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Liu X, Moamer A, Gomes da Silva R, Shoham-Amizlev A, Hamam D, Shams A, Lebrun JJ, Ali S. A novel clinically relevant antagonistic interplay between prolactin and oncogenic YAP-CCN2 pathways as a differentiation therapeutic target in breast cancer. Cell Death Dis 2025; 16:221. [PMID: 40157909 PMCID: PMC11954952 DOI: 10.1038/s41419-025-07547-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 02/11/2025] [Accepted: 03/17/2025] [Indexed: 04/01/2025]
Abstract
Cellular differentiation limits cellular plasticity allowing cells to attain their specialized functional characteristics and phenotypes, whereas loss of differentiation is a hallmark of cancer. Thus, characterizing mechanisms underlying differentiation is key to discover new cancer therapeutics. We report a novel functional antagonistic relationship between the prolactin (PRL)/prolactin receptor (PRLR) differentiation pathway and YAP-CCN2 oncogenic pathway in normal mammary epithelial cells and breast cancer cells that is essential for establishing/maintaining acinar morphogenesis, cell-cell junctions and the intracellular localization of apical-basal polarity protein complexes (Par, Crumb and Scrib). Importantly, using CRISPR knockout of the PRLR in MCF7, HR+ breast cancer cells, further revealed that the negative relationship between PRL/PRLR pathway and YAP-CCN2 pathway is critical in suppressing luminal-to-basal stem-like lineage plasticity. Furthermore, the clinical relevance of this interplay was evaluated using bioinformatics approaches on several human datasets, including samples from normal breast epithelium, breast cancer, and 33 other cancer types. This analysis revealed a positive correlation between PRLR and the YAP suppressor Hippo pathway and a co-expression gene network driving favourable patients' survival outcomes in breast cancer. The therapeutic potential of this interplay was also evaluated in vitro using MDA-MB-231 cells, a preclinical model of human triple-negative breast cancer, where treatment with PRL and Verteporfin, an FDA-approved pharmacological YAP-inhibitor, alone or their combination suppressed the expression of the mesenchymal marker vimentin and the stem cell marker CD44 as well as reduced their Ki67 proliferative marker expression. Collectively, our results emphasize the pro-differentiation role of PRL/PRLR pathway in mammary and breast cancer cells and highlight that promoting PRL/PRLR signaling while inhibiting the YAP-CCN2 oncogenic pathway can be exploited as a differentiation-based combination therapeutic strategy in breast cancer.
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Affiliation(s)
- Xueqing Liu
- Department of Medicine, Cancer Research Program, Centre for Translational Biology, McGill University Health Centre, McGill University, Montreal, QC, Canada
| | - Alaa Moamer
- Department of Medicine, Cancer Research Program, Centre for Translational Biology, McGill University Health Centre, McGill University, Montreal, QC, Canada
| | - Roger Gomes da Silva
- Department of Medicine, Cancer Research Program, Centre for Translational Biology, McGill University Health Centre, McGill University, Montreal, QC, Canada
| | - Aidan Shoham-Amizlev
- Department of Medicine, Cancer Research Program, Centre for Translational Biology, McGill University Health Centre, McGill University, Montreal, QC, Canada
| | - Dana Hamam
- Department of Medicine, Cancer Research Program, Centre for Translational Biology, McGill University Health Centre, McGill University, Montreal, QC, Canada
| | - Anwar Shams
- Department of Medicine, Cancer Research Program, Centre for Translational Biology, McGill University Health Centre, McGill University, Montreal, QC, Canada
- Department of Pharmacology, College of Medicine, Taif University, Taif, Saudi Arabia
| | - Jean-Jacques Lebrun
- Department of Medicine, Cancer Research Program, Centre for Translational Biology, McGill University Health Centre, McGill University, Montreal, QC, Canada
| | - Suhad Ali
- Department of Medicine, Cancer Research Program, Centre for Translational Biology, McGill University Health Centre, McGill University, Montreal, QC, Canada.
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Perbal B. The case of Connective Tissue Growth Factor (CTGF) and the pit of misleading and improper nomenclatures. J Cell Commun Signal 2025; 19:e12062. [PMID: 39712858 PMCID: PMC11656398 DOI: 10.1002/ccs3.12062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2024] Open
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Quan T, Shao Y, Purohit T, Jiang Y, Qin Z, Fisher GJ, Lents NH, Baldassare JJ. CCN2 functions as a modulator of cell cycle regulation in human dermal fibroblasts. J Cell Commun Signal 2025; 19:e70003. [PMID: 39898007 PMCID: PMC11786592 DOI: 10.1002/ccs3.70003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 07/31/2024] [Accepted: 01/20/2025] [Indexed: 02/04/2025] Open
Abstract
CCN2 is widely regarded as a profibrotic factor involved in fibrotic disorders by regulating extracellular matrix (ECM). We report here that CCN2 functions as a critical cell cycle regulator in primary human dermal fibroblasts (HDFs). siRNA-mediated knockdown of CCN2 halted proliferation of primary HDFs, which was rescued by a siRNA-resistant CCN2 expression vector. Furthermore, CCN2 knockdown caused a significant accumulation of cells in G1/G0 phase and blocked entry into S-phase. Mechanistically, CCN2 knockdown blocked cyclin E and CDK4/cyclin D nuclear translocation, and abrogated CDK2 activity. Markedly, CCN2 translocated to the nucleus and co-localized with cyclin D1 upon cell cycle stimulation. Finally, we show that CCN2, a bona fide YAP/TAZ target gene, partially mediates YAP/TAZ-dependent proliferation of primary HDFs. These data provide evidence of a novel CCN2 function as a cell cycle regulator in primary HDFs proliferation, in addition to its known role in ECM regulation.
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Affiliation(s)
- Taihao Quan
- Department of DermatologyUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Yuan Shao
- Department of DermatologyUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Trupta Purohit
- Department of DermatologyUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Yiou Jiang
- Department of DermatologyUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Zhaoping Qin
- Department of DermatologyUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Gary J. Fisher
- Department of DermatologyUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Nathan H. Lents
- Department of Pharmacological Sciences at Saint Louis UniversitySt. LouisMissouriUSA
| | - Joseph J. Baldassare
- Department of Pharmacological Sciences at Saint Louis UniversitySt. LouisMissouriUSA
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Lu W, Feng W, Zhen H, Jiang S, Li Y, Liu S, Ru Q, Xiao W. Unlocking the therapeutic potential of WISP-1: A comprehensive exploration of its role in age-related musculoskeletal disorders. Int Immunopharmacol 2025; 145:113791. [PMID: 39667044 DOI: 10.1016/j.intimp.2024.113791] [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: 05/15/2024] [Revised: 10/03/2024] [Accepted: 12/03/2024] [Indexed: 12/14/2024]
Abstract
As the global population ages, the incidence of age-related musculoskeletal diseases continues to increase, driven by numerous complex and poorly understood factors. WNT-1 inducible secreted protein 1 (WISP-1), a secreted matrix protein, plays a critical role in the growth and development of the musculoskeletal system, including chondrogenesis, osteogenesis, and myogenesis. Numerous in vivo and in vitro studies have demonstrated that WISP-1 is significantly upregulated in age-related musculoskeletal conditions, such as osteoarthritis, osteoporosis, and sarcopenia, suggesting its involvement in the pathogenesis of these diseases. Regulating WISP-1 expression holds promise as a therapeutic strategy for improving musculoskeletal function, potentially offering new avenues for treating age-related musculoskeletal diseases in clinical practice. This review highlights the signaling pathways associated with WISP-1, its physiological roles within the musculoskeletal system, and its therapeutic potential in treating age-related musculoskeletal disorders.
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Affiliation(s)
- Wenhao Lu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Wenjie Feng
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Haozu Zhen
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya School of Medicine, Central South University, Changsha, Hunan 410083, China
| | - Shide Jiang
- The Central Hospital of Yongzhou, Yongzhou 425000, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Shuguang Liu
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710001, Shaanxi, China.
| | - Qin Ru
- Department of Health and Physical Education, Jianghan University, Wuhan 430056, China.
| | - Wenfeng Xiao
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
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Gündel B, Liu X, Pfützenreuter A, Engelsberger V, Weiskirchen R, Löhr JM, Heuchel R. The Crosstalk Analysis between mPSCs and Panc1 Cells Identifies CCN1 as a Positive Regulator of Gemcitabine Sensitivity in Pancreatic Cancer Cells. Int J Mol Sci 2024; 25:9369. [PMID: 39273316 PMCID: PMC11394772 DOI: 10.3390/ijms25179369] [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: 06/26/2024] [Revised: 08/15/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is almost entirely resistant to conventional chemotherapy and radiation therapy. A significant factor in this resistance appears to be the dense desmoplastic stroma, which contains various cancer-associated fibroblast (CAF) populations. However, our understanding of the communication between tumor cells and CAFs that contributes to this aggressive malignancy is still developing. Recently, we used an advanced three-dimensional heterospecies, heterospheroid co-culture model to investigate the signaling between human pancreatic tumor Panc1 cells and mouse pancreatic stellate cells (mPSCs) through global expression profiling. Upon discovering that CCN1 was significantly upregulated in Panc1 cells during co-culture, we decided to explore the role of CCN1 using CRISPR-Cas9 knockout technology. Panc1 cells lacking CCN1 showed reduced differentiation and decreased sensitivity to gemcitabine, primarily due to lower expression of genes involved in gemcitabine transport and metabolism. Additionally, we observed that stimulation with TGF-β1 and lysophosphatidic acid increased CCN1 expression in Panc1 cells and induced a shift in mPSCs towards a more myofibroblastic CAF-like phenotype.
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Affiliation(s)
- Beate Gündel
- Pancreas Cancer Research Lab, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, SE 141 86 Huddinge, Sweden; (B.G.); (J.-M.L.)
| | - Xinyuan Liu
- Pancreas Cancer Research Lab, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, SE 141 86 Huddinge, Sweden; (B.G.); (J.-M.L.)
| | - Anna Pfützenreuter
- Pancreas Cancer Research Lab, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, SE 141 86 Huddinge, Sweden; (B.G.); (J.-M.L.)
| | - Veronika Engelsberger
- Pancreas Cancer Research Lab, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, SE 141 86 Huddinge, Sweden; (B.G.); (J.-M.L.)
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany;
| | - J.-Matthias Löhr
- Pancreas Cancer Research Lab, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, SE 141 86 Huddinge, Sweden; (B.G.); (J.-M.L.)
| | - Rainer Heuchel
- Pancreas Cancer Research Lab, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, SE 141 86 Huddinge, Sweden; (B.G.); (J.-M.L.)
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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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Hu K, Xie L, Wu W, Zhang J, Li Y, He J, Zhang Y, Lu D, Koeffler HP, Lin L, Yin D. CYR61 Acts as an Intracellular Microtubule-Associated Protein and Coordinates Mitotic Progression via PLK1-FBW7 Pathway. Int J Biol Sci 2024; 20:3140-3155. [PMID: 38904029 PMCID: PMC11186368 DOI: 10.7150/ijbs.93335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 05/24/2024] [Indexed: 06/22/2024] Open
Abstract
Cysteine-rich angiogenic inducer 61 (CYR61), also called CCN1, has long been characterized as a secretory protein. Nevertheless, the intracellular function of CYR61 remains unclear. Here, we found that CYR61 is important for proper cell cycle progression. Specifically, CYR61 interacts with microtubules and promotes microtubule polymerization to ensure mitotic entry. Moreover, CYR61 interacts with PLK1 and accumulates during the mitotic process, followed by degradation as mitosis concludes. The proteolysis of CYR61 requires the PLK1 kinase activity, which directly phosphorylates two conserved motifs on CYR61, enhancing its interaction with the SCF E3 complex subunit FBW7 and mediating its degradation by the proteasome. Mutations of phosphorylation sites of Ser167 and Ser188 greatly increase CYR61's stability, while deletion of CYR61 extends prophase and metaphase and delays anaphase onset. In summary, our findings highlight the precise control of the intracellular CYR61 by the PLK1-FBW7 pathway, accentuating its significance as a microtubule-associated protein during mitotic progression.
