduced cardiomyocyte apoptosis and hypertrophy in the post-MI hearts. Treatment of cultured cardiomyocytes with recombinant NDNF protein led to reduced apoptosis under conditions of hypoxia. NDNF also promoted the phosphorylation of Akt and focal adhesion kinase in cardiomyocytes. Blockade of focal adhesion kinase activation blocked the stimulatory effects of NDNF on cardiomyocyte survival and Akt phosphorylation. Similarly, treatment of cultured endothelial cells with NDNF protein led to enhancement of network formation and Akt phosphorylation, which was diminished by focal adhesion kinase inhibition. CONCLUSIONS These data suggest that NDNF ameliorates adverse myocardial remodeling after MI by its abilities to enhance myocyte survival and angiogenesis in the heart through focal adhesion kinase/Akt-dependent mechanisms.
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Affiliation(s)
- Yusuke Joki
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Koji Ohashi
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
| | - Daisuke Yuasa
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Rei Shibata
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Yoshiyuki Kataoka
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Takahiro Kambara
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Yusuke Uemura
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Kazuhiro Matsuo
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Satoko Hayakawa
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Mizuho Hiramatsu-Ito
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Noriyoshi Kanemura
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Masanori Ito
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Hayato Ogawa
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Hiroyuki Daida
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Toyoaki Murohara
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.)
| | - Noriyuki Ouchi
- From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
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Zhang F, Hao F, An D, Zeng L, Wang Y, Xu X, Cui MZ. The matricellular protein Cyr61 is a key mediator of platelet-derived growth factor-induced cell migration. J Biol Chem 2015; 290:8232-42. [PMID: 25623072 DOI: 10.1074/jbc.m114.623074] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Platelet-derived growth factor (PDGF), a potent chemoattractant, induces cell migration via the MAPK and PI3K/Akt pathways. However, the downstream mediators are still elusive. In particular, the role of extracellular mediators is largely unknown. In this study, we identified the matricellular protein Cyr61, which is de novo synthesized in response to PDGF stimulation, as the key downstream mediator of the ERK and JNK pathways, independent of the p38 MAPK and AKT pathways, and, thereby, it mediates PDGF-induced smooth muscle cell migration but not proliferation. Our results revealed that, when Cyr61 was newly synthesized by PDGF, it was promptly translocated to the extracellular matrix and physically interacted with the plasma membrane integrins α6β1 and αvβ3. We further demonstrate that Cyr61 and integrins are integral components of the PDGF signaling pathway via an "outside-in" signaling route to activate intracellular focal adhesion kinase (FAK), leading to cell migration. Therefore, this study provides the first evidence that the PDGF-induced endogenous extracellular matrix component Cyr61 is a key mediator in modulating cell migration by connecting intracellular PDGF-ERK and JNK signals with integrin/FAK signaling. Therefore, extracellular Cyr61 convergence with growth factor signaling and integrin/FAK signaling is a new concept of growth factor-induced cell migration. The discovered signaling pathway may represent an important therapeutic target in growth factor-mediated cell migration/invasion-related vascular diseases and tumorigenesis.
