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1
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Feng J, Zheng X. Histone Deacetylase 2 Stabilizes SPARC-related Modular Calcium Binding 2 to Promote Metastasis and Stemness in Gallbladder Cancer. Curr Mol Med 2025; 25:56-68. [PMID: 38173203 DOI: 10.2174/0115665240257970231013094101] [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: 04/14/2023] [Revised: 08/31/2023] [Accepted: 09/05/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND We aimed to investigate the relationship between histone deacetylase 2 (HDAC2) and SPARC-related modular calcium binding 2 (SMOC2) and the role of SMOC2 in gallbladder cancer (GBC). METHODS The expression of HDAC2 and SMOC2 in GBC and normal cells was detected by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), which was also used to detect the mRNA stability of SMOC2. The combination between HDAC2 and SMOC2 was detected by Chromatin immunoprecipitation (ChIP) assay. After silencing and/or overexpressing HDAC2 and SMOC2, cell viability, migration, invasion, and stemness were respectively tested by the Cell Counting Kit-8 (CCK-8), cell scratch, transwell, and sphere-formation assay. RESULTS In GBC cells, HDAC2 and SMOC2 were highly expressed. HDAC2 combined with SMOC2 promoted mRNA stability of SMOC2. HDAC2 or SMOC2 overexpression promoted GBC cell metastasis and stemness. SMOC2 overexpression rescued the negative effects of silencing HDAC2 in GBC. CONCLUSION HDAC2 stabilizes SMOC2 to promote metastasis and stemness in gallbladder cancer.
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Affiliation(s)
- Ji Feng
- Department of General Surgery, Sir Run Run Shaw Hospital (SRRSH), Affiliated with the Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310000, China
| | - Xueyong Zheng
- Department of General Surgery, Sir Run Run Shaw Hospital (SRRSH), Affiliated with the Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310000, China
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2
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Yoshihara T, Morimoto T, Hirata H, Murayama M, Nonaka T, Tsukamoto M, Toda Y, Kobayashi T, Izuhara K, Mawatari M. Mechanisms of tissue degeneration mediated by periostin in spinal degenerative diseases and their implications for pathology and diagnosis: a review. Front Med (Lausanne) 2023; 10:1276900. [PMID: 38020106 PMCID: PMC10645150 DOI: 10.3389/fmed.2023.1276900] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 09/18/2023] [Indexed: 12/01/2023] Open
Abstract
Periostin (POSTN) serves a dual role as both a matricellular protein and an extracellular matrix (ECM) protein and is widely expressed in various tissues and cells. As an ECM protein, POSTN binds to integrin receptors, transduces signals to cells, enabling cell activation. POSTN has been linked with various diseases, including atopic dermatitis, asthma, and the progression of multiple cancers. Recently, its association with orthopedic diseases, such as osteoporosis, osteoarthritis resulting from cartilage destruction, degenerative diseases of the intervertebral disks, and ligament degenerative diseases, has also become apparent. Furthermore, POSTN has been shown to be a valuable biomarker for understanding the pathophysiology of orthopedic diseases. In addition to serum POSTN, synovial fluid POSTN in joints has been reported to be useful as a biomarker. Risk factors for spinal degenerative diseases include aging, mechanical stress, trauma, genetic predisposition, obesity, and metabolic syndrome, but the cause of spinal degenerative diseases (SDDs) remains unclear. Studies on the pathophysiological effects of POSTN may significantly contribute toward the diagnosis and treatment of spinal degenerative diseases. Therefore, in this review, we aim to examine the mechanisms of tissue degeneration caused by mechanical and inflammatory stresses in the bones, cartilage, intervertebral disks, and ligaments, which are crucial components of the spine, with a focus on POSTN.