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Affiliation(s)
- Kaishun Hu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China
| | - Limin Xie
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China
| | - Wenjing Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China
- Department of Breast Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China
| | - Jingyuan Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China
| | - Yu Li
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen 518000, P.R. China
| | - Jiehua He
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China
| | - Yin Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China
| | - Daning Lu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China
| | - H. Phillip Koeffler
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Lehang Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China
| | - Dong Yin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China
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Idrissi YA, Rajabi MR, Beumer JH, Monga SP, Saeed A. Exploring the Impact of the β-Catenin Mutations in Hepatocellular Carcinoma: An In-Depth Review. Cancer Control 2024; 31:10732748241293680. [PMID: 39428608 PMCID: PMC11528747 DOI: 10.1177/10732748241293680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 09/30/2024] [Accepted: 10/04/2024] [Indexed: 10/22/2024] Open
Abstract
Liver cancer, primarily hepatocellular carcinoma, represents a major global health issue with significant clinical, economic, and psychological impacts. Its incidence continues to rise, driven by risk factors such as hepatitis B and C infections, nonalcoholic steatohepatitis, and various environmental influences. The Wnt/β-Catenin signaling pathway, frequently dysregulated in HCC, emerges as a promising therapeutic target. Critical genetic alterations, particularly in the CTNNB1 gene, involve mutations at key phosphorylation sites on β-catenin's N-terminal domain (S33, S37, T41, and S45) and in armadillo repeat domains (K335I and N387 K). These mutations impede β-catenin degradation, enhancing its oncogenic potential. In addition to genetic alterations, molecular and epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding RNAs, further influence β-catenin signaling and tumor progression. However, β-catenin activation alone is insufficient for hepatocarcinogenesis; additional genetic "hits" are required for tumor initiation. Mutations or alterations in genes such as Ras, c-Met, NRF2, and LKB1, when combined with β-catenin activation, significantly contribute to HCC development and progression. Understanding these cooperative mutations provides crucial insights into the disease and reveals potential therapeutic strategies. The complex interplay between genetic variations and the tumor microenvironment, coupled with novel therapeutic approaches targeting the Wnt/β-Catenin pathway, offers promise for improved treatment of HCC. Despite advances, translating preclinical findings into clinical practice remains a challenge. Future research should focus on elucidating how specific β-catenin mutations and additional genetic alterations contribute to HCC pathogenesis, leveraging genetically clengineered mouse models to explore distinct signaling impacts, and identifying downstream targets. Relevant clinical trials will be essential for advancing personalized therapies and enhancing patient outcomes. This review provides a comprehensive analysis of β-Catenin signaling in HCC, highlighting its role in pathogenesis, diagnosis, and therapeutic targeting, and identifies key research directions to improve understanding and clinical outcomes.
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Affiliation(s)
- Yassine Alami Idrissi
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Mohammad Reza Rajabi
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Jan H. Beumer
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, PA, USA
| | - Satdarshan P. Monga
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Division of Gastroenterology, Hepatology and Nutrition; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA
| | - Anwaar Saeed
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
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Hassan MDS, Razali N, Abu Bakar AS, Abu Hanipah NF, Agarwal R. Connective tissue growth factor: Role in trabecular meshwork remodeling and intraocular pressure lowering. Exp Biol Med (Maywood) 2023; 248:1425-1436. [PMID: 37873757 PMCID: PMC10657592 DOI: 10.1177/15353702231199466] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2023] Open
Abstract
Connective tissue growth factor (CTGF) is a distinct signaling molecule modulating many physiological and pathophysiological processes. This protein is upregulated in numerous fibrotic diseases that involve extracellular matrix (ECM) remodeling. It mediates the downstream effects of transforming growth factor beta (TGF-β) and is regulated via TGF-β SMAD-dependent and SMAD-independent signaling routes. Targeting CTGF instead of its upstream regulator TGF-β avoids the consequences of interfering with the pleotropic effects of TGF-β. Both CTGF and its upstream mediator, TGF-β, have been linked with the pathophysiology of glaucomatous optic neuropathy due to their involvement in the regulation of ECM homeostasis. The excessive expression of these growth factors is associated with glaucoma pathogenesis via elevation of the intraocular pressure (IOP), the most important risk factor for glaucoma. The raised in the IOP is due to dysregulation of ECM turnover resulting in excessive ECM deposition at the site of aqueous humor outflow. It is therefore believed that CTGF could be a potential therapeutic target in glaucoma therapy. This review highlights the CTGF biology and structure, its regulation and signaling, its association with the pathophysiology of glaucoma, and its potential role as a therapeutic target in glaucoma management.
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Affiliation(s)
| | - Norhafiza Razali
- Institute of Medical Molecular Biotechnology (IMMB), Universiti Teknologi MARA (UiTM), 47000 Sungai Buloh, Malaysia
- Department of Pharmacology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), 47000 Sungai Buloh, Malaysia
- Center for Neuroscience Research (NeuRon), Faculty of Medicine, Universiti Teknologi MARA (UiTM), 47000 Sungai Buloh, Malaysia
| | - Amy Suzana Abu Bakar
- Institute of Medical Molecular Biotechnology (IMMB), Universiti Teknologi MARA (UiTM), 47000 Sungai Buloh, Malaysia
- Center for Neuroscience Research (NeuRon), Faculty of Medicine, Universiti Teknologi MARA (UiTM), 47000 Sungai Buloh, Malaysia
| | - Noor Fahitah Abu Hanipah
- Institute of Medical Molecular Biotechnology (IMMB), Universiti Teknologi MARA (UiTM), 47000 Sungai Buloh, Malaysia
- Department of Pharmacology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), 47000 Sungai Buloh, Malaysia
| | - Renu Agarwal
- School of Medicine, International Medical University (IMU), 57000 Kuala Lumpur, Malaysia
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Kubota S, Kawaki H, Perbal B, Takigawa M, Kawata K, Hattori T, Nishida T. Do not overwork: cellular communication network factor 3 for life in cartilage. J Cell Commun Signal 2023:10.1007/s12079-023-00723-4. [PMID: 36745317 DOI: 10.1007/s12079-023-00723-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 01/07/2023] [Indexed: 02/07/2023] Open
Abstract
Cellular communication network factor (CCN) 3, which is one of the founding members of the CCN family, displays diverse functions. However, this protein generally represses the proliferation of a variety of cells. Along with skeletal development, CCN3 is produced in cartilaginous anlagen, growth plate cartilage and epiphysial cartilage. Interestingly, CCN3 is drastically induced in the growth plates of mice lacking CCN2, which promotes endochondral ossification. Notably, chondrocytes in these mutant mice with elevated CCN3 production also suffer from impaired glycolysis and energy metabolism, suggesting a critical role of CCN3 in cartilage metabolism. Recently, CCN3 was found to be strongly induced by impaired glycolysis, and in our study, we located an enhancer that mediated CCN3 regulation via starvation. Subsequent investigations specified regulatory factor binding to the X-box 1 (RFX1) as a transcription factor mediating this CCN3 regulation. Impaired glycolysis is a serious problem, resulting in an energy shortage in cartilage without vasculature. CCN3 produced under such starved conditions restricts energy consumption by repressing cell proliferation, leading chondrocytes to quiescence and survival. This CCN3 regulatory system is indicated to play an important role in articular cartilage maintenance, as well as in skeletal development. Furthermore, CCN3 continues to regulate cartilage metabolism even during the aging process, probably utilizing this regulatory system. Altogether, CCN3 seems to prevent "overwork" by chondrocytes to ensure their sustainable life in cartilage by sensing energy metabolism. Similar roles are suspected to exist in relation to systemic metabolism, since CCN3 is found in the bloodstream.
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Affiliation(s)
- Satoshi Kubota
- Department of Biochemistry and Molecular Dentistry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan.
| | - Harumi Kawaki
- Department of Oral Biochemistry, Asahi University School of Dentistry, Mizuho, Japan
| | | | - Masaharu Takigawa
- Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences/Dental School, Okayama, Japan
| | - Kazumi Kawata
- Department of Biochemistry and Molecular Dentistry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan
| | - Takako Hattori
- Department of Biochemistry and Molecular Dentistry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan
| | - Takashi Nishida
- Department of Biochemistry and Molecular Dentistry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan
- Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences/Dental School, Okayama, Japan
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Takigawa M. CCN Proteins (Cellular Communication Network Factors): Expanding Their Repertoire Toward a New Concept. Methods Mol Biol 2023; 2582:1-10. [PMID: 36370338 DOI: 10.1007/978-1-0716-2744-0_1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
I herein report the general structures and functions of CCN proteins and possible molecular mechanisms involved in the unique biological actions of this family of intercellular signaling regulators, which are considered matricellular proteins and were once referred to as "signal conductors" but have recently been renamed "Cellular Communication Network Factors." Their repertoire of functions beyond their role as matricellular proteins is also described to aid in future studies. Advanced research concerning their relevance to pathology is briefly introduced as well. The information provided in this chapter is expected to be useful for readers of subsequent chapters.
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Affiliation(s)
- Masaharu Takigawa
- Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School/Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
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Perbal B. Inception and establishment of the International CCN Society (ICCNS) and of the Journal of Cell Communication and Signaling (JCCS): A response to A. Leask's Editorial entitled "Modeling the microenvironment special issue". J Cell Commun Signal 2022; 16:627-629. [PMID: 36098895 PMCID: PMC9733759 DOI: 10.1007/s12079-022-00694-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
A little over a year ago, on January 25, 2021, the new Editor-in-Chief (EiC) of JCCS stated in his Editorial: "ICCNS and JCCS were the brainchildren of Bernard Perbal, and without his energy and drive, neither would exist, to the detriment of us who are driven to solve difficult problems in science, and not picking low-hanging fruit. All one has to do is examine all the editorials written in JCCS (and CCS!) to see evidence of this. It will be tough to fill those shoes."I disagree with the assertion in the Editorial published on March 29, 2022 that G. Martin contributed "to the initial growth of the International CCN Society, and, ultimately, to the establishment of this journal." My opinion is based on the evidence that the International CCN Society (ICCNS) and its official organ journal, the Journal of Cell Communication and Signaling (JCCS), were created by myself. Over a span of 21 years until the present, and in spite of his contribution to the early history of CTGF, we never heard from G. Martin being involved or interested in any aspect of the ICCNS and its biannual meetings, nor in any aspect in the growth of JCCS.In order to further clarify the confusion stemming from the Editorial in question and to give credit where it is due, I provide below detailed evidence that undoubtedly ascribes the true inception of both ICCNS and JCCS, and merit to the efforts of all those who trusted and supported us during the initial difficult creative moments.I am of the opinion that the Editorial, and the implications that it carries do not justice to the efforts of those who were really involved in the creation of both the ICCNS and JCCS.In the name of respectful scientific integrity, I will provide the evidence that correctly attributes the inception of ICCNS and JCCS.
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Fibroblast Growth Factors and Cellular Communication Network Factors: Intimate Interplay by the Founding Members in Cartilage. Int J Mol Sci 2022; 23:ijms23158592. [PMID: 35955724 PMCID: PMC9369280 DOI: 10.3390/ijms23158592] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/28/2022] [Accepted: 07/28/2022] [Indexed: 02/04/2023] Open
Abstract
Fibroblast growth factors (FGFs) constitute a large family of signaling molecules that act in an autocrine/paracrine, endocrine, or intracrine manner, whereas the cellular communication network factors (CCN) family is composed of six members that manipulate extracellular signaling networks. FGFs and CCNs are structurally and functionally distinct, except for the common characteristics as matricellular proteins. Both play significant roles in the development of a variety of tissues and organs, including the skeletal system. In vertebrates, most of the skeletal parts are formed and grow through a process designated endochondral ossification, in which chondrocytes play the central role. The growth plate cartilage is the place where endochondral ossification occurs, and articular cartilage is left to support the locomotive function of joints. Several FGFs, including FGF-2, one of the founding members of this family, and all of the CCNs represented by CCN2, which is required for proper skeletal development, can be found therein. Research over a decade has revealed direct binding of CCN2 to FGFs and FGF receptors (FGFRs), which occasionally affect the biological outcome via FGF signaling. Moreover, a recent study uncovered an integrated regulation of FGF and CCN genes by FGF signaling. In this review, after a brief introduction of these two families, molecular and genetic interactions between CCN and FGF family members in cartilage, and their biological effects, are summarized. The molecular interplay represents the mutual involvement of the other in their molecular functions, leading to collaboration between CCN2 and FGFs during skeletal development.