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Affiliation(s)
- Fuqiang Zhang
- From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996 and the Department of Regenerative Medicine, College of Pharmacy, and
| | - Feng Hao
- From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996 and
| | - Dong An
- From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996 and College of Life Sciences, Jilin University, Changchun 130021, China
| | - Linlin Zeng
- From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996 and
| | - Yi Wang
- the Department of Regenerative Medicine, College of Pharmacy, and
| | - Xuemin Xu
- From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996 and
| | - Mei-Zhen Cui
- From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996 and
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Park YS, Hwang S, Jin YM, Yu Y, Jung SA, Jung SC, Ryu KH, Kim HS, Jo I. CCN1 secreted by tonsil-derived mesenchymal stem cells promotes endothelial cell angiogenesis via integrin αv β3 and AMPK. J Cell Physiol 2015; 230:140-9. [PMID: 24909560 DOI: 10.1002/jcp.24690] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 05/21/2014] [Indexed: 11/12/2022]
Abstract
CCN1 is highly expressed in cancer cells and has been identified in the secretome of bone marrow-derived mesenchymal stem cells (BM-MSC). Although secreted CCN1 is known to promote angiogenesis, its underlying mechanism remains unclear. Here, we examined whether our recently-established tonsil-derived MSC (T-MSC) secrete CCN1 and, if any, how CCN1 promotes the angiogenesis of human umbilical vein endothelial cells (HUVEC). Compared with untreated control T-MSC, a higher level of CCN1 was secreted by T-MSC treated with activin A and sonic hedgehog, drugs known to induce endodermal differentiation. Expectedly, conditioned medium collected from differentiated T-MSC (DCM) significantly increased HUVEC migration and tube formation compared with that from control T-MSC (CCM), and these stimulatory effects were reversed by neutralization with anti-CCN1 antibody. Treatment with recombinant human CCN1 (rh-CCN1) alone also mimicked the stimulatory effects of DCM. Furthermore, treatment with either DCM or rh-CCN1 increased the phosphorylation of AMP kinase (AMPK), and ectopic expression of siRNA of the AMPK gene inhibited all observed effects of both DCM and rh-CCN1. However, no alteration of intracellular ATP levels or phosphorylation of LKB1, a well-known upstream factor of AMPK activation, was observed under our conditions. Finally, the neutralization of integrin α(v) β(3) with anti-integrin α(v) β(3) antibody almost completely reversed the effects of CCN1 on AMPK phosphorylation, and EC migration and tube formation. Taken together, we demonstrated that T-MSC increase the secretion of CCN1 in response to endodermal differentiation and that integrin α(v) β(3) and AMPK mediate CCN1-induced EC migration and tube formation independent of intracellular ATP levels alteration.
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Affiliation(s)
- Yoon Shin Park
- Department of Molecular Medicine, School of Medicine, and Global Top 5 Research Program, Ewha Womans University, Mok-6-dong, Yangcheon-gu, Seoul 158-710, Republic of Korea
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Cyr61 silencing reduces vascularization and dissemination of osteosarcoma tumors. Oncogene 2014; 34:3207-13. [PMID: 25065593 DOI: 10.1038/onc.2014.232] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 06/10/2014] [Accepted: 06/24/2014] [Indexed: 01/10/2023]
Abstract
Osteosarcoma is the most prevalent primary pediatric cancer-related bone disease. These tumors frequently develop resistance to chemotherapy and are highly metastatic, leading to poor outcome. Thus, there is a need for new therapeutic strategies that can prevent cell dissemination. We previously showed that CYR61/CCN1 expression in osteosarcoma cells is correlated to aggressiveness both in vitro and in vivo in mouse models, as well as in patients. In this study, we found that CYR61 is a critical contributor to the vascularization of primary tumor. We demonstrate that silencing CYR61, using lentiviral transduction, leads to a significant reduction in expression level of pro-angiogenic markers such as VEGF, FGF2, PECAM and angiopoietins concomitantly to an increased expression of major anti-angiogenic markers such as thrombospondin-1 and SPARC. Matrix metalloproteinase-2 family member expression, a key pathway in osteosarcoma metastatic capacity was also downregulated when CYR61 was downregulated in osteosarcoma cells. Using a metastatic murine model, we show that CYR61 silencing in osteosarcoma cells results in reduced tumor vasculature and slows tumor growth compared with control. We also find that microvessel density correlates with lung metastasis occurrence and that CYR61 silencing in osteosarcoma cells limits the number of metastases. Taken together, our data indicate that CYR61 silencing can blunt the malignant behavior of osteosarcoma tumor cells by limiting primary tumor growth and dissemination process.