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Affiliation(s)
- Tomohito Yoshihara
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Tadatsugu Morimoto
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Hirohito Hirata
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Masatoshi Murayama
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Toshihiro Nonaka
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Masatsugu Tsukamoto
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Yu Toda
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Takaomi Kobayashi
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Kenji Izuhara
- Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga, Japan
| | - Masaaki Mawatari
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
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3
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Sumioka T, Matsumoto KI, Reinach PS, Saika S. Tenascins and osteopontin in biological response in cornea. Ocul Surf 2023; 29:131-149. [PMID: 37209968 DOI: 10.1016/j.jtos.2023.05.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/01/2023] [Accepted: 05/16/2023] [Indexed: 05/22/2023]
Abstract
The structural composition, integrity and regular curvature of the cornea contribute to the maintenance of its transparency and vision. Disruption of its integrity caused by injury results in scarring, inflammation and neovascularization followed by losses in transparency. These sight compromising effects is caused by dysfunctional corneal resident cell responses induced by the wound healing process. Upregulation of growth factors/cytokines and neuropeptides affect development of aberrant behavior. These factors trigger keratocytes to first transform into activated fibroblasts and then to myofibroblasts. Myofibroblasts express extracellular matrix components for tissue repair and contract the tissue to facilitate wound closure. Proper remodeling following primary repair is critical for restoration of transparency and visual function. Extracellular matrix components contributing to the healing process are divided into two groups; a group of classical tissue structural components and matrix macromolecules that modulate cell behaviors/activities besides being integrated into the matrix structure. The latter components are designated as matricellular proteins. Their functionality is elicited through mechanisms which modulate the scaffold integrity, cell behaviors, activation/inactivation of either growth factors or cytoplasmic signaling regulation. We discuss here the functional roles of matricellular proteins in mediating injury-induced corneal tissue repair. The roles are described of major matricellular proteins, which include tenascin C, tenascin X and osteopontin. Focus is directed towards dealing with their roles in modulating individual activities of wound healing-related growth factors, e. g., transforming growth factor β (TGF β). Modulation of matricellular protein functions could encompass a potential novel strategy to improve the outcome of injury-induced corneal wound healing.
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Affiliation(s)
- Takayoshi Sumioka
- Department of Ophthalmology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, 641-0012, Japan.
| | - Ken-Ichi Matsumoto
- Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, 89-1 Enya-cho, Izumo, 693-8501, Japan
| | - Peter Sol Reinach
- Department of Biological. Sciences SUNY Optometry, New York, NY, 10036, USA
| | - Shizuya Saika
- Department of Ophthalmology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, 641-0012, Japan
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4
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Kałuzińska-Kołat Ż, Kołat D, Kośla K, Płuciennik E, Bednarek AK. Delineating the glioblastoma stemness by genes involved in cytoskeletal rearrangements and metabolic alterations. World J Stem Cells 2023; 15:302-322. [PMID: 37342224 PMCID: PMC10277965 DOI: 10.4252/wjsc.v15.i5.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 02/03/2023] [Accepted: 03/08/2023] [Indexed: 05/26/2023] Open
Abstract
Literature data on glioblastoma ongoingly underline the link between metabolism and cancer stemness, the latter is one responsible for potentiating the resistance to treatment, inter alia due to increased invasiveness. In recent years, glioblastoma stemness research has bashfully introduced a key aspect of cytoskeletal rearrangements, whereas the impact of the cytoskeleton on invasiveness is well known. Although non-stem glioblastoma cells are less invasive than glioblastoma stem cells (GSCs), these cells also acquire stemness with greater ease if characterized as invasive cells and not tumor core cells. This suggests that glioblastoma stemness should be further investigated for any phenomena related to the cytoskeleton and metabolism, as they may provide new invasion-related insights. Previously, we proved that interplay between metabolism and cytoskeleton existed in glioblastoma. Despite searching for cytoskeleton-related processes in which the investigated genes might have been involved, not only did we stumble across the relation to metabolism but also reported genes that were found to be implicated in stemness. Thus, dedicated research on these genes in GSCs seems justifiable and might reveal novel directions and/or biomarkers that could be utilized in the future. Herein, we review the previously identified cytoskeleton/metabolism-related genes through the prism of glioblastoma stemness.
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Affiliation(s)
- Żaneta Kałuzińska-Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland.