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WISP2/CCN5 Suppresses Vasculogenic Mimicry through Inhibition of YAP/TAZ Signaling in Breast Cancer Cells. Cancers (Basel) 2022; 14:cancers14061487. [PMID: 35326638 PMCID: PMC8945957 DOI: 10.3390/cancers14061487] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Breast cancer is the most frequent malignancy in women worldwide. Advanced breast cancer with distant organ metastases is considered incurable with currently available therapies. The vasculogenic mimicry (VM) process is associated with an invasive and metastatic cancer phenotype and a poor prognosis for human breast cancer patients. Our aim was to study the effect of WISP2, a matricellular protein, on VM. We found that WISP2 inhibits VM through inhibition of CYR61 protein expression and YAP-TAZ signaling. Our finding may open promising candidates for blocking VM in breast cancer. Abstract Vasculogenic mimicry (VM) formed by aggressive tumor cells to create vascular networks connected with the endothelial cells, plays an important role in breast cancer progression. WISP2 has been considered as a tumor suppressor protein; however, the relationship between WISP2 and VM formation remains unclear. We used the in vitro tube formation assay and in vivo immunohistochemical analysis in a mouse model, and human breast tumors were used to evaluate the effect of WISP2 on VM formation. Here we report that WISP2 acts as a potent inhibitor of VM formation in breast cancer. Enforced expression of WISP2 decreased network formation while knockdown of WISP2 increased VM. Mechanistically, WISP2 increased retention of oncogenic activators YAP/TAZ in cytoplasm, leading to decreased expression of the angiogenic factor CYR61. Studies using an in vivo mouse model and human breast tumors confirmed the in vitro cell lines data. In conclusion, our results indicate that WISP2 may play a critical role in VM and highlight the critical role of WISP2 as a tumor suppressor.
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Metabolic Effects of CCN5/WISP2 Gene Deficiency and Transgenic Overexpression in Mice. Int J Mol Sci 2021; 22:ijms222413418. [PMID: 34948212 PMCID: PMC8709456 DOI: 10.3390/ijms222413418] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/08/2021] [Accepted: 12/12/2021] [Indexed: 11/17/2022] Open
Abstract
CCN5/WISP2 is a matricellular protein, the expression of which is under the regulation of Wnt signaling and IGF-1. Our initial characterization supports the notion that CCN5 might promote the proliferation and survival of pancreatic β-cells and thus improve the metabolic profile of the animals. More recently, the roles of endogenous expression of CCN5 and its ectopic, transgenic overexpression on metabolic regulation have been revealed through two reports. Here, we attempt to compare the experimental findings from those studies, side-by-side, in order to further establish its roles in metabolic regulation. Prominent among the discoveries was that a systemic deficiency of CCN5 gene expression caused adipocyte hypertrophy, increased adipogenesis, and lipid accumulation, resulting in insulin resistance and glucose intolerance, which were further exacerbated upon high-fat diet feeding. On the other hand, the adipocyte-specific and systemic overexpression of CCN5 caused an increase in lean body mass, improved insulin sensitivity, hyperplasia of cardiomyocytes, and increased heart mass, but decreased fasting glucose levels. CCN5 is clearly a regulator of adipocyte proliferation and maturation, affecting lean/fat mass ratio and insulin sensitivity. Not all results from these models are consistent; moreover, several important aspects of CCN5 physiology are yet to be explored.
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Siddiqui S, Pandey V, Ali S, Singh A, Sharma D, Yadav M, Raikwar A. CCN3 Proteins as a diagnostic marker in osteosarcoma patients: A case control study. Cancer Treat Res Commun 2021; 28:100381. [PMID: 33946014 DOI: 10.1016/j.ctarc.2021.100381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 02/28/2021] [Accepted: 04/19/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Osteosarcoma is the most prevalent type of primary bone sarcoma and is the major cause of deaths associated with cancer in children and adolescents. Despite novel and innovative therapies, early diagnosis of the osteosarcoma is still critically needed. Our study aimed to analyse the CCN3 proteins as a diagnostic marker and correlate their expression level with the severity of primary osteosarcoma patients. METHODS In this prospective case-control study, after ethical clearance and informed consent, a total of 35 cases with primary osteosarcoma and ten otherwise healthy controls were enroled according to our strict inclusion-exclusion criteria. Tissue samples were collected during biopsy procedures in suspected cases and in controls during bone grafting procedures. The CCN3 expression level was measured by the western blotting assay. The clinic-radiological examinations were done in cases and graded according to the AJCC classification. Comparisons of CCN3 expression were measured between cases and controls, followed by correlation of their expression level with severity/grade of osteosarcoma in cases. RESULTS All the demographic parameters showed insignificant differences. The CCN3 protein expressions were significantly upregulated in tissue samples of osteosarcoma patients (cases) compared to controls. The mean difference (p<0.0001) in CCN3 protein expression between cases' and controls' bony tissues was significant but showed insignificant correlation with the different grades of osteosarcoma. CONCLUSIONS The upregulated CCN3 protein expression in osteosarcoma tissue along with significant differential manifestation in accordance with different grades of osteosarcoma make CCN3 suitable for a potential diagnostic biomarker. However, the author recommends further extensive multi-centric collaborative studies to increase our study reliability and generalizability.
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Affiliation(s)
- Salma Siddiqui
- Department of Biochemistry, King George's Medical University, Lucknow, U.P., India
| | - Vaishnavi Pandey
- Department of Paediatric Orthopaedic, King George's Medical University, Lucknow U.P., India
| | - Sabir Ali
- Department of Paediatric Orthopaedic, King George's Medical University, Lucknow U.P., India
| | - Ajai Singh
- Department of Paediatric Orthopaedic, King George's Medical University, Lucknow U.P., India.
| | - Dilutpal Sharma
- Department of Biochemistry, King George's Medical University, Lucknow, U.P., India
| | - Manish Yadav
- Department of Paediatric Orthopaedic, King George's Medical University, Lucknow U.P., India
| | - Archana Raikwar
- Department of Paediatric Orthopaedic, King George's Medical University, Lucknow U.P., India
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Leguit RJ, Raymakers RAP, Hebeda KM, Goldschmeding R. CCN2 (Cellular Communication Network factor 2) in the bone marrow microenvironment, normal and malignant hematopoiesis. J Cell Commun Signal 2021; 15:25-56. [PMID: 33428075 PMCID: PMC7798015 DOI: 10.1007/s12079-020-00602-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 12/20/2020] [Indexed: 02/06/2023] Open
Abstract
CCN2, formerly termed Connective Tissue Growth Factor, is a protein belonging to the Cellular Communication Network (CCN)-family of secreted extracellular matrix-associated proteins. As a matricellular protein it is mainly considered to be active as a modifier of signaling activity of several different signaling pathways and as an orchestrator of their cross-talk. Furthermore, CCN2 and its fragments have been implicated in the regulation of a multitude of biological processes, including cell proliferation, differentiation, adhesion, migration, cell survival, apoptosis and the production of extracellular matrix products, as well as in more complex processes such as embryonic development, angiogenesis, chondrogenesis, osteogenesis, fibrosis, mechanotransduction and inflammation. Its function is complex and context dependent, depending on cell type, state of differentiation and microenvironmental context. CCN2 plays a role in many diseases, especially those associated with fibrosis, but has also been implicated in many different forms of cancer. In the bone marrow (BM), CCN2 is highly expressed in mesenchymal stem/stromal cells (MSCs). CCN2 is important for MSC function, supporting its proliferation, migration and differentiation. In addition, stromal CCN2 supports the maintenance and longtime survival of hematopoietic stem cells, and in the presence of interleukin 7, stimulates the differentiation of pro-B lymphocytes into pre-B lymphocytes. Overexpression of CCN2 is seen in the majority of B-acute lymphoblastic leukemias, especially in certain cytogenetic subgroups associated with poor outcome. In acute myeloid leukemia, CCN2 expression is increased in MSCs, which has been associated with leukemic engraftment in vivo. In this review, the complex function of CCN2 in the BM microenvironment and in normal as well as malignant hematopoiesis is discussed. In addition, an overview is given of data on the remaining CCN family members regarding normal and malignant hematopoiesis, having many similarities and some differences in their function.
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Affiliation(s)
- Roos J. Leguit
- Department of Pathology, University Medical Center Utrecht, H04-312, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
| | - Reinier A. P. Raymakers
- Department of Hematology, UMCU Cancer Center, Heidelberglaan 100 B02.226, 3584 CX Utrecht, The Netherlands
| | - Konnie M. Hebeda
- Department of Pathology, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Roel Goldschmeding
- Department of Pathology, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
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An Update to the WISP-1/CCN4 Role in Obesity, Insulin Resistance and Diabetes. ACTA ACUST UNITED AC 2021; 57:medicina57020100. [PMID: 33498604 PMCID: PMC7911315 DOI: 10.3390/medicina57020100] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 01/20/2021] [Indexed: 01/22/2023]
Abstract
Insulin resistance refers to the diminished response of peripheral tissues to insulin and is considered the major risk factor for type 2 diabetes. Although many possible mechanisms have been reported to develop insulin resistance, the exact underlying processes remain unclear. In recent years, the role of adipose tissue as a highly active metabolic and endocrine organ, producing proteins called adipokines and their multidirectional activities has gained interest. The physiological effects of adipokines include energy homeostasis and insulin sensitivity regulation. In addition, an excess of adipose tissue is followed by proinflammatory state which results in dysregulation of secreted cytokines contributing to insulin resistance. Wingless-type (Wnt) inducible signalling pathway protein-1 (WISP-1), also known as CCN4, has recently been described as a novel adipokine, whose circulating levels are elevated in obese and insulin resistant individuals. Growing evidence suggests that WISP-1 may participate in the impaired glucose homeostasis. In this review, we characterize WISP-1 and summarize the latest reports on the role of WISP-1 in obesity, insulin resistance and type 2 diabetes.
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Choi C, Jeong W, Ghang B, Park Y, Hyun C, Cho M, Kim J. Cyr61 synthesis is induced by interleukin-6 and promotes migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res Ther 2020; 22:275. [PMID: 33228785 PMCID: PMC7685583 DOI: 10.1186/s13075-020-02369-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 11/05/2020] [Indexed: 12/17/2022] Open
Abstract
Background Interleukin-6 (IL-6) is involved in fibroblast-like synoviocyte (FLS) activation and promotes pannus formation and bone and cartilage destruction in rheumatoid arthritis (RA). Cysteine-rich 61 (Cyr61) protein regulates cell proliferation, migration, and differentiation. The aim of this study was to investigate the role of Cyr61 in RA-FLS migration and invasion after IL-6 stimulation. Methods Western blotting, immunohistochemistry, reverse transcription-polymerase chain reaction, and real time-polymerase chain reaction were used to examine protein and mRNA levels of Cyr61, matrix metalloproteinases (MMPs), and other signalling proteins. Knockdown of gene expression was performed with siRNA, and RNA sequencing was performed for differential gene analysis. Migration and invasion were assessed by wound healing and Boyden chamber assays. Results Cyr61 levels were elevated in FLSs from RA patients compared to those in osteoarthritis patients. Control and IL-6-treated FLSs showed differential gene expression. IL-6 stimulated protein synthesis of Cyr61, which was attenuated by the extracellular signal-related kinase 1/2 (ERK 1/2) inhibitor, PD98059, and knockdown of early growth response 3 (EGR3), but not of JUN. IL-6-induced Cyr61 protein synthesis increased expression of MMP2. Cyr61 promoted FLS migration and invasion in an autocrine manner. Knockdown of CYR61 and a neutralising antibody attenuated Cyr61 synthesis and IL-6-induced FLS migration. Conclusions By modulating the ERK/EGR3 pathway, IL-6 stimulated Cyr61 production and in turn increased invasiveness of FLS. Our data suggest that Cyr61 might be a potential target to prevent the progression of joint damage in RA.
