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Winkelmann A, Wendler O, Schuster J, Agaimy A, Haderlein M, Frey B, Mueller SK. Early Detection and