| | - Damian Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Katarzyna Kośla
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Elżbieta Płuciennik
- Department of Functional Genomics, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
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5
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Wang Z, An J, Zhu D, Chen H, Lin A, Kang J, Liu W, Kang X. Periostin: an emerging activator of multiple signaling pathways. J Cell Commun Signal 2022; 16:515-530. [PMID: 35412260 PMCID: PMC9733775 DOI: 10.1007/s12079-022-00674-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/07/2022] [Indexed: 12/13/2022] Open
Abstract
Matricellular proteins are responsible for regulating the microenvironment, the behaviors of surrounding cells, and the homeostasis of tissues. Periostin (POSTN), a non-structural matricellular protein, can bind to many extracellular matrix proteins through its different domains. POSTN usually presents at low levels in most adult tissues but is highly expressed in pathological sites such as in tumors and inflamed organs. POSTN can bind to diverse integrins to interact with multiple signaling pathways within cells, which is one of its core biological functions. Increasing evidence shows that POSTN can activate the TGF-β, the PI3K/Akt, the Wnt, the RhoA/ROCK, the NF-κB, the MAPK and the JAK pathways to promote the occurrence and development of many diseases, especially cancer and inflammatory diseases. Furthermore, POSTN can interact with some pathways in an upstream and downstream relationship, forming complicated crosstalk. This article focuses on the interactions between POSTN and different signaling pathways in diverse diseases, attempting to explain the mechanisms of interaction and provide novel guidelines for the development of targeted therapies.
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Affiliation(s)
- Zhaoheng Wang
- grid.411294.b0000 0004 1798 9345Lanzhou University Second Hospital, 82, Cuiyingmen, Lanzhou, 730030 People’s Republic of China ,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730030 People’s Republic of China
| | - Jiangdong An
- grid.411294.b0000 0004 1798 9345Lanzhou University Second Hospital, 82, Cuiyingmen, Lanzhou, 730030 People’s Republic of China
| | - Daxue Zhu
- grid.411294.b0000 0004 1798 9345Lanzhou University Second Hospital, 82, Cuiyingmen, Lanzhou, 730030 People’s Republic of China ,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730030 People’s Republic of China
| | - Haiwei Chen
- grid.411294.b0000 0004 1798 9345Lanzhou University Second Hospital, 82, Cuiyingmen, Lanzhou, 730030 People’s Republic of China ,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730030 People’s Republic of China
| | - Aixin Lin
- grid.411294.b0000 0004 1798 9345Lanzhou University Second Hospital, 82, Cuiyingmen, Lanzhou, 730030 People’s Republic of China ,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730030 People’s Republic of China
| | - Jihe Kang
- grid.411294.b0000 0004 1798 9345Lanzhou University Second Hospital, 82, Cuiyingmen, Lanzhou, 730030 People’s Republic of China ,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730030 People’s Republic of China
| | - Wenzhao Liu
- grid.411294.b0000 0004 1798 9345Lanzhou University Second Hospital, 82, Cuiyingmen, Lanzhou, 730030 People’s Republic of China ,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730030 People’s Republic of China
| | - Xuewen Kang
- grid.411294.b0000 0004 1798 9345Lanzhou University Second Hospital, 82, Cuiyingmen, Lanzhou, 730030 People’s Republic of China ,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730030 People’s Republic of China
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6
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Gopinath P, Natarajan A, Sathyanarayanan A, Veluswami S, Gopisetty G. The multifaceted role of Matricellular Proteins in health and cancer, as biomarkers and therapeutic targets. Gene 2022; 815:146137. [PMID: 35007686 DOI: 10.1016/j.gene.2021.146137] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/07/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023]
Abstract
The extracellular matrix (ECM) is composed of a mesh of proteins, proteoglycans, growth factors, and other secretory components. It constitutes the tumor microenvironment along with the endothelial cells, cancer-associated fibroblasts, adipocytes, and immune cells. The proteins of ECM can be functionally classified as adhesive proteins and matricellular proteins (MCP). In the tumor milieu, the ECM plays a major role in tumorigenesis and therapeutic resistance. The current review encompasses thrombospondins, osteonectin, osteopontin, tenascin C, periostin, the CCN family, laminin, biglycan, decorin, mimecan, and galectins. The matrix metalloproteinases (MMPs) are also discussed as they are an integral part of the ECM with versatile functions in the tumor stroma. In this review, the role of these proteins in tumor initiation, growth, invasion and metastasis have been highlighted, with emphasis on their contribution to tumor therapeutic resistance. Further, their potential as biomarkers and therapeutic targets based on existing evidence are discussed. Owing to the recent advancements in protein targeting, the possibility of agents to modulate MCPs in cancer as therapeutic options are discussed.
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Affiliation(s)
- Prarthana Gopinath
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India
| | - Aparna Natarajan
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India
| | | | - Sridevi Veluswami
- Deaprtment of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
| | - Gopal Gopisetty
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India.