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Shen H, Cai M, Zhao S, Wang H, Li M, Yao S, Jiang N. CYR61 overexpression associated with the development and poor prognosis of ovarian carcinoma. Med Oncol 2014; 31:117. [PMID: 25048722 DOI: 10.1007/s12032-014-0117-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 07/02/2014] [Indexed: 01/09/2023]
Abstract
Cysteine-rich 61 (CYR61) has been proven to be an oncogene with potential predictive and prognostic implications in a variety of human cancers. However, the expression pattern of CYR61 and its role in ovarian carcinoma remains largely unknown. In this study, the mRNA and protein levels of CYR61 in normal ovaries and ovarian carcinoma tissues were evaluated using reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blotting. Compared to normal ovarian tissues, the mRNA and protein levels of CYR61 were significantly higher in ovarian carcinoma tissues. Moreover, receiver operating characteristic (ROC) curve analysis, Spearman's rank correlation, Kaplan-Meier plots, and the Cox proportional hazards regression model were used to investigate the potential association of the CYR61 protein with the development of ovarian carcinoma in an ovarian carcinoma cohort. Based on ROC curve analysis, high expression of CYR61 was defined as a tumor in which more than 70 % of cells were positively stained. Based on this cutoff value, high expression of CYR61 was detected in 51.5 % of invasive carcinomas, 35.3 % of borderline tumors, 25.9 % of cystadenomas, and 20 % in the normal ovaries. In ovarian carcinomas, CYR61 overexpression was associated with advanced FIGO stage. Univariate survival analysis on the ovarian carcinoma cohorts showed that overexpression of CYR61 was associated with poor survival of ovarian cancer patients. Multivariate analysis suggested that the protein level of CYR61 was an independent and significant prognostic factor for ovarian carcinoma. Our results suggest that the CYR61 protein is an important and independent biomarker for prognostic implications of ovarian carcinoma.
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Affiliation(s)
- Huimin Shen
- The First Affiliated Hospital, Sun Yat-sen University, Guang Zhou, 510080, China
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38
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Ohashi K, Enomoto T, Joki Y, Shibata R, Ogura Y, Kataoka Y, Shimizu Y, Kambara T, Uemura Y, Yuasa D, Matsuo K, Hayakawa S, Hiramatsu-Ito M, Murohara T, Ouchi N. Neuron-derived neurotrophic factor functions as a novel modulator that enhances endothelial cell function and revascularization processes. J Biol Chem 2014; 289:14132-44. [PMID: 24706764 DOI: 10.1074/jbc.m114.555789] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Strategies to stimulate revascularization are valuable for cardiovascular diseases. Here we identify neuron-derived neurotrophic factor (NDNF)/epidermacan as a secreted molecule that is up-regulated in endothelial cells in ischemic limbs of mice. NDNF was secreted from cultured human endothelial cells, and its secretion was stimulated by hypoxia. NDNF promoted endothelial cell network formation and survival in vitro through activation of Akt/endothelial NOS (eNOS) signaling involving integrin αvβ3. Conversely, siRNA-mediated knockdown of NDNF in endothelial cells led to reduction of cellular responses and basal Akt signaling. Intramuscular overexpression of NDNF led to enhanced blood flow recovery and capillary density in ischemic limbs of mice, which was accompanied by enhanced phosphorylation of Akt and eNOS. The stimulatory actions of NDNF on perfusion recovery in ischemic muscles of mice were abolished by eNOS deficiency or NOS inhibition. Furthermore, siRNA-mediated reduction of NDNF in muscles of mice resulted in reduction of perfusion recovery and phosphorylation of Akt and eNOS in response to ischemia. Our data indicate that NDNF acts as an endogenous modulator that promotes endothelial cell function and ischemia-induced revascularization through eNOS-dependent mechanisms. Thus, NDNF can represent a therapeutic target for the manipulation of ischemic vascular disorders.