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Affiliation(s)
- Changmin Choi
- Department of Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Wooseong Jeong
- Department of Internal Medicine, Division of Rheumatology, Jeju National University Hospital, Aran 13gil, Jeju, 690-797, Republic of Korea
| | - Byeongzu Ghang
- Department of Internal Medicine, Division of Rheumatology, Jeju National University Hospital, Aran 13gil, Jeju, 690-797, Republic of Korea
| | - Yonggeun Park
- Department of Orthopaedic Surgery, Jeju National University Hospital, Jeju, Republic of Korea
| | - Changlim Hyun
- Department of Pathology, Jeju National University Hospital, Jeju, Republic of Korea
| | - Moonjae Cho
- Department of Biochemistry, Jeju National University School of Medicine, Aran 13gil, Jeju, 690-797, Republic of Korea.
| | - Jinseok Kim
- Department of Internal Medicine, Division of Rheumatology, Jeju National University Hospital, Aran 13gil, Jeju, 690-797, Republic of Korea.
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Sun C, Zhang H, Liu X. Emerging role of CCN family proteins in fibrosis. J Cell Physiol 2020; 236:4195-4206. [PMID: 33222181 DOI: 10.1002/jcp.30171] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 10/30/2020] [Accepted: 11/10/2020] [Indexed: 12/11/2022]
Abstract
Fibrosis is a common pathological change characterized by the excessive accumulation of fibrous connective tissue. Once uncontrolled, this pathological progress can lead to irreversible damage to the structure and function of organs, which is a serious threat to human health and life. Actually, the disability and death of patients caused by many chronic diseases have a closed relationship with fibrosis. The CCN protein family, including six members, is a small group of matrix proteins exhibiting structurally similar features. In the past 20 years, different biological functions of CCN proteins have been identified in various diseases. Of note, it has been recently shown that they are implicated in the key pathological process of fibrosis. In this review, we summarize the current status of knowledge regarding the role of CCN proteins involved in the pathogenesis of fibrosis diseases in detail. Furthermore, we highlight some of the underlying interaction mechanisms of CCN protein acting in fibrosis that helps to develop new drugs and determine appropriate clinical strategies for fibrotic diseases.
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Affiliation(s)
- Chao Sun
- Department of Spine Surgery, the Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Han Zhang
- Department of Spine Surgery, the Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xinhui Liu
- Department of Spine Surgery, the Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
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21
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Shi ZQ, Chen ZY, Han Y, Zhu HY, Lyu MD, Zhang H, Zhang Y, Yang LQ, Pan WW. WISP2 promotes cell proliferation via targeting ERK and YAP in ovarian cancer cells. J Ovarian Res 2020; 13:85. [PMID: 32711570 PMCID: PMC7382796 DOI: 10.1186/s13048-020-00687-8] [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: 03/31/2020] [Accepted: 07/15/2020] [Indexed: 12/25/2022] Open
Abstract
Background Wnt-inducible signaling pathway protein 2 (WISP2) is a wnt1-induced signaling pathway protein 2. Although studies indicate that WISP2 may promote the development of various tumors, its role in ovarian cancer remains unclear. The objective of the current study was to analyze the effects of WISP2 on the proliferation and migration of ovarian cancer cells in vitro and in vivo. Results Immunohistochemistry and western blotting indicated that WISP2 was highly expressed in various ovarian cancer tissues and cell lines, but weakly expressed in normal ovary tissue. WISP2 deletion inhibited cell growth, clone formation, and migration of ovarian cancer cells while promoting cell apoptosis and affecting the cell cycle. This growth inhibitory effect caused by WISP2 loss is due to the inhibition of phosphorylated extracellular signal-related kinase (p-ERK)1/2, as well as CCAAT/enhancer-binding protein α (CEBPα) and CEPBβ. In addition, WISP2 deletion also activated the Yes-associated protein (YAP). Conclusion WISP2 deletion inhibits ovarian cancer cell proliferation by affecting ERK signaling pathways.
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Affiliation(s)
- Zi-Qing Shi
- School of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Zi-Yan Chen
- School of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Yao Han
- School of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Heng-Yan Zhu
- School of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Meng-Dan Lyu
- School of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Han Zhang
- School of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Yi Zhang
- School of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Liu-Qing Yang
- School of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Wei-Wei Pan
- School of Medicine, Jiaxing University, Jiaxing, 314001, China.
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Leask A. Conjunction junction, what's the function? CCN proteins as targets in fibrosis and cancers. Am J Physiol Cell Physiol 2020; 318:C1046-C1054. [PMID: 32130070 PMCID: PMC7311738 DOI: 10.1152/ajpcell.00028.2020] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/28/2020] [Accepted: 03/03/2020] [Indexed: 12/11/2022]
Abstract
Cellular communication network (CCN) proteins are matricellular proteins that coordinate signaling among extracellular matrix, secreted proteins, and cell surface receptors. Their specific in vivo function is context-dependent, but they play profound roles in pathological conditions, such as fibrosis and cancers. Anti-CCN therapies are in clinical consideration. Only recently, however, has the function of these complex molecules begun to emerge. This review summarizes and interprets our current knowledge regarding these fascinating molecules and provides experimental evidence for their utility as therapeutic targets.
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Affiliation(s)
- Andrew Leask
- School of Dentistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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Abou-Kheir W, Mukherji D, Hadadeh O, Saleh E, Bahmad HF, Kanso M, Khalifeh M, Shamseddine A, Tamraz S, Jaafar R, Dagher C, Khalifeh I, Faraj W. CYR61/CCN1 expression in resected pancreatic ductal adenocarcinoma: A retrospective pilot study of the interaction between the tumors and their surrounding microenvironment. Heliyon 2020; 6:e03842. [PMID: 32395647 PMCID: PMC7205742 DOI: 10.1016/j.heliyon.2020.e03842] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 02/10/2020] [Accepted: 04/20/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND CCN1 is an extracellular matrix-associated protein thought to be implicated in tumor-stromal interaction in several solid tumors. The aim of our pilot study was to evaluate the correlation between CCN1 expression in stromal cells, pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma cells in resected pancreatic ductal adenocarcinoma (PDAC) specimens, and correlate that clinically. METHODS A total of 42 paraffin-embedded PDAC tumor specimens were stained for CCN1 and evaluated via immunohistochemical (IHC) analysis. Statistical analysis was performed to correlate between CCN1 expression profiles in tumor tissues and clinicopathological parameters of patients. RESULTS Our results showed CCN1 (CYR61) gene was highly expressed in PDAC tissues relative to other organ specific tumor tissues. Also, moderate and overexpression of CCN1 in PanIN was associated with PanIN grade 3 tissues. A statistically significant association was found between PanIN CCN1 scores on one hand and cancer stage, cancer grade, and CCN1 expression among ductal tumor cells and adjacent stromal cells on the other hand. DISCUSSION The associations demonstrated suggest that CCN1 might be contributing to a substantial role in the interaction between the pancreatic tumors on one hand and their surrounding microenvironment and their precursors on the other hand; hence, it might serve as a potential therapeutic target for PDAC.
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Affiliation(s)
- Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Deborah Mukherji
- Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ola Hadadeh
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Eman Saleh
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Hisham F. Bahmad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Mariam Kanso
- Department of Surgery, Division of General Surgery, Liver Transplantation and Hepatopancreaticobiliary (HPB) Unit, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mohamad Khalifeh
- Department of Surgery, Division of General Surgery, Liver Transplantation and Hepatopancreaticobiliary (HPB) Unit, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ali Shamseddine
- Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Sally Tamraz
- Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Rola Jaafar
- Department of Surgery, Division of General Surgery, Liver Transplantation and Hepatopancreaticobiliary (HPB) Unit, American University of Beirut Medical Center, Beirut, Lebanon
| | - Christelle Dagher
- Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ibrahim Khalifeh
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Walid Faraj
- Department of Surgery, Division of General Surgery, Liver Transplantation and Hepatopancreaticobiliary (HPB) Unit, American University of Beirut Medical Center, Beirut, Lebanon
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Xu ER, Lafita A, Bateman A, Hyvönen M. The thrombospondin module 1 domain of the matricellular protein CCN3 shows an atypical disulfide pattern and incomplete CWR layers. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY 2020; 76:124-134. [PMID: 32038043 DOI: 10.1107/s2059798319016747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 12/14/2019] [Indexed: 05/04/2023]
Abstract
The members of the CCN (Cyr61/CTGF/Nov) family are a group of matricellular regulatory proteins that are essential to a wide range of functional pathways in cell signalling. Through interacting with extracellular matrix components and growth factors via one of their four domains, the CCN proteins are involved in critical biological processes such as angiogenesis, cell proliferation, bone development, fibrogenesis and tumorigenesis. Here, the crystal structure of the thrombospondin module 1 (TSP1) domain of CCN3 (previously known as Nov) is presented, which shares a similar three-stranded fold with the thrombospondin type 1 repeats of thrombospondin-1 and spondin-1, but with variations in the disulfide connectivity. Moreover, the CCN3 TSP1 domain lacks the typical π-stacked ladder of charged and aromatic residues on one side of the domain that is seen in other TSP1 domains. Using conservation analysis among orthologous domains, it is shown that a charged cluster in the centre of the domain is the most conserved site and this cluster is predicted to be a potential functional epitope for heparan sulfate binding. This variant TSP1 domain has also been used to revise the sequence determinants of TSP1 domains and to derive improved Pfam sequence profiles for the identification of novel TSP1 domains in more than 10 000 proteins across diverse phyla.
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Affiliation(s)
- Emma Ruoqi Xu
- Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, England
| | - Aleix Lafita
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton CB10 1SD, England
| | - Alex Bateman
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton CB10 1SD, England
| | - Marko Hyvönen
- Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, England
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Shimbo A, Kajiyama H, Tamauchi S, Yoshikawa N, Ikeda Y, Nishino K, Suzuki S, Niimi K, Sakata J, Kikkawa F. Expression of connective tissue growth factor as a prognostic indicator and its possible involvement in the aggressive properties of epithelial ovarian carcinoma. Oncol Rep 2019; 42:2323-2332. [PMID: 31578579 PMCID: PMC6826307 DOI: 10.3892/or.2019.7352] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 09/03/2019] [Indexed: 12/27/2022] Open
Abstract
Recently, connective tissue growth factor (CTGF) was demonstrated to be associated with aggressive characteristics, including proliferation, invasion and metastasis, in a number of malignancies. Here, we investigated the expression and function of CTGF in epithelial ovarian carcinoma (EOC) to clarify its molecular mechanism and clinical significance. Paraffin sections from clinical samples of EOC (N=104) were immunostained with the CTGF antibody, and then the staining positivity was semiquantitatively examined. Moreover, we explored the role of CTGF expression in the migration-promoting effect on and chemoresistance of EOC cells. The results revealed that of the 104 EOC patients, the low and high CTGF staining expression rates were 65 (62.5%) and 39 (37.5%), respectively. Patients belonging to the higher-level CTGF group showed poorer progression-free (PFS) and overall survival (OS) rates than those in the lower-level group [PFS (log-rank: P=0.0076) and OS (log-rank: P=0.0078), respectively]. Multivariable analysis showed that CTGF expression was a significant predictor of poorer PFS and OS [PFS: HR (high vs. low): 1.837, 95% CI: 1.023–3.289 (P=0.0418); OS: HR: 2.141, 95% CI: 1.077–4.296 (P=0.0300)]. In in vitro studies, in acquired paclitaxel (PTX)-resistant EOC cells, the silencing of CTGF expression led to the restoration of PTX sensitivity. Furthermore, we confirmed that the TGF-β-dependent migration-promoting effect on these CTGF-depleted cells was completely inhibited. In conclusion, the results of the present study suggest the possible involvement of CTGF in the migration-promoting effect and chemoresistance of EOC, suggesting that it may be a target for overcoming the malignant properties of EOC.