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7
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Matricellular proteins in intrahepatic cholangiocarcinoma. Adv Cancer Res 2022; 156:249-281. [DOI: 10.1016/bs.acr.2022.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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8
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Ye Z, Chen J, Hu X, Yang S, Xuan Z, Lu X, Zhao Q. SPOCK1: a multi-domain proteoglycan at the crossroads of extracellular matrix remodeling and cancer development. Am J Cancer Res 2020; 10:3127-3137. [PMID: 33163261 PMCID: PMC7642659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 09/24/2020] [Indexed: 06/11/2023] Open
Abstract
The SPARC/osteonectin, CWCV and Kazal-like domains proteoglycan 1 (SPOCK1) is a highly conserved, multi-domain proteoglycan that regulates the dynamic equilibrium of extracellular matrix (ECM). Besides, SPOCK1 is one of the key regulatory genes in the tumor ECM dynamic homeostasis process, which activates many molecular signaling pathways (such as EMT process, Wnt/β-catenin, PI3K/Akt, and mTOR/S6K signaling pathways). This activation leads to ECM remodeling and promotes cell proliferation and invasion, but inhibits cell apoptosis. Whereas there is immense information about SPOCK1's roles in different biological settings, there is need for further studies that interrogate this protein as a potential therapeutic target in cancer.
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Affiliation(s)
- Ziqi Ye
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of MedicineHangzhou 310003, China
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of MedicineHangzhou 310003, China
| | - Jie Chen
- Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of MedicineHangzhou 310009, China
| | - Xi Hu
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of MedicineHangzhou 310003, China
| | - Si Yang
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of MedicineHangzhou 310003, China
| | - Zixue Xuan
- Department of Pharmacy, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical CollegeHangzhou, China
| | - Xiaoyang Lu
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of MedicineHangzhou 310003, China
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of MedicineHangzhou 310003, China
| | - Qingwei Zhao
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of MedicineHangzhou 310003, China
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of MedicineHangzhou 310003, China
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9
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Ni S, Xiong XB, Ni XY. MgCl2 promotes mouse mesenchymal stem cell osteogenic differentiation by activating the p38/Osx/Runx2 signaling pathway. Mol Med Rep 2020; 22:3904-3910. [PMID: 32901870 PMCID: PMC7533493 DOI: 10.3892/mmr.2020.11487] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 07/15/2020] [Indexed: 12/30/2022] Open
Abstract
Magnesium, an important inorganic mineral component in bones, enhances osteoblast adhesion and osteogenic gene expression. Mg2+‑containing hydroxyapatite promotes mouse mesenchymal stem cell (MMSC) osteogenic differentiation. In the present study, MMSCs were cultured in media containing different concentrations of MgCl2 (0 and 20 mM) for different time periods. Western blotting and reverse transcription‑quantitative PCR were performed to determine the expression levels of phosphorylated (p)‑p38 mitogen‑activated protein kinase (MAPK), the osteoblast‑specific transcription factor Osterix (Osx), runt‑related transcription factor 2 (Runx2), and p38 downstream genes, such as 27 kDa heat shock protein (hsp27), activating transcription factor 4 (Atf4), myocyte enhancer factor 2C (Mef2c) and CCAAT/enhancer‑binding protein homologous protein (Ddit3). The facilitatory effect of MgCl2 on MMSC osteogenic differentiation was assessed via Alizarin Red staining. The results suggested that MgCl2 increased p38 phosphorylation compared with the control group. Downstream genes of the p38 signaling pathway, including Osx and Runx2, as well as several osteogenesis‑associated downstream target genes, including Hsp27, Atf4, Ddit3 and Mef2c, were significantly upregulated in the Mg2+‑treated group compared with the control group. The increased osteogenic differentiation in the Mg2+‑treated group was significantly attenuated in MMSCs treated with SB203580, a specific inhibitor of the p38 signaling pathway. The results suggested that appropriate concentrations of MgCl2 promoted MMSC osteogenic differentiation via regulation of the p38/Osx/Runx2 signaling pathway.