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Affiliation(s)
- Koji Ohashi
- From the Department of Molecular Cardiology and
| | - Takashi Enomoto
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yusuke Joki
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Rei Shibata
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yasuhiro Ogura
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yoshiyuki Kataoka
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yuuki Shimizu
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Takahiro Kambara
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yusuke Uemura
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Daisuke Yuasa
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Kazuhiro Matsuo
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Satoko Hayakawa
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Mizuho Hiramatsu-Ito
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
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Jeong D, Heo S, Sung Ahn T, Lee S, Park S, Kim H, Park D, Byung Bae S, Lee SS, Soo Lee M, Kim CJ, Jun Baek M. Cyr61 expression is associated with prognosis in patients with colorectal cancer. BMC Cancer 2014; 14:164. [PMID: 24606730 PMCID: PMC3975645 DOI: 10.1186/1471-2407-14-164] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Accepted: 02/28/2014] [Indexed: 01/22/2023] Open
Abstract
Background Cysteine-rich 61 (Cyr61), a member of the CCN protein family, possesses diverse functionality in cellular processes such as adhesion, migration, proliferation, and survival. Cyr61 can also function as an oncogene or a tumour suppressor, depending on the origin of the cancer. Only a few studies have reported Cyr61 expression in colorectal cancer. In this study, we assessed the Cyr61 expression in 251 colorectal cancers with clinical follow up. Methods We examined Cyr61 expression in 6 colorectal cancer cell lines (HT29, Colo205, Lovo, HCT116, SW480, SW620) and 20 sets of paired normal and colorectal cancer tissues by western blot. To validate the association of Cyr61 expression with clinicopathological parameters, we assessed Cyr61 expression using tissue microarray analysis of primary colorectal cancer by immunohistochemical analysis. Results We verified that all of the cancer cell lines expressed Cyr61; 2 cell lines (HT29 and Colo205) demonstrated Cyr61 expression to a slight extent, while 4 cell lines (Lovo, HCT116, SW480, SW620) demonstrated greater Cyr61 expression than HT29 and Colo205 cell lines. Among the 20 cases of paired normal and tumour tissues, greater Cyr61 expression was observed in 16 (80%) tumour tissues than in normal tissues. Furthermore, 157 out of 251 cases (62.5%) of colorectal cancer examined in this study displayed strong Cyr61 expression. Cyr61 expression was found to be associated with pN (p = 0.018). Moreover, Cyr61 expression was associated with statistically significant cancer-specific mortality (p = 0.029). The duration of survival was significantly lesser in patients with Cyr61 high expression than in patients with Cyr61 low expression (p = 0.001). These results suggest that Cyr61 expression plays several important roles in carcinogenesis and may also be a good prognostic marker for colorectal cancer. Conclusions Our data confirmed that Cyr61 was expressed in colorectal cancers and the expression was correlated with worse prognosis of colorectal cancers.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Moo Jun Baek
- Department of Surgery, College of Medicine, Soonchunhyang University, 31 soonchunhyang 6 gil, Dongnam-gu, Cheonan, Chungcheongnam-do 330-722, Republic of Korea.
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Cheng TY, Wu MS, Hua KT, Kuo ML, Lin MT. Cyr61/CTGF/Nov family proteins in gastric carcinogenesis. World J Gastroenterol 2014; 20:1694-1700. [PMID: 24587648 PMCID: PMC3930969 DOI: 10.3748/wjg.v20.i7.1694] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/07/2013] [Accepted: 01/05/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the second leading cause of cancer-related death. The poor survival rate may reflect the relatively aggressive tumor biology of GC. Recently, the importance of the tumor microenvironment in carcinogenesis has emerged. In the tumor microenvironment, tumor cells and the surrounding stromal cells aberrantly secrete matricellular proteins capable of modulating carcinogenesis and regulating metastasis. The Cyr61/CTGF/Nov (CCN) proteins are a family of matricellular proteins with variable roles in many physiological and pathological processes. The evidence suggests that CCN family proteins contribute to GC carcinogenic processes. Here, we briefly review recent research on the effects of CCN family proteins in GC carcinogenesis and the development of new targeted agents in this field.
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Myers RB, Wei L, Castellot JJ. The matricellular protein CCN5 regulates podosome function via interaction with integrin αvβ 3. J Cell Commun Signal 2014; 8:135-46. [PMID: 24488697 DOI: 10.1007/s12079-013-0218-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Accepted: 11/26/2013] [Indexed: 12/30/2022] Open
Abstract
CCN proteins play crucial roles in cell motility, matrix turnover, and proliferation. In particular, CCN5 plays a role in cell motility and proliferation in several cell types; however, no functional binding proteins for CCN5 have been identified. In this study we report that CCN5 binds to the cell surface receptor integrin αvβ3 in vascular smooth muscle cells. Furthermore, this interaction takes place in podosomes, organelles known to degrade matrix and mediate motility. We show that CCN5 regulates the ability of podosomes to degrade matrix, but does not affect podosome formation. The level of CCN5 present in a podosome negatively correlates with its ability to degrade matrix. Conversely, knockdown of CCN5 greatly enhances the matrix-degrading ability of podosomes. These findings suggest that the antimotility effects of CCN5 may be mediated through the direct interaction of CCN5 and integrin αvβ3 in podosomes and the concomitant suppression of matrix degradation that is required for cell migration.