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Affiliation(s)
- Akiko Shimbo
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466‑8550, Japan
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466‑8550, Japan
| | - Satoshi Tamauchi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466‑8550, Japan
| | - Nobuhisa Yoshikawa
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466‑8550, Japan
| | - Yoshiki Ikeda
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466‑8550, Japan
| | - Kimihiro Nishino
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466‑8550, Japan
| | - Shiro Suzuki
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466‑8550, Japan
| | - Kaoru Niimi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466‑8550, Japan
| | - Jun Sakata
- Department of Gynecology, Graduate School of Medicine, Aichi Cancer Center Hospital, Nagoya, Aichi 464‑8681, Japan
| | - Fumitaka Kikkawa
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466‑8550, Japan
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Pan WQ, Wang JP, Tu ZH, Gan T, Hu J, Wei J, Leng XJ, Li XQ. Cloning, molecular characterization, and tissue differential expression of connective tissue growth factor (ctgf) of grass carp. FISH PHYSIOLOGY AND BIOCHEMISTRY 2019; 45:1431-1443. [PMID: 31267430 DOI: 10.1007/s10695-019-00653-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 05/02/2019] [Indexed: 06/09/2023]
Abstract
Connective tissue growth factor (ctgf) is involved in the proliferation, migration, adhesion of cell, and the constituent of extracellular matrix, which plays an important role in embryogenesis, angiogenesis, wound repair, and fibrosis diseases. In this study, the cDNA sequence of grass carp ctgf gene was cloned by rapid amplification of cDNA ends (RACE) method; then, the characteristics of this gene and the predicted protein sequence were analyzed by bioinformatics methods, and the tissue differential expression pattern was detected by the quantitative real-time PCR. The results showed that the grass carp ctgf gene has a full-length of 2223 bp, encoding 343 amino acids. The deduced CTGF protein is a hydrophilic and secretary protein with a molecular mass of 37,978.2 Da and an isoelectric point of 8.22. The signal peptide locates between residue positions 1 and 22 of the polypeptide chain. The protein contains α-helix, β-strand, and loops. The CTGF protein of grass carp shows a homology of 98%, 96%, 91%, and 91% with Wuchang bream (Megalobrama amblycephala), zebrafish (Danio rerio), common carp (Cyprinus carpio), and Mexican tetra (Astyanax mexicanus). The grass carp ctgf gene expressed significantly higher in blood and spleen than that in other tissues (P < 0.05). The low expression tissues included the heart, gill, skin, muscle, kidney, brain, and intestinal, and the lowest expression tissue was the liver. The results are consistent with the function of this gene.
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Affiliation(s)
- Wen-Qian Pan
- The College of Fisheries and Life Science, Shanghai Ocean University, No. 999, Huchenghuan Road, Shanghai, 201306, China
| | - Jun-Peng Wang
- The College of Fisheries and Life Science, Shanghai Ocean University, No. 999, Huchenghuan Road, Shanghai, 201306, China
| | - Zhi-Han Tu
- The College of Fisheries and Life Science, Shanghai Ocean University, No. 999, Huchenghuan Road, Shanghai, 201306, China
| | - Tian Gan
- The College of Fisheries and Life Science, Shanghai Ocean University, No. 999, Huchenghuan Road, Shanghai, 201306, China
| | - Jing Hu
- The College of Fisheries and Life Science, Shanghai Ocean University, No. 999, Huchenghuan Road, Shanghai, 201306, China
| | - Jing Wei
- The College of Fisheries and Life Science, Shanghai Ocean University, No. 999, Huchenghuan Road, Shanghai, 201306, China
| | - Xiang-Jun Leng
- The College of Fisheries and Life Science, Shanghai Ocean University, No. 999, Huchenghuan Road, Shanghai, 201306, China.
- Key Laboratory of Freshwater Fishery Germplasm Resources, Ministry of Agriculture, No. 999, Huchenghuan Road, Shanghai, 201306, China.
- Shanghai Engineering Research Center of Aquaculture, No.999, Huchenghuan Road, Shanghai, 201306, China.
- Shanghai University Knowledge Service Platform, Shanghai Ocean University Aquatic Animal Breeding Center, No. 999, Huchenghuan Road, Shanghai, 201306, China.
| | - Xiao-Qin Li
- The College of Fisheries and Life Science, Shanghai Ocean University, No. 999, Huchenghuan Road, Shanghai, 201306, China.
- Key Laboratory of Freshwater Fishery Germplasm Resources, Ministry of Agriculture, No. 999, Huchenghuan Road, Shanghai, 201306, China.
- Shanghai Engineering Research Center of Aquaculture, No.999, Huchenghuan Road, Shanghai, 201306, China.
- Shanghai University Knowledge Service Platform, Shanghai Ocean University Aquatic Animal Breeding Center, No. 999, Huchenghuan Road, Shanghai, 201306, China.
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CCN2-MAPK-Id-1 loop feedback amplification is involved in maintaining stemness in oxaliplatin-resistant hepatocellular carcinoma. Hepatol Int 2019; 13:440-453. [PMID: 31250351 PMCID: PMC6661033 DOI: 10.1007/s12072-019-09960-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 06/11/2019] [Indexed: 12/24/2022]
Abstract
Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Chemotherapy is an alternative treatment for advanced HCCs, but chemo-resistance prevents cancer therapies from achieving stable and complete responses. Understanding the underlying mechanisms in chemo-resistance is critical to improve the efficacy of HCC. Methods The expression levels of Id-1 and CCN2 were detected in large cohorts of HCCs, and functional analyses of Id-1 and CCN2 were performed both in vitro and in vivo. cDNA microarrays were performed to evaluate the alterations of expression profiling of HCC cells with overexpression of CCN2. Finally, the role of downstream signaling of MAPK/Id-1 signaling pathway in oxaliplatin resistance were also explored. Results The increased expression of Id-1 and CCN2 were closely related to oxaliplatin resistance in HCC. Upregulation of CCN2 and Id-1 was independently associated with shorter survival and increased recurrence in HCC patients, and significantly enhanced oxaliplatin resistance and promoted lung metastasis in vivo, whereas knock-down of their expression significantly reversed the chemo-resistance and inhibited HCC cell stemness. cDNA microarrays and PCR revealed that Id-1 and MAPK pathway were the downstream signaling of CCN2. CCN2 significantly enhanced oxaliplatin resistance by activating the MAPK/Id-1 signaling pathway, and Id-1 could upregulate CCN2 in a positive feedback manner. Conclusions CCN2/MAPK/Id-1 loop feedback amplification is involved in oxaliplatin resistance, and the combination of oxaliplatin with inhibitor of CCN2 or MAPK signaling could provide a promising approach to ameliorating oxaliplatin resistance in HCC. Electronic supplementary material The online version of this article (10.1007/s12072-019-09960-5) contains supplementary material, which is available to authorized users.
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A Comparative Genomic and Phylogenetic Analysis of the Origin and Evolution of the CCN Gene Family. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8620878. [PMID: 31321242 PMCID: PMC6610741 DOI: 10.1155/2019/8620878] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 05/04/2019] [Accepted: 05/26/2019] [Indexed: 11/18/2022]
Abstract
CCN gene family members have recently been identified as multifunctional regulators involved in diverse biological functions, especially in vascular and skeletal development. In the present study, a comparative genomic and phylogenetic analysis was performed to show the similarities and differences in structure and function of CCNs from different organisms and to reveal their potential evolutionary relationship. First, CCN homologs of metazoans from different species were identified. Then we made multiple sequence alignments, MEME analysis, and functional sites prediction, which show the highly conserved structural features among CCN metazoans. The phylogenetic tree was further established, and thus CCNs were found undergoing extensive lineage-specific duplication events and lineage-specific expansion during the evolutionary process. Besides, comparative analysis about the genomic organization and chromosomal CCN gene surrounding indicated a clear orthologous relationship among these species counterparts. At last, based on these research results above, a potential evolutionary scenario was generated to overview the origin and evolution of the CCN gene family.
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29
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Dankner M, Ouellet V, Communal L, Schmitt E, Perkins D, Annis MG, Barrès V, Caron C, Mes-Masson AM, Saad F, Siegel PM. CCN3/Nephroblastoma Overexpressed Is a Functional Mediator of Prostate Cancer Bone Metastasis That Is Associated with Poor Patient Prognosis. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1451-1461. [PMID: 31202437 DOI: 10.1016/j.ajpath.2019.04.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 03/19/2019] [Accepted: 04/02/2019] [Indexed: 12/28/2022]
Abstract
Prostate cancer (PC) commonly metastasizes to the bone, resulting in pathologic fractures and poor prognosis. CCN3/nephroblastoma overexpressed is a secreted protein with a known role in promoting breast cancer metastasis to bone. However, in PC, CCN3 has been ascribed conflicting roles; some studies suggest that CCN3 promotes PC metastasis, whereas others argue a tumor suppressor role for CCN3 in this disease. Indeed, in the latter context, CCN3 has been shown to sequester the androgen receptor (AR) and suppress AR signaling. In the present study, we demonstrate that CCN3 functions as a bone-metastatic mediator, which is dependent on its C-terminal domain for this function. Analysis of tissue microarrays comprising >1500 primary PC patient radical prostatectomy specimens reveals that CCN3 expression correlates with aggressive disease and is negatively correlated with the expression of prostate-specific antigen, a marker of AR signaling. Together, these findings point to CCN3 as a biomarker to predict PC aggressiveness while providing clarity on its role as a functional mediator of PC bone metastasis.
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Affiliation(s)
- Matthew Dankner
- Goodman Cancer Research Centre, Department of Medicine, McGill University, Montréal, Québec, Canada
| | - Véronique Ouellet
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Laudine Communal
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Estelle Schmitt
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Dru Perkins
- Goodman Cancer Research Centre, Department of Medicine, McGill University, Montréal, Québec, Canada
| | - Matthew G Annis
- Goodman Cancer Research Centre, Department of Medicine, McGill University, Montréal, Québec, Canada
| | - Véronique Barrès
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Christine Caron
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Anne-Marie Mes-Masson
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; Institut du Cancer de Montréal, Montréal, Québec, Canada; Department of Medicine, Université de Montréal, Montréal, Québec, Canada
| | - Fred Saad
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; Institut du Cancer de Montréal, Montréal, Québec, Canada; Department of Surgery, Université de Montréal, Montréal, Québec, Canada
| | - Peter M Siegel
- Goodman Cancer Research Centre, Department of Medicine, McGill University, Montréal, Québec, Canada.
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Henrot P, Truchetet ME, Fisher G, Taïeb A, Cario M. CCN proteins as potential actionable targets in scleroderma. Exp Dermatol 2018; 28:11-18. [PMID: 30329180 DOI: 10.1111/exd.13806] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 10/01/2018] [Accepted: 10/10/2018] [Indexed: 12/26/2022]
Abstract
Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease combining inflammatory, vasculopathic and fibrotic manifestations. Skin features, which give their name to the disease and are considered as diagnostic as well as prognostic markers, have not been thoroughly investigated in terms of therapeutic targets. CCN proteins (CYR61/CCN1, CTGF/CCN2, NOV/CCN3 and WISP1-2-3 as CCN4-5-6) are a family of secreted matricellular proteins implicated in major cellular processes such as cell growth, migration, differentiation. They have already been implicated in key pathophysiological processes of SSc, namely fibrosis, vasculopathy and inflammation. In this review, we discuss the possible implication of CCN proteins in SSc pathogenesis, with a special focus on skin features, and identify the potential actionable CCN targets.
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Affiliation(s)
- Pauline Henrot
- University of Bordeaux, Inserm, BMGIC, UMR1035, Bordeaux, France.,Department of Rheumatology, National Reference Center for Rare Diseases, Bordeaux University Hospital, Bordeaux, France
| | - Marie-Elise Truchetet
- Department of Rheumatology, National Reference Center for Rare Diseases, Bordeaux University Hospital, Bordeaux, France.,University of Bordeaux, CNRS, Immunoconcept, UMR 5164, Bordeaux, France
| | - Gary Fisher
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Alain Taïeb
- University of Bordeaux, Inserm, BMGIC, UMR1035, Bordeaux, France.,Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Muriel Cario
- University of Bordeaux, Inserm, BMGIC, UMR1035, Bordeaux, France.,Department of Dermatology and Pediatric Dermatology, National Center for Rare Skin Disorders, Hôpital Saint André, Bordeaux, France
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de la Vega Gallardo N, Dittmer M, Dombrowski Y, Fitzgerald DC. Regenerating CNS myelin: Emerging roles of regulatory T cells and CCN proteins. Neurochem Int 2018; 130:104349. [PMID: 30513363 DOI: 10.1016/j.neuint.2018.11.024] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 11/19/2018] [Accepted: 11/30/2018] [Indexed: 02/08/2023]
Abstract
Efficient myelin regeneration in the central nervous system (CNS) requires the migration, proliferation and differentiation of oligodendrocyte progenitor cells (OPC) into myelinating oligodendrocytes. In demyelinating diseases such as multiple sclerosis (MS), this regenerative process can fail, and therapies targeting myelin repair are currently completely lacking in the clinic. The immune system is emerging as a key regenerative player in many tissues, such as muscle and heart. We recently reported that regulatory T cells (Treg) are required for efficient CNS remyelination. Furthermore, Treg secrete CCN3, a matricellular protein from the CCN family, implicated in regeneration of other tissues. Treg-derived CCN3 promoted oligodendrocyte differentiation and myelination. In contrast, previous studies showed that CCN2 inhibited myelination. These studies highlight the need for further scrutiny of the roles that CCN proteins play in myelin development and regeneration. Collectively, these findings open up exciting avenues of research to uncover the regenerative potential of the adaptive immune system.