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Affiliation(s)
- Su Ni
- Medical Research Center, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China
| | - Xin-Bo Xiong
- Shenzhen Key Laboratory of Special Functional Materials, College of Materials, Shenzhen University, Shenzhen, Guangdong 518086, P.R. China
| | - Xin-Ye Ni
- Medical Research Center, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China
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10
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Du Z, Lin Z, Wang Z, Liu D, Tian D, Xia L. SPOCK1 overexpression induced by platelet-derived growth factor-BB promotes hepatic stellate cell activation and liver fibrosis through the integrin α5β1/PI3K/Akt signaling pathway. J Transl Med 2020; 100:1042-1056. [PMID: 32291390 DOI: 10.1038/s41374-020-0425-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/16/2020] [Accepted: 03/20/2020] [Indexed: 12/13/2022] Open
Abstract
Sparc/osteonectin, cwcv, and kazal-like domain proteoglycan 1 (SPOCK1) is a matricellular protein which regulates cell proliferation, invasion, and survival but the function of SPOCK1 in liver fibrosis is obscure. In this study, we found that SPOCK1 expression increased significantly in fibrotic liver tissues and activated primary rat hepatic stellate cells (R-HSCs). SPOCK1 co-localized with α-smooth muscle actin (α-SMA) in the cytoplasm. Mechanistically, we found platelet-derived growth factor-BB (PDGF-BB) induced SPOCK1 expression by activating the PI3K/Akt/forkhead box M1 (FoxM1) signaling pathway. Intracellular SPOCK1 downregulation decreased the HSC activation, proliferation, and migration induced by PDGF-BB. Furthermore, intracellular SPOCK1 overexpression or recombinant SPOCK1 treatment promoted HSC activation, proliferation, and migration by activating the PI3K/Akt signaling pathway. Co-immunoprecipitation, double immunofluorescence staining indicated that SPOCK1 interacted with integrin α5β1, and neutralization of integrin α5β1 significantly reduced the role of recombinant SPOCK1 in HSCs. In vivo HSC-specific SPOCK1 knockdown following lentivirus administration dramatically ameliorated thioacetamide (TAA)-induced collagen deposition in rat livers. Collectively, our study indicates that SPOCK1 is crucial for hepatic fibrosis and it might be a promising therapeutic target.
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Affiliation(s)
- Zhipeng Du
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.,Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Zhuoying Lin
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.,Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Zhihui Wang
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.,Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Danfei Liu
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.,Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China. .,Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
| | - Limin Xia
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China. .,Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
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11
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Gerarduzzi C, Hartmann U, Leask A, Drobetsky E. The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment. Cancer Res 2020; 80:2705-2717. [PMID: 32193287 DOI: 10.1158/0008-5472.can-18-2098] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 12/04/2019] [Accepted: 03/17/2020] [Indexed: 11/16/2022]
Abstract
The extracellular matrix (ECM) surrounding cells is indispensable for regulating their behavior. The dynamics of ECM signaling are tightly controlled throughout growth and development. During tissue remodeling, matricellular proteins (MCP) are secreted into the ECM. These factors do not serve classical structural roles, but rather regulate matrix proteins and cell-matrix interactions to influence normal cellular functions. In the tumor microenvironment, it is becoming increasingly clear that aberrantly expressed MCPs can support multiple hallmarks of carcinogenesis by interacting with various cellular components that are coupled to an array of downstream signals. Moreover, MCPs also reorganize the biomechanical properties of the ECM to accommodate metastasis and tumor colonization. This realization is stimulating new research on MCPs as reliable and accessible biomarkers in cancer, as well as effective and selective therapeutic targets.
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Affiliation(s)
- Casimiro Gerarduzzi
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada. .,Département de Médecine, Université de Montréal, Montréal, Québec, Canada
| | - Ursula Hartmann
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Andrew Leask
- College of Dentistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Elliot Drobetsky
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.,Département de Médecine, Université de Montréal, Montréal, Québec, Canada
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12
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Akaiwa M, Fukui E, Matsumoto H. Tubulointerstitial nephritis antigen-like 1 deficiency alleviates age-dependent depressed ovulation associated with ovarian collagen deposition in mice. Reprod Med Biol 2020; 19:50-57. [PMID: 31956285 PMCID: PMC6955583 DOI: 10.1002/rmb2.12301] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/16/2019] [Accepted: 09/01/2019] [Indexed: 12/14/2022] Open
Abstract
PURPOSE This study aimed to examine whether the Tinagl1 might be associated with ovulation in aged females and reproductive age-associated fibrosis in the stroma of the ovary. METHODS To address the ovulatory ability and quality of ovulated oocytes, we induced ovulation by treatment with equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG) followed by in vitro fertilization. We also performed Picrosirius Red (PSR) staining to evaluate ovarian collagen deposition. RESULTS As compared to ovulation in 8- to 9-month-old Tinagl1flox/flox mice, the number of ovulated oocytes from Tinagl1flox/flox mice decreased in an age-dependent manner in mice more than 10-11 months old, whereas the ovulated oocyte numbers in Tinagl1 -/- mice decreased significantly at 14-15 months. In vitro fertilization followed by embryo culture demonstrated the normal developmental potential of Tinagl1-null embryos during the preimplantation period. PSR staining indicated that collagen was found throughout the ovarian stroma in an age-dependent manner in Tinagl1flox/flox females, whereas those distributions were delayed to 14-15 months in Tinagl1 -/- females. This timing was consistent with the delayed timing of age-related decline of ovulation in Tinagl1 -/- females. CONCLUSIONS The alleviation of age-associated depression of ovulation was caused by delayed ovarian collagen deposition in Tinagl1-null female mice.