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Affiliation(s)
- Ronald B Myers
- Program in Cell, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA
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The CCN family proteins: modulators of bone development and novel targets in bone-associated tumors. BIOMED RESEARCH INTERNATIONAL 2014; 2014:437096. [PMID: 24551846 PMCID: PMC3914550 DOI: 10.1155/2014/437096] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Accepted: 12/19/2013] [Indexed: 12/18/2022]
Abstract
The CCN family of proteins is composed of six extracellular matrix-associated proteins that play crucial roles in skeletal development, wound healing, fibrosis, and cancer. Members of the CCN family share four conserved cysteine-rich modular domains that trigger signal transduction in cell adhesion, migration, proliferation, differentiation, and survival through direct binding to specific integrin receptors and heparan sulfate proteoglycans. In the present review, we discuss the roles of the CCN family proteins in regulating resident cells of the bone microenvironment. In vertebrate development, the CCN family plays a critical role in osteo/chondrogenesis and vasculo/angiogenesis. These effects are regulated through signaling via integrins, bone morphogenetic protein, vascular endothelial growth factor, Wnt, and Notch via direct binding to CCN family proteins. Due to the important roles of CCN family proteins in skeletal development, abnormal expression of CCN proteins is related to the tumorigenesis of primary bone tumors such as osteosarcoma, Ewing sarcoma, and chondrosarcoma. Additionally, emerging studies have suggested that CCN proteins may affect progression of secondary metastatic bone tumors by moderating the bone microenvironment. CCN proteins could therefore serve as potential therapeutic targets for drug development against primary and metastatic bone tumors.
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Cyr61 induces the expression of monocyte chemoattractant protein-1 via the integrin ανβ3, FAK, PI3K/Akt, and NF-κB pathways in retinal vascular endothelial cells. Cell Signal 2014; 26:133-40. [DOI: 10.1016/j.cellsig.2013.08.026] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Revised: 08/04/2013] [Accepted: 08/27/2013] [Indexed: 11/23/2022]
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Wu DD, Zhang F, Hao F, Chun J, Xu X, Cui MZ. Matricellular protein Cyr61 bridges lysophosphatidic acid and integrin pathways leading to cell migration. J Biol Chem 2013; 289:5774-83. [PMID: 24371135 DOI: 10.1074/jbc.m113.533042] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Lysophosphatidic acid (LPA), a potent bioactive lipid found in atherosclerotic lesions, markedly induces smooth muscle cell (SMC) migration, which is an important process in atherogenesis. Therefore, understanding the mechanism of LPA-induced SMC migration is important. Several microarray databases suggest that the matricellular protein Cyr61 is highly induced by LPA. We hypothesized that Cyr61 mediates LPA-induced cell migration. Our data show that LPA induced temporal and spatial expression of Cyr61, which promptly accumulated in the cellular Golgi apparatus and then translocated to the extracellular matrix. Cyr61 antibody blockade and siRNA inhibition both diminished LPA-induced SMC migration, indicating a novel regulatory role of Cyr61. SMCs derived from LPA receptor 1 (LPA1) knock-out mice lack the ability of Cyr61 induction and cell migration, supporting the concept that LPA1 is required for Cyr61 expression and migration. By contrast, PPARγ was not found to be involved in LPA-mediated effects. Furthermore, focal adhesion kinase (FAK), a nonreceptor tyrosine kinase important for regulating cell migration, was activated by LPA at a late time frame coinciding with Cyr61 accumulation. Interestingly, knockdown of Cyr61 blocked LPA-induced FAK activation, indicating that an LPA-Cyr61-FAK axis leads to SMC migration. Our results further demonstrate that plasma membrane integrins α6β1 and ανβ3 transduced the LPA-Cyr61 signal toward FAK activation and migration. Taken together, these data reveal that de novo Cyr61 in the extracellular matrix bridges LPA and integrin pathways, which in turn, activate FAK, leading to cell migration. The current study provides new insights into mechanisms underlying cell migration-related disorders, including atherosclerosis, restenosis, and cancers.