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Affiliation(s)
- Nira de la Vega Gallardo
- Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK
| | - Marie Dittmer
- Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK
| | - Yvonne Dombrowski
- Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK
| | - Denise C Fitzgerald
- Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK.
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Perbal B, Tweedie S, Bruford E. The official unified nomenclature adopted by the HGNC calls for the use of the acronyms, CCN1-6, and discontinuation in the use of CYR61, CTGF, NOV and WISP 1-3 respectively. J Cell Commun Signal 2018; 12:625-629. [PMID: 30393824 DOI: 10.1007/s12079-018-0491-1] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 10/18/2018] [Indexed: 12/01/2022] Open
Abstract
An examination of the confusion generated around the use of different acronyms for CCN proteins has been performed by the editors of the HUGO Gene Nomenclature Committee upon the request of the International CCN Society Scientific Committee. After careful consideration of the various arguments, and after polling the community of researchers who have published in the field over the past ten years, the HGNC have decided to adopt and approve the CCN nomenclature for all 6 genes. Effective October 2018, the genes referred to as CYR61, CTGF, NOV and WISP1-3 will be respectively designated by the gene symbols CCN1-6 with corresponding gene names « cellular communication Q2 network factor 1-6 ». We believe that this decision will be a step towards better communication between researchers working in the field, and will set the stage for fruitful collaborative projects. Accordingly, the Journal of Cell Communication and Signaling, the official journal of the International CCN Society, available both in print and online, constitutes a unique window into the CCN field. This official nomenclature will benefit the international scientific community that is supported by the established and renowned professionalism of the Springer-Nature publishing group.
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Affiliation(s)
| | - Susan Tweedie
- HUGO Gene Nomenclature Committee, EMBL-EBI, Hinxton, CB10 1SD, UK
| | - Elspeth Bruford
- HUGO Gene Nomenclature Committee, EMBL-EBI, Hinxton, CB10 1SD, UK
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Borkham-Kamphorst E, Steffen BT, van de Leur E, Haas U, Weiskirchen R. Portal myofibroblasts are sensitive to CCN-mediated endoplasmic reticulum stress-related apoptosis with potential to attenuate biliary fibrogenesis. Cell Signal 2018; 51:72-85. [DOI: 10.1016/j.cellsig.2018.07.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/13/2018] [Accepted: 07/18/2018] [Indexed: 12/21/2022]
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Hiyama A, Morita K, Sakai D, Watanabe M. CCN family member 2/connective tissue growth factor (CCN2/CTGF) is regulated by Wnt-β-catenin signaling in nucleus pulposus cells. Arthritis Res Ther 2018; 20:217. [PMID: 30268161 PMCID: PMC6162946 DOI: 10.1186/s13075-018-1723-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 09/11/2018] [Indexed: 12/15/2022] Open
Abstract
Background The aims of this study were to investigate the gene expression of CCN family members in rat intervertebral disc (IVD) cells and to examine whether Wnt–β-catenin signaling regulates the expression of CCN family 2 (CCN2)/connective tissue growth factor (CTGF) in rat nucleus pulposus (NP) cells. Methods The gene expression of CCN family members were assessed in rat IVD cells using real-time reverse transcription polymerase chain reaction (RT-PCR). The expression pattern of CCN2 was also assessed in rat IVD cells using western blot and immunohistochemical analyses. Gain-of-function and loss-of-function experiments were performed to identify the mechanisms by which Wnt–β-catenin signaling influences the activity of the CCN2 promoter. To further determine if the mitogen-activated protein kinase (MAPK) pathway is required for the Wnt–β-catenin signaling-induced regulation of CCN2 expression in the NP cells, CCN2 expression was analyzed by reporter assay, RT-PCR and western blot analysis. Results CCN2 messenger RNA (mRNA) and protein were expressed in rat IVDs. Expression of CCN2 was significantly higher than for mRNA of other CCN family members in both rat NP and annulus fibrosus (AF) cells. The relative activity of the CCN2 promoter decreased 24 h after treatment with 6-bromoindirubin-3′-oxime (1.0 μM) (0.773 (95% 0.735, 0.812) P = 0.0077) in NP cells. In addition, treatment with the WT–β-catenin vector (500 ng) significantly decreased CCN2 promoter activity (0.688 (95% 0.535, 0.842) P = 0.0063), whereas β-catenin small interfering RNA (500 ng) significantly increased CCN2 promoter activity (1.775 (95% 1.435, 2.115) P < 0.001). Activation of Wnt–β-catenin signaling decreased the expression of CCN2 mRNA and protein by NP cells. Regulation of CCN2 by Wnt–β-catenin signaling involved the MAPK pathway in rat NP cells. Conclusions This study shows that Wnt–β-catenin signaling regulates the expression of CCN2 through the MAPK pathway in NP cells. Understanding the balance between Wnt–β-catenin signaling and CCN2 is necessary for developing therapeutic alternatives for the treatment of IVD degeneration. Electronic supplementary material The online version of this article (10.1186/s13075-018-1723-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Akihiko Hiyama
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan. .,Research Center for Regenerative Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
| | - Kosuke Morita
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.,Research Center for Regenerative Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan
| | - Daisuke Sakai
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.,Research Center for Regenerative Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan
| | - Masahiko Watanabe
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.,Research Center for Regenerative Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan
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Marchand M, Monnot C, Muller L, Germain S. Extracellular matrix scaffolding in angiogenesis and capillary homeostasis. Semin Cell Dev Biol 2018; 89:147-156. [PMID: 30165150 DOI: 10.1016/j.semcdb.2018.08.007] [Citation(s) in RCA: 116] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 07/31/2018] [Accepted: 08/14/2018] [Indexed: 01/03/2023]
Abstract
The extracellular matrix (ECM) of blood vessels, which is composed of both the vascular basement membrane (BM) and the interstitial ECM is identified as a crucial component of the vasculature. We here focus on the unique molecular composition and scaffolding of the capillary ECM, which provides structural support to blood vessels and regulates properties of endothelial cells and pericytes. The major components of the BM are collagen IV, laminins, heparan sulfate proteoglycans and nidogen and also associated proteins such as collagen XVIII and fibronectin. Their organization and scaffolding in the BM is required for proper capillary morphogenesis and maintenance of vascular homeostasis. The BM also regulates vascular mechanosensing. A better understanding of the mechanical and structural properties of the vascular BM and interstitial ECM therefore opens new perspectives to control physiological and pathological angiogenesis and vascular homeostasis. The overall aim of this review is to explain how ECM scaffolding influences angiogenesis and capillary integrity.
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Affiliation(s)
- Marion Marchand
- Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, 11 Place Marcelin Berthelot, 75005, Paris, France; Sorbonne Université, Collège Doctoral, F-75005 Paris, France
| | - Catherine Monnot
- Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, 11 Place Marcelin Berthelot, 75005, Paris, France
| | - Laurent Muller
- Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, 11 Place Marcelin Berthelot, 75005, Paris, France
| | - Stéphane Germain
- Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, 11 Place Marcelin Berthelot, 75005, Paris, France.
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Hong L, Lai H, Fang Y, Tao Y, Qiu Y. Silencing CTGF/CCN2 inactivates the MAPK signaling pathway to alleviate myocardial fibrosis and left ventricular hypertrophy in rats with dilated cardiomyopathy. J Cell Biochem 2018; 119:9519-9531. [PMID: 30129221 DOI: 10.1002/jcb.27268] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 06/26/2018] [Indexed: 01/04/2023]
Affiliation(s)
- Lang Hong
- 2nd Department of Cardiology Jiangxi Provincial People’s Hospital Nanchang China
| | - Heng‐Li Lai
- 2nd Department of Cardiology Jiangxi Provincial People’s Hospital Nanchang China
| | - Yan Fang
- 2nd Department of Cardiology Jiangxi Provincial People’s Hospital Nanchang China
| | - Yu Tao
- 2nd Department of Cardiology Jiangxi Provincial People’s Hospital Nanchang China
| | - Yun Qiu
- 2nd Department of Cardiology Jiangxi Provincial People’s Hospital Nanchang China
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Toda N, Mukoyama M, Yanagita M, Yokoi H. CTGF in kidney fibrosis and glomerulonephritis. Inflamm Regen 2018; 38:14. [PMID: 30123390 PMCID: PMC6091167 DOI: 10.1186/s41232-018-0070-0] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 05/08/2018] [Indexed: 01/27/2023] Open
Abstract
Background Glomerulonephritis, which causes inflammation in glomeruli, is a common cause of end-stage renal failure. Severe and prolonged inflammation can damage glomeruli and lead to kidney fibrosis. Connective tissue growth factor (CTGF) is a member of the CCN matricellular protein family, consisting of four domains, that regulates the signaling of other growth factors and promotes kidney fibrosis. Main body of the abstract CTGF can simultaneously interact with several factors with its four domains. The microenvironment differs depending on the types of cells and tissues and differentiation stages of these cells. The diverse biological actions of CTGF on various types of cells and tissues depend on this difference in microenvironment. In the kidney, CTGF is expressed at low levels in normal condition and its expression is upregulated by kidney fibrosis. CTGF expression is known to be upregulated in the extra-capillary and mesangial lesions of glomerulonephritis in human kidney biopsy samples. In addition to involvement in fibrosis, CTGF modulates the expression of inflammatory mediators, including cytokines and chemokines, through distinct signaling pathways, in various cell systems. In anti-glomerular basement membrane (GBM) glomerulonephritis, systemic CTGF knockout (Rosa-CTGF cKO) mice exhibit 50% reduction of proteinuria and decreased crescent formation and mesangial expansion compared with control mice. In addition to fibrotic markers, the glomerular mRNA expression of Ccl2 is increased in the control mice with anti-GBM glomerulonephritis, and this increase is reduced in Rosa-CTGF cKO mice with nephritis. Accumulation of MAC2-positive cells in glomeruli is also reduced in Rosa-CTGF cKO mice. These results suggest that CTGF may be required for the upregulation of Ccl2 expression not only in anti-GBM glomerulonephritis but also in other types of glomerulonephritis, such as IgA nephropathy; CTGF expression and accumulation of macrophages in the mesangial area have been documented in these glomerular diseases. CTGF induces the expression of inflammatory mediators and promotes cell adhesion. Short conclusion CTGF plays an important role in the development of glomerulonephritis by inducing the inflammatory process. CTGF is a potentiate target for the treatment of glomerulonephritis.
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Affiliation(s)
- Naohiro Toda
- 1Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan
| | - Masashi Mukoyama
- 2Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Motoko Yanagita
- 1Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan
| | - Hideki Yokoi
- 1Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan
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Tarr JT, Lambi AG, Bradley JP, Barbe MF, Popoff SN. Development of Normal and Cleft Palate: A Central Role for Connective Tissue Growth Factor (CTGF)/CCN2. J Dev Biol 2018; 6:jdb6030018. [PMID: 30029495 PMCID: PMC6162467 DOI: 10.3390/jdb6030018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 07/15/2018] [Accepted: 07/15/2018] [Indexed: 02/06/2023] Open
Abstract
Development of the palate is the result of an organized series of events that require exquisite spatial and temporal regulation at the cellular level. There are a myriad of growth factors, receptors and signaling pathways that have been shown to play an important role in growth, elevation and/or fusion of the palatal shelves. Altered expression or activation of a number of these factors, receptors and signaling pathways have been shown to cause cleft palate in humans or mice with varying degrees of penetrance. This review will focus on connective tissue growth factor (CTGF) or CCN2, which was recently shown to play an essential role in formation of the secondary palate. Specifically, the absence of CCN2 in KO mice results in defective cellular processes that contribute to failure of palatal shelf growth, elevation and/or fusion. CCN2 is unique in that it has been shown to interact with a number of other factors important for palate development, including bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), epidermal growth factor (EGF), Wnt proteins and transforming growth factor-βs (TGF-βs), thereby influencing their ability to bind to their receptors and mediate intracellular signaling. The role that these factors play in palate development and their specific interactions with CCN2 will also be reviewed. Future studies to elucidate the precise mechanisms of action for CCN2 and its interactions with other regulatory proteins during palatogenesis are expected to provide novel information with the potential for development of new pharmacologic or genetic treatment strategies for clinical intervention of cleft palate during development.