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Affiliation(s)
- Masato Akaiwa
- Laboratory of Animal Breeding and ReproductionDivision of Animal ScienceSchool of AgricultureUtsunomiya UniversityUtsunomiyaJapan
| | - Emiko Fukui
- Laboratory of Animal Breeding and ReproductionDivision of Animal ScienceSchool of AgricultureUtsunomiya UniversityUtsunomiyaJapan
- Center for Bioscience Research and EducationUtsunomiya UniversityUtsunomiyaJapan
| | - Hiromichi Matsumoto
- Laboratory of Animal Breeding and ReproductionDivision of Animal ScienceSchool of AgricultureUtsunomiya UniversityUtsunomiyaJapan
- Center for Bioscience Research and EducationUtsunomiya UniversityUtsunomiyaJapan
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13
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Cui D, Huang Z, Liu Y, Ouyang G. The multifaceted role of periostin in priming the tumor microenvironments for tumor progression. Cell Mol Life Sci 2017; 74:4287-4291. [PMID: 28884337 PMCID: PMC11107730 DOI: 10.1007/s00018-017-2646-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 09/04/2017] [Indexed: 12/13/2022]
Abstract
Tumor microenvironment consists of tumor cells, stromal cells, extracellular matrix and a plethora of soluble components. The complex array of interactions between tumor cells and their surrounding tumor microenvironments contribute to the determination of the fate of tumor cells during tumorigenesis and metastasis. Matricellular protein periostin is generally absent in most adult tissues but is highly expressed in tumor microenvironments. Current evidence reveals that periostin plays a critical role in establishing and remodeling tumor microenvironments such as the metastatic niche, cancer stem cell niche, perivascular niche, pre-metastatic niche, fibrotic microenvironment and bone marrow microenvironment. Here, we summarize the current knowledge of the multifaceted role of periostin in the tumor microenvironments.
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Affiliation(s)
- Dan Cui
- First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Zhengjie Huang
- First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Yingfu Liu
- Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China
| | - Gaoliang Ouyang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361102, China.
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14
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Huang XQ, Zhou ZQ, Zhang XF, Chen CL, Tang Y, Zhu Q, Zhang JH, Xia JC. Overexpression of SMOC2 Attenuates the Tumorigenicity of Hepatocellular Carcinoma Cells and Is Associated With a Positive Postoperative Prognosis in Human Hepatocellular Carcinoma. J Cancer 2017; 8:3812-3827. [PMID: 29151969 PMCID: PMC5688935 DOI: 10.7150/jca.20775] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 08/21/2017] [Indexed: 01/05/2023] Open
Abstract
Secreted modular calcium binding protein-2 (SMOC2), a recently identified matricellular protein that belongs to the SPARC protein family, has been reported to be downregulated in various cancers. The purpose of this study was to investigate the clinical significance and biological function of SMOC2 in human hepatocellular carcinoma. Real-time quantitative PCR and western blotting analyses revealed that SMOC2 mRNA and protein levels were significantly downregulated in human HCC tissues compared to the matched adjacent normal tissues. Clinicopathological analysis indicated that SMOC2 expression was significantly associated with tumor size, number of tumors, tumor-node-metastasis (TNM) stage and distant metastasis. Kaplan-Meier survival analysis showed that high tumor SMOC2 expression was associated with improved overall survival and disease-free survival in patients with HCC. Functional analyses (cell proliferation and colony formation assays, cell migration and invasion assays, cell cycle and apoptosis assays) demonstrated that stable overexpression of SMOC2 using a lentiviral vector significantly inhibited cell proliferation, colony formation, migration and invasion, and induced G0/G1 phase arrest in HCC cells in vitro. In addition, experiments with a mouse model revealed the suppressed effect of SMOC2 on HCC tumorigenicity and metastases in vivo. These results suggest that SMOC2 functions as a tumor suppressor during the development of HCC and may represent an effective prognostic factor and novel therapeutic target for HCC.