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Affiliation(s)
- Daniel Dongwei Wu
- From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996
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Onishi M, Kurozumi K, Ichikawa T, Date I. Mechanisms of tumor development and anti-angiogenic therapy in glioblastoma multiforme. Neurol Med Chir (Tokyo) 2013; 53:755-63. [PMID: 24162241 PMCID: PMC4508716 DOI: 10.2176/nmc.ra2013-0200] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Despite advances in surgical and medical therapy, glioblastoma multiforme (GBM) remains a fatal disease. There has been no significant increase in survival for patients with this disease over the last 20 years. Tumor vasculature formation and glioma cell invasion along the white matter tracts both play a pivotal role in glioma development. Angiogenesis and invasion are the major factors believed to be responsible for treatment resistance in tumors, and a better understanding of the glioma invasion and angiogenesis mechanisms will lead to the development of potential new treatments. In this review, we focus on the molecular characteristics of angiogenesis and invasion in human malignant glioma. We discuss bevacizumab and cilengitide, which are used to inhibit angiogenesis in GBM.
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Affiliation(s)
- Manabu Onishi
- Department of Neurological Surgery, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama
- Address reprint requests to: Manabu Onishi, MD, PhD, Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, Okayama 700-8558, Japan. e-mail:
| | - Kazuhiko Kurozumi
- Department of Neurological Surgery, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama
| | - Tomotsugu Ichikawa
- Department of Neurological Surgery, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama
| | - Isao Date
- Department of Neurological Surgery, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama
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Kurozumi K, Ichikawa T, Onishi M, Fujii K, Date I. Cilengitide treatment for malignant glioma: current status and future direction. Neurol Med Chir (Tokyo) 2013; 52:539-47. [PMID: 22976135 DOI: 10.2176/nmc.52.539] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Malignant glioma is the most common primary brain tumor and accounts for the majority of diagnoses. Treatment has involved a combination of surgery, radiation, and chemotherapy, yet these modalities rarely extend the life of the patient to more than one year from diagnosis. Integrins are expressed in tumor cells and tumor endothelial cells, and are important in angiogenesis and invasion in glioma. αvβ3 and αvβ5 integrins regulate cell adhesion, and inhibitors of these integrins suppress tumor growth in certain pre-clinical models. Several integrin-targeted drugs are in clinical trials as potential compounds for the treatment of cancer. Among them, cilengitide is a novel integrin antagonist for the treatment of glioblastoma. The multimodal anti-glioma effects are based on its cytotoxic, anti-angiogenic, anti-invasive, and synergetic effects. Preclinical studies showed a promising synergy between cilengitide and radiochemotherapy in order to normalize tumor vasculature and attenuate tumor invasion. Cilengitide is currently being assessed in phase III trials for patients with glioblastoma multiforme and in phase II trials for other types of cancers, demonstrating promising therapeutic outcomes to date. The results of these and other clinical studies are expected with great hope and interest. A more clear understanding of the benefits and pitfalls of each approach can then lead to the design of strategies to derive maximal benefit from these therapies.
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Affiliation(s)
- Kazuhiko Kurozumi
- Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.
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Qin Z, Fisher GJ, Quan T. Cysteine-rich protein 61 (CCN1) domain-specific stimulation of matrix metalloproteinase-1 expression through αVβ3 integrin in human skin fibroblasts. J Biol Chem 2013; 288:12386-94. [PMID: 23504324 DOI: 10.1074/jbc.m112.424358] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Human skin largely comprises collagenous extracellular matrix. The hallmark of skin aging is fragmentation of collagen fibrils. Matrix metalloproteinases (MMPs) are largely responsible for collagen degradation. MMP-1, principally derived from dermal fibroblasts, is the major protease capable of initiating degradation of native fibrillar collagens. Presently, we report that CCN1, a secreted and extracellular matrix-associated protein, is elevated in aged human skin dermal fibroblasts in vivo and stimulates MMP-1 expression through functional interaction with αVβ3 integrin in human dermal fibroblasts. CCN1 contains four conserved structural domains. Our results indicate that the three N-terminal domains (IGFBP, VWC, and TSP1), but not the C-terminal CT domain, are required for CCN1 to stimulate MMP-1 expression. This stimulation is dependent on interaction between the active structural domains and αVβ3 integrin. The interaction of VWC domain with integrin αVβ3 is necessary and requires functional cooperation with adjacent IGFBP and TSP1 domains to stimulate MMP-1 expression. Finally, induction of MMP-1 expression in dermal fibroblasts by CCN1 N-terminal domains resulted in fragmentation of type I collagen fibrils in a three-dimensional collagen lattice model. These data suggest that domain-specific interactions of CCN1 with αVβ3 integrin contribute to human skin aging by stimulating MMP-1-mediated collagen fibril fragmentation.