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Affiliation(s)
- Joseph T Tarr
- Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
| | - Alex G Lambi
- Division of Plastic and Reconstructive Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
| | - James P Bradley
- Northwell Health Surgical Service Line, Department of Surgery, Zucker School of Medicine, Lake Success, NY 11042, USA.
| | - Mary F Barbe
- Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
| | - Steven N Popoff
- Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
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Umehara T, Murase T, Abe Y, Yamashita H, Shibaike Y, Kagawa S, Yamamoto T, Ikematsu K. Identification of potential markers of fatal hypothermia by a body temperature-dependent gene expression assay. Int J Legal Med 2018; 133:335-345. [PMID: 29959558 DOI: 10.1007/s00414-018-1888-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 06/22/2018] [Indexed: 12/13/2022]
Abstract
Diagnosis of fatal hypothermia is considered to be difficult in forensic practice and even if findings due to cold exposure are evident, cold exposure is not necessarily a direct cause of death. Identification of useful molecular markers for the diagnosis of fatal hypothermia has not been successful. In this study, to identify novel molecular markers that inform the diagnosis of fatal hypothermia, we focused on skeletal muscle, which plays a role in cold-induced thermogenesis in mammals. We made rat models of mild, moderate, and severe hypothermia and performed body temperature-dependent gene expression analysis in the iliopsoas muscle using next-generation sequencing (NGS). NGS showed that after severe hypothermia, the expression levels of 91 mRNAs were more than double those in mild and moderate hypothermia and control animals. Gene ontology (GO) analysis indicated that these mRNAs are involved in a number of biological processes, including response to stress and lipids, and cellular response to hypoxia. The expression of four genes [connective tissue growth factor (Ctgf), JunB proto-oncogene, AP-1 transcription factor subunit (Junb), nuclear receptor subfamily 4, group A, member 1 (Nr4a1), and Syndecan 4 (Sdc4)] and the level of one protein (CTGF) were induced only by severe hypothermia. These genes and protein are involved in muscle regeneration, tissue repair, and lipid metabolism. These results indicate that heat production to maintain body temperature in a process leading to fatal hypothermia might be performed by the iliopsoas muscle, and that Ctgf, Junb, Nr4a1, and Sdc4 genes are potential diagnostic markers for fatal hypothermia.
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Affiliation(s)
- Takahiro Umehara
- Division of Forensic Pathology and Science, Unit of Social Medicine, Course of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan.
| | - Takehiko Murase
- Division of Forensic Pathology and Science, Unit of Social Medicine, Course of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan
| | - Yuki Abe
- Division of Forensic Pathology and Science, Unit of Social Medicine, Course of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan
| | - Hiromi Yamashita
- Center for Forensic Pathology and Science, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan
| | - Yoshinori Shibaike
- Division of Forensic Pathology and Science, Unit of Social Medicine, Course of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan
| | - Shinichiro Kagawa
- Division of Forensic Pathology and Science, Unit of Social Medicine, Course of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan
| | - Takuma Yamamoto
- Division of Forensic Pathology and Science, Unit of Social Medicine, Course of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan
| | - Kazuya Ikematsu
- Division of Forensic Pathology and Science, Unit of Social Medicine, Course of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan
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The in vitro effects of CCN2 on odontoblast-like cells. Arch Oral Biol 2018; 94:54-61. [PMID: 30168419 DOI: 10.1016/j.archoralbio.2018.06.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 05/30/2018] [Accepted: 06/18/2018] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To investigate the in vitro effects of CCN2 on odontoblast-like cells proliferation and differentiation. DESIGN MDPC-23 cells were cultured in DMEM supplemented with 5% FBS. CCN2 was either added to culture media or coated onto culture polystyrene, addition or coating of dH2O was served as control. In the addition group, CCN2 (100 ng/mL) was added into culture media. In the coating group, CCN2 at the concentration of 1000 ng/mL was employed. Cell proliferation was performed using CCK-8 assay. Cell differentiation and mineralization were analyzed by ALPase activity assay, real time RT-PCR and alizarin red staining. One-way ANOVA with post-hoc tukey HSD test was used for statistical analysis. RESULTS MDPC-23 cells exhibited robust proliferative activity upon exposure to either soluble or immobilized CCN2. ALP activity of cells cultured on CCN2-modified surface was continuously strengthened from day six (0.831 ± 0.024 units/μg protein versus 0.563 ± 0.006 units/μg protein of control) till day eight (1.035 ± 0.139 units/μg protein versus 0.704 ± 0.061 units/μg protein of control). Gene expression of BSP, OCN and OPN were promoted by soluble CCN2 after 48 h exposure. Moreover, gene expression of BSP, OCN, OPN, ALP, COL1 A1, Runx-2, DSPP and DMP-1 was significantly enhanced by immobilized CCN2. Finally, mineralization of MDPC-23 cells was accelerated by both soluble and immobilized CCN2 to different extent. CONCLUSIONS The findings indicate that CCN2 promoted proliferation, odontogenic gene expression and mineralization of MDPC-23 cells. It is proposed that CCN2 may be a promising adjunctive formula for dentin regeneration.
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Seleem AA, Sultan ARS, Said A, Shahat MM, Moustafa MA. Localization of connective tissue growth factor (CTGF) and transforming growth factor beta-2 (TGF-β2) during eye development of four species of birds. J Histotechnol 2018. [DOI: 10.1080/01478885.2018.1475861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Affiliation(s)
- Amin A. Seleem
- Biology Department, Faculty of Science and Arts, Taibah University, Allula, Kingdom of Saudi Arabia
- Zoology Department, Faculty of Science, Sohag University, Sohag, Egypt
| | | | - Ahmed Said
- Zoology Department, Faculty of Science, Al-Azhar University, Assiut, Egypt
| | - Mohamed M. Shahat
- Zoology Department, Faculty of Science, Al-Azhar University, Assiut, Egypt
| | - Mohsen A. Moustafa
- Zoology Department, Faculty of Science, Al-Azhar University, Assiut, Egypt
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Rayego-Mateos S, Morgado-Pascual JL, Rodrigues-Diez RR, Rodrigues-Diez R, Falke LL, Mezzano S, Ortiz A, Egido J, Goldschmeding R, Ruiz-Ortega M. Connective tissue growth factor induces renal fibrosis via epidermal growth factor receptor activation. J Pathol 2018; 244:227-241. [PMID: 29160908 DOI: 10.1002/path.5007] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 10/20/2017] [Accepted: 11/14/2017] [Indexed: 01/04/2023]
Abstract
Connective tissue growth factor (CCN2/CTGF) is a matricellular protein that is overexpressed in progressive human renal diseases, mainly in fibrotic areas. In vitro studies have demonstrated that CCN2 regulates the production of extracellular matrix (ECM) proteins and epithelial-mesenchymal transition (EMT), and could therefore contribute to renal fibrosis. CCN2 blockade ameliorates experimental renal damage, including diminution of ECM accumulation. We have reported that CCN2 and its C-terminal degradation product CCN2(IV) bind to epidermal growth factor receptor (EGFR) to modulate renal inflammation. However, the receptor involved in CCN2 profibrotic actions has not been described so far. Using a murine model of systemic administration of CCN2(IV), we have unveiled a fibrotic response in the kidney that was diminished by EGFR blockade. Additionally, in conditional CCN2 knockout mice, renal fibrosis elicited by folic acid-induced renal damage was prevented, and this was linked to inhibition of EGFR pathway activation. Our in vitro studies demonstrated a direct effect of CCN2 via the EGFR pathway on ECM production by fibroblasts and the induction of EMT in tubular epithelial cells. Our studies clearly show that the EGFR regulates CCN2 fibrotic signalling in the kidney, and suggest that EGFR pathway blockade could be a potential therapeutic option to block CCN2-mediated profibrotic effects in renal diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Sandra Rayego-Mateos
- Cellular Biology in Renal Diseases Laboratory. School of Medicine, Universidad Autónoma Madrid, Madrid, Spain
| | - José Luis Morgado-Pascual
- Cellular Biology in Renal Diseases Laboratory. School of Medicine, Universidad Autónoma Madrid, Madrid, Spain
| | | | - Raquel Rodrigues-Diez
- Cellular Biology in Renal Diseases Laboratory. School of Medicine, Universidad Autónoma Madrid, Madrid, Spain
| | - Lucas L Falke
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Sergio Mezzano
- Division of Nephrology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile
| | - Alberto Ortiz
- IIS-Fundación Jiménez Díaz-UAM, School of Medicine, UAM, Madrid, Spain
| | - Jesús Egido
- IIS-Fundación Jiménez Díaz-UAM, School of Medicine, UAM, Madrid, Spain.,Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Roel Goldschmeding
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marta Ruiz-Ortega
- Cellular Biology in Renal Diseases Laboratory. School of Medicine, Universidad Autónoma Madrid, Madrid, Spain
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CCN4/WISP1 controls cutaneous wound healing by modulating proliferation, migration and ECM expression in dermal fibroblasts via α5β1 and TNFα. Matrix Biol 2018; 68-69:533-546. [PMID: 29330021 DOI: 10.1016/j.matbio.2018.01.004] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 12/21/2017] [Accepted: 01/05/2018] [Indexed: 02/01/2023]
Abstract
Understanding the mechanisms that control cutaneous wound healing is crucial to successfully manage repair of damaged skin. The goal of the current study was to uncover novel extracellular matrix (ECM) components that control the wound healing process. Full thickness skin defects were created in mice and used to show CCN4 up-regulation during wound-healing as early as 1 day after surgery, suggesting a role in inflammation and subsequent dermal migration and proliferation. To determine how CCN4 could regulate wound healing we used Ccn4-KO mice and showed they had delayed wound closure accompanied by reduced expression of Col1a1 and Fn mRNA. Boyden chamber assays using Ccn4-deficient dermal fibroblasts showed they have reduced migration and proliferation compared to WT counterparts. To confirm CCN4 has a role in proliferation and migration of dermal cells, siRNA knockdown and transduction of CCN4 adenoviral transduction were used and resulted in reduced or enhanced migration of human adult dermal fibroblast (hADF) cells respectively. The induced migration of the dermal fibroblasts by CCN4 appears to work via α5β1 integrin receptors that further stimulates down-stream ERK/JNK signaling. The regulation of CCN4 by TNF-α prompted us look further at their potential relationship. Treatment of hADFs with CCN4 and TNF-α alone or together showed CCN4 counteracted the inhibition of TNF-α on COL1A1 and FN mRNA expression and the stimulation of TNF-α on MMP-1 and MMP3 mRNA expression. CCN4 appeared to counterbalance the effects of TNF-α by inhibiting downstream NF-κB/p-65 signaling. Taken together we show CCN4 stimulates dermal fibroblast cell migration, proliferation and inhibits TNF-α stimulation, all of which could regulate wound healing.