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Affiliation(s)
- Xu-Qiong Huang
- Huadu District People's Hospital of Guangzhou, Southern Medical University, Guangzhou, Guangdong province, 510800, China.,Department of Epidemiology and Health Statistics, Guangdong Pharmaceutical University, Guangzhou, Guangdong province, 510010, China
| | - Zi-Qi Zhou
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, 510060, China
| | - Xiao-Fei Zhang
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, 510060, China
| | - Chang-Long Chen
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, 510060, China
| | - Yan Tang
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, 510060, China
| | - Qian Zhu
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, 510060, China
| | - Jian-Hua Zhang
- Department of Epidemiology and Health Statistics, Guangdong Pharmaceutical University, Guangzhou, Guangdong province, 510010, China.,Department of Health Service Management, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong province, 510006, China
| | - Jian-Chuan Xia
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong province, 510060, China
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15
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Wang Z, Xiong S, Mao Y, Chen M, Ma X, Zhou X, Ma Z, Liu F, Huang Z, Luo Q, Ouyang G. Periostin promotes immunosuppressive premetastatic niche formation to facilitate breast tumour metastasis. J Pathol 2016; 239:484-95. [PMID: 27193093 DOI: 10.1002/path.4747] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 04/14/2016] [Accepted: 05/14/2016] [Indexed: 01/19/2023]
Abstract
Periostin (POSTN) is a limiting factor in the metastatic colonization of disseminated tumour cells. However, the role of POSTN in regulating the immunosuppressive function of immature myeloid cells in tumour metastasis has not been documented. Here, we demonstrate that POSTN promotes the pulmonary accumulation of myeloid-derived suppressor cells (MDSCs) during the early stage of breast tumour metastasis. Postn deletion decreases neutrophil and monocytic cell populations in the bone marrow of mice and suppresses the accumulation of MDSCs to premetastatic sites. We also found that POSTN-deficient MDSCs display reduced activation of ERK, AKT and STAT3 and that POSTN deficiency decreases the immunosuppressive functions of MDSCs during tumour progression. Moreover, the pro-metastatic role of POSTN is largely limited to ER-negative breast cancer patients. Lysyl oxidase contributes to POSTN-promoted premetastatic niche formation and tumour metastasis. Our findings indicate that POSTN is essential for immunosuppressive premetastatic niche formation in the lungs during breast tumour metastasis and is a potential target for the prevention and treatment of breast tumour metastasis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Zhe Wang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, People's Republic of China
- Engineering Research Centre of Molecular Diagnostics, Ministry of Education, School of Life Sciences, Xiamen University, People's Republic of China
| | - Shanshan Xiong
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, People's Republic of China
- Engineering Research Centre of Molecular Diagnostics, Ministry of Education, School of Life Sciences, Xiamen University, People's Republic of China
| | - Yubin Mao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, People's Republic of China
- Medical College of Xiamen University, People's Republic of China
| | - Mimi Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, People's Republic of China
| | - Xiaohong Ma
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, People's Republic of China
| | - Xueliang Zhou
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, People's Republic of China
| | - Zhenling Ma
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, People's Republic of China
| | - Fan Liu
- Medical College of Xiamen University, People's Republic of China
| | - Zhengjie Huang
- Department of Surgical Oncology, First Affiliated Hospital of Xiamen University, People's Republic of China
| | - Qi Luo
- Department of Surgical Oncology, First Affiliated Hospital of Xiamen University, People's Republic of China
| | - Gaoliang Ouyang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, People's Republic of China
- Engineering Research Centre of Molecular Diagnostics, Ministry of Education, School of Life Sciences, Xiamen University, People's Republic of China
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16
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Zhou L, Liu F, Wang X, Ouyang G. The roles of microRNAs in the regulation of tumor metastasis. Cell Biosci 2015; 5:32. [PMID: 26146543 PMCID: PMC4491246 DOI: 10.1186/s13578-015-0028-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Accepted: 06/14/2015] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) are small noncoding regulatory RNAs that regulate gene expression post-transcriptionally by either inhibiting protein translation or degrading target mRNAs. The differential expression profiles of miRNAs in different types of cancers and in the multi-step process of tumor progression indicate that miRNAs are involved in tumor onset, growth and progression. Metastasis is the most common cause of cancer-related mortality. Current evidence demonstrates that aberrant miRNA expression promotes or inhibits tumor metastasis by modulating the expression of numerous target genes. Therefore, the identification of metastasis-related miRNAs and a better understanding of the complex functions of miRNAs in tumor metastasis will provide potential diagnostic and prognostic biomarkers, as well as therapeutic targets for clinical application. Here, we review the functions of miRNAs in the control of multiple steps of tumor metastasis.