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Affiliation(s)
- Zhaoping Qin
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
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Han SW, Jung YK, Lee EJ, Park HR, Kim GW, Jeong JH, Han MS, Choi JY. DICAM inhibits angiogenesis via suppression of AKT and p38 MAP kinase signalling. Cardiovasc Res 2013; 98:73-82. [DOI: 10.1093/cvr/cvt019] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
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Tao L, Chen J, Zhou H, Qin C, Li P, Cao Q, Li J, Ju X, Zhu C, Wang M, Zhang Z, Shao P, Yin C. A functional polymorphism in the CYR61 (IGFBP10) gene is associated with prostate cancer risk. Prostate Cancer Prostatic Dis 2012; 16:95-100. [PMID: 23045290 DOI: 10.1038/pcan.2012.41] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND CYR61 (cysteine-rich protein 61, also named IGFBP10) is a secreted signaling molecule that promotes angiogenesis and tumor growth. The goal of this study is to determine whether a functional polymorphism in the promoter region of the CYR61 gene (rs3753793) is associated with prostate cancer (PCa) risk and gene expression in Chinese patients. METHODS A total of 665 patients diagnosed with PCa and 703 cancer-free controls were genotyped in this hospital-based case-control study, and 26 PCa tissue samples were evaluated for mRNA expression of CYR61 by real-time quantitative reverse-transcription PCR. RESULTS Men carrying the G allele of rs3753793 (TG+GG) had significantly lower risk of PCa when compared with the TT genotype (odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.61-0.95). The association was generally more pronounced among subgroups of PCa patients with advanced stage (OR = 0.70, 95% CI = 0.53-0.94), Gleason score >7 (OR = 0.63, 95% CI = 0.46-0.86) and PSA>20 ng ml(-1) (OR = 0.68, 95% CI = 0.53-0.88). Prostate tumors derived from cases with the GT/GG genotypes had significantly lower levels of CYR61 mRNA when compared with cases with the TT genotypes (P = 0.02). CONCLUSIONS Our results indicate that the genetic variation of rs3753793 in the CYR61 promoter may contribute to genetic predisposition to PCa and intra-tumor expression gene expression.
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Affiliation(s)
- L Tao
- State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Löbel M, Bauer S, Meisel C, Eisenreich A, Kudernatsch R, Tank J, Rauch U, Kühl U, Schultheiss HP, Volk HD, Poller W, Scheibenbogen C. CCN1: a novel inflammation-regulated biphasic immune cell migration modulator. Cell Mol Life Sci 2012; 69:3101-13. [PMID: 22527715 PMCID: PMC11114836 DOI: 10.1007/s00018-012-0981-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2011] [Revised: 03/21/2012] [Accepted: 03/26/2012] [Indexed: 01/07/2023]
Abstract
In this study, we performed a comprehensive analysis of the effect of CCN1 on the migration of human immune cells. The molecule CCN1, produced by fibroblasts and endothelial cells, is considered as an important matrix protein promoting tissue repair and immune cell adhesion by binding various integrins. We recently reported that CCN1 therapy is able to suppress acute inflammation in vivo. Here, we show that CCN1 binds to various immune cells including T cells, B cells, NK cells, and monocytes. The addition of CCN1 in vitro enhances both actin polymerization and transwell migration. Prolonged incubation with CCN1, however, results in the inhibition of migration of immune cells by a mechanism that involves downregulation of PI3Kγ, p38, and Akt activation. Furthermore, we observed that immune cells themselves produce constitutively CCN1 and secretion is induced by pro-inflammatory stimuli. In line with this finding, patients suffering from acute inflammation had enhanced serum levels of CCN1. These findings extend the classical concept of CCN1 as a locally produced cell matrix adhesion molecule and suggest that CCN1 plays an important role in regulating immune cell trafficking by attracting and locally immobilizing immune cells.
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Affiliation(s)
- Madlen Löbel
- Institute of Medical Immunology, Charité University Medicine Berlin, 13353, Berlin, Germany.
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