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The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells. Oncotarget 2018; 7:25180-93. [PMID: 26933820 PMCID: PMC5041896 DOI: 10.18632/oncotarget.7734] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 02/08/2016] [Indexed: 01/04/2023] Open
Abstract
Increasing evidence supports that the epithelial to mesenchymal transition (EMT) in breast cancer cells generates tumor initiating cells (TICs) but the contribution of the tumor microenvironment to these programs needs further elucidation. CCN6 (WISP3) is a secreted matrix-associated protein (36.9 kDa) of the CCN family (named after CTGF, Cyr61 and Nov) that is reduced or lost in invasive carcinomas of the breast with lymph node metastasis and in inflammatory breast cancer. CCN6 exerts breast cancer growth and invasion inhibitory functions, but the mechanisms remain to be defined. In the present study we discovered that ectopic CCN6 overexpression in triple negative (TN) breast cancer cells and in cells derived from patients is sufficient to induce a mesenchymal to epithelial transition (MET) and to reduce TICs. In vivo, CCN6 overexpression in the TIC population of MDA-MB-231 cells delayed tumor initiation, reduced tumor volume, and inhibited the development of metastasis. Our studies reveal a novel CCN6/Slug signaling axis that regulates Notch1 signaling activation, epithelial cell phenotype and breast TICs, which requires the conserved thrombospondin type 1 (TSP1) motif of CCN6. The relevance of these data to human breast cancer is highlighted by the finding that CCN6 protein levels are inversely correlated with Notch1 intracellular activated form (NICD1) in 69.5% of invasive breast carcinomas. These results demonstrate that CCN6 regulates epithelial and mesenchymal states transition and TIC programs, and pinpoint one responsible mechanism.
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Takigawa M. An early history of CCN2/CTGF research: the road to CCN2 via hcs24, ctgf, ecogenin, and regenerin. J Cell Commun Signal 2017; 12:253-264. [PMID: 29076115 DOI: 10.1007/s12079-017-0414-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 09/27/2017] [Indexed: 02/06/2023] Open
Abstract
The principal aim of this historical review is to present the processes by which the different aspects of CCN2/CTGF/Hcs24 were discovered by different groups and how much CCN2/CTGF, by being integrated into CCN family, has contributed to the establishment of the basic concepts regarding the role and functions of this new class of proteins. This review should be particularly useful to new investigators who have recently entered this exciting field of study and also provides a good opportunity to acknowledge the input of those individuals who participated in the development of this scientific field.
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Affiliation(s)
- Masaharu Takigawa
- Advanced Research Center for Oral and Craniofacial Sciences (ARCOCS), Okayama University Dental School/Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama, 700-8525, Japan.
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Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling. Cell Death Dis 2017; 8:e2885. [PMID: 28617438 PMCID: PMC5520906 DOI: 10.1038/cddis.2017.248] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 04/30/2017] [Accepted: 05/03/2017] [Indexed: 12/27/2022]
Abstract
Limited benefits and clinical utility of temozolomide (TMZ) for glioblastoma (GB) are frequently compromised by the development of acquired drug resistance. Overcoming TMZ resistance and uncovering the underlying mechanisms are challenges faced during GB chemotherapy. In this study, we reported that connective tissue growth factor (CTGF) was associated with GB chemoresistance and significantly upregulated in TMZ-treated GB cells. CTGF knockdown promoted TMZ-induced cell apoptosis and enhanced chemosensitivity, whereas its overexpression markedly conferred TMZ resistance in vitro and in vivo. Moreover, CTGF promoted TMZ resistance through stem-like properties acquisition and CD44 interference reversed the CTGF-induced TMZ resistance. Mechanistically, further investigation revealed that the TMZ-induced CTGF upregulation was tissue growth factor (TGF-β) dependent, and regulated by TGF-β1 activation through Smad and ERK1/2 signaling. Together, our results suggest a pivotal role of CTGF-mediated TMZ resistance through TGF-β1-dependent activation of Smad/ERK signaling pathways. These data provide us insights for identifying potential targets that are beneficial for overcoming TMZ resistance in GB.
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Ferrand N, Béreziat V, Moldes M, Zaoui M, Larsen AK, Sabbah M. WISP1/CCN4 inhibits adipocyte differentiation through repression of PPARγ activity. Sci Rep 2017; 7:1749. [PMID: 28496206 PMCID: PMC5431985 DOI: 10.1038/s41598-017-01866-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 04/04/2017] [Indexed: 01/18/2023] Open
Abstract
WISP1 (Wnt1-inducible signaling pathway protein-1, also known as CCN4) is a member of the CCN family able to mediate cell growth, transformation and survival in a tissue-specific manner. Here, we report that WISP1 expression was highly increased in preadipocytes and decreased during adipocyte differentiation. Moreover, we observed an increase in WISP1 gene expression in adipose tissue from both diet-induced and leptin-deficient ob/ob obese mice, suggesting that WISP1 could be involved in the pathophysiological onset of obesity. Interestingly, overexpression of WISP1 in 3T3-F442A cells prevented adipocyte differentiation via downregulation of peroxisome proliferator-activated receptor (PPARγ) transcriptional activity thereby attenuating the expression of adipogenic markers. Conversely, silencing of WISP1 enhanced adipocyte differentiation. We further show that the inactivation of PPARγ transcriptional activity was mediated, at least in part, by a direct physical association between WISP1 and PPARγ, followed by proteasome-dependent degradation of PPARγ. These results suggest for the first time that WISP1 interacts with PPARγ and that this interaction results in the inhibition of PPARγ activity. Taken together our results suggest that WISP1 functions as a negative regulator of adipogenesis.
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Affiliation(s)
- Nathalie Ferrand
- Sorbonne Universités, Cancer Biology and Therapeutics, UPMC Univ Paris 06, INSERM, CNRS, Institut Universitaire de Cancérologie, Saint-Antoine Research Center (CRSA), F-75012, Paris, France
| | - Véronique Béreziat
- Sorbonne Universités, Genetic and Acquired Lipodystrophies, UPMC Univ Paris 06, INSERM, Hospitalo-Universitary Institute, ICAN, Saint-Antoine Research Center (CRSA), F-75012, Paris, France
| | - Marthe Moldes
- Sorbonne Universités, Genetic and Acquired Lipodystrophies, UPMC Univ Paris 06, INSERM, Hospitalo-Universitary Institute, ICAN, Saint-Antoine Research Center (CRSA), F-75012, Paris, France
| | - Maurice Zaoui
- Sorbonne Universités, Cancer Biology and Therapeutics, UPMC Univ Paris 06, INSERM, CNRS, Institut Universitaire de Cancérologie, Saint-Antoine Research Center (CRSA), F-75012, Paris, France
| | - Annette K Larsen
- Sorbonne Universités, Cancer Biology and Therapeutics, UPMC Univ Paris 06, INSERM, CNRS, Institut Universitaire de Cancérologie, Saint-Antoine Research Center (CRSA), F-75012, Paris, France
| | - Michèle Sabbah
- Sorbonne Universités, Cancer Biology and Therapeutics, UPMC Univ Paris 06, INSERM, CNRS, Institut Universitaire de Cancérologie, Saint-Antoine Research Center (CRSA), F-75012, Paris, France.
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Liu JL, Kaddour N, Chowdhury S, Li Q, Gao ZH. Role of CCN5 (WNT1 inducible signaling pathway protein 2) in pancreatic islets. J Diabetes 2017; 9:462-474. [PMID: 27863006 DOI: 10.1111/1753-0407.12507] [Citation(s) in RCA: 9] [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: 11/02/2016] [Accepted: 11/07/2016] [Indexed: 12/15/2022] Open
Abstract
In search of direct targets of insulin-like growth factor (IGF)-1 action, we discovered CCN5 (WNT1 inducible signaling pathway protein 2 [WISP2]) as a novel protein expressed in pancreatic β-cells. As a member of the "CCN" ( C ysteine-rich angiogenic inducer 61 [Cyr61], C onnective tissue growth factor [CTGF in humans], and N ephroblastoma overexpressed [Nov; in chickens]) family, the expression of CCN5/WISP2 is stimulated by IGF-1 together with Wnt signaling. When overexpressed in insulinoma cells, CCN5 promotes cell proliferation and cell survival against streptozotocin-induced cell death. The cell proliferation effect seems to be caused by AKT phosphorylation and increased cyclin D1 levels. These properties resemble those of CCN2/CTGF, another isoform of the CCN family, although CCN5 is the only one within the family of six proteins that lacks the C-terminal repeat. Treatment of primary mouse islets with recombinant CCN5 protein produced similar effects to those of gene transfection, indicating that either as a matricellular protein or a secreted growth factor, CCN5 stimulates β-cell proliferation and regeneration in a paracrine fashion. This review also discusses the regulation of CCN5/WISP2 by estrogen and its involvement in angiogenesis and tumorigenesis.
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Affiliation(s)
- Jun-Li Liu
- Fraser Laboratories, Department of Medicine, The Research Institute of McGill University Health Centre, Montreal, Canada
| | - Nancy Kaddour
- Fraser Laboratories, Department of Medicine, The Research Institute of McGill University Health Centre, Montreal, Canada
| | - Subrata Chowdhury
- Fraser Laboratories, Department of Medicine, The Research Institute of McGill University Health Centre, Montreal, Canada
| | - Qing Li
- Fraser Laboratories, Department of Medicine, The Research Institute of McGill University Health Centre, Montreal, Canada
| | - Zu-Hua Gao
- Department of Pathology, The Research Institute of McGill University Health Centre, Montreal, Canada
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Wu YL, Li HY, Zhao XP, Jiao JY, Tang DX, Yan LJ, Wan Q, Pan CB. Mesenchymal stem cell-derived CCN2 promotes the proliferation, migration and invasion of human tongue squamous cell carcinoma cells. Cancer Sci 2017; 108:897-909. [PMID: 28208216 PMCID: PMC5448615 DOI: 10.1111/cas.13202] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 02/03/2017] [Accepted: 02/12/2017] [Indexed: 01/08/2023] Open
Abstract
Recent studies have demonstrated that mesenchymal stem cells (MSC) exhibit a tropism to tumors and form the tumor stroma. In addition, we found that MSC can secrete different types of factors. However, the involvement of MSC‐derived factors in human tongue squamous cell carcinoma (TSCC) growth has not been clearly addressed. The CCN family includes multifunctional signaling molecules that affect the initiation and development events of various tumors. In our study, we report that CCN2/connective tissue growth factor (CTGF) was the most highly induced among the CCN family members in MSC that were co‐cultured with TSCC cells. To evaluate the relationship between CCN2 and TSCC growth, we downregulated MSC‐derived CCN2 expression with shRNA targeting CCN2 and found that MSC‐secreted CCN2 promotes TSCC cell proliferation, migration and invasion. We also confirmed that MSC‐derived CCN2 partially accelerated tumor growth in vitro. Taken together, these results suggest that MSC‐derived CCN2 contributes to the promotion of proliferation, migration and invasion of TSCC cells and may be a possible therapy target in the future.
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Affiliation(s)
- Yu-Ling Wu
- Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Hong-Yu Li
- Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, China.,Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xiao-Peng Zhao
- Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Jiu-Yang Jiao
- Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Dong-Xiao Tang
- Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Ling-Jian Yan
- Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Quan Wan
- Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Chao-Bin Pan
- Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, China
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Purohit T, Qin Z, Quan C, Lin Z, Quan T. Smad3-dependent CCN2 mediates fibronectin expression in human skin dermal fibroblasts. PLoS One 2017; 12:e0173191. [PMID: 28267785 PMCID: PMC5340390 DOI: 10.1371/journal.pone.0173191] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 02/16/2017] [Indexed: 01/12/2023] Open
Abstract
The potential involvement of connective tissue growth factor (CCN2/CTGF) in extracellular matrix (ECM) production is recognized. However, the role CCN2 in fibronectin (FN) gene expression has remained incompletely understood and even controversial. Here we report that CCN2 is absolutely necessary for FN expression in primary human skin dermal fibroblasts, the major cells responsible for ECM production in skin. Gain- and loss-of-function approaches demonstrate that CCN2 is an essential component of FN expression in both basal and stimulation by TGF-β signaling, the major regulator of FN expression. CCN2 is significantly induced by Smad3, a critical mediator of TGF-β signaling. CCN2 acts as a downstream mediator of TGF-β/Smad signaling and acting synergistically with TGF-β to regulate FN gene expression. Finally, we observed that CCN2 and FN predominantly expressed in the dermis of normal human skin, stromal tissues of skin squamous cell carcinoma (SCC), and simultaneously induced in wounded human skin in vivo. These findings provide evidence that CCN2 is responsible for mediating the stimulatory effects of TGF-β/Smad on FN gene expression, and attenuation of CCN2 expression may benefit to reduce fibrotic ECM microenvironment in disease skin.
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Affiliation(s)
- Trupta Purohit
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Zhaoping Qin
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Chunji Quan
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji, China
| | - Zhenhua Lin
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji, China
| | - Taihao Quan
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
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