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Affiliation(s)
- Lei Zhou
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Medical College, Xiamen University, Xiamen, 361004 China.,Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029 China
| | - Fan Liu
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Medical College, Xiamen University, Xiamen, 361004 China.,Medical College, Xiamen University, Xiamen, 361102 China
| | - Xiaomin Wang
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Medical College, Xiamen University, Xiamen, 361004 China
| | - Gaoliang Ouyang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361102 China
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18
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Huang Y, Liu W, Xiao H, Maitikabili A, Lin Q, Wu T, Huang Z, Liu F, Luo Q, Ouyang G. Matricellular protein periostin contributes to hepatic inflammation and fibrosis. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 185:786-97. [PMID: 25541330 DOI: 10.1016/j.ajpath.2014.11.002] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 09/29/2014] [Accepted: 11/05/2014] [Indexed: 01/07/2023]
Abstract
Periostin actively contributes to tissue injury, fibrosis, atherosclerosis, and inflammatory diseases; however, its role in hepatic fibrosis is unclear. Herein, we revealed that periostin expression was significantly up-regulated in carbon tetrachloride- and bile duct ligation-induced mice with acute and chronic liver fibrosis. Deficiency in periostin abrogated the development of liver fibrosis in mice. Carbon tetrachloride treatment significantly increased α-smooth muscle actin, fibronectin, and collagen I levels in wild-type mice, which were unaffected in periostin-knockout mice. Periostin-deficient mice showed a significantly reduced area of collagen deposition and decreased levels of serum alanine aminotransferase and aspartate aminotransferase compared with wild-type mice after 2 weeks of carbon tetrachloride administration. Chemokine ligand 2, IL-6, IL-1β, tumor necrosis factor-α, and tissue inhibitor of metalloproteinases 1 mRNA levels were significantly lower in periostin-deficient mice than in wild-type mice after carbon tetrachloride treatment. Periostin colocalized with hepatic stellate cell-derived collagen I and α-smooth muscle actin in mouse acute and chronic fibrotic liver tissues. Transforming growth factor (TGF)-β1 markedly induced periostin expression in primary mouse hepatic stellate cells. Periostin-deficient mice showed significantly lower levels of TGF-β1 and TGF-β2 compared with wild-type mice after carbon tetrachloride treatment. High levels of periostin in patients with acute or chronic hepatitis correlated with TGF-β1 and TGF-β2 expression in serum from patients with hepatitis. Data indicate that periostin is a novel mediator of hepatic fibrosis development.
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Affiliation(s)
- Yangmei Huang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China
| | - Weiping Liu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China
| | - Hongjun Xiao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China
| | - Alaiyi Maitikabili
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China
| | - Qinghua Lin
- Clinical Laboratory, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, China
| | - Tiantian Wu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China
| | - Zhengjie Huang
- Department of Surgical Oncology, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Fan Liu
- Medical College, Xiamen University, Xiamen, China
| | - Qi Luo
- Department of Surgical Oncology, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Gaoliang Ouyang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
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19
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Liu AY, Zheng H, Ouyang G. Periostin, a multifunctional matricellular protein in inflammatory and tumor microenvironments. Matrix Biol 2014; 37:150-6. [DOI: 10.1016/j.matbio.2014.04.007] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2014] [Revised: 04/28/2014] [Accepted: 04/28/2014] [Indexed: 02/06/2023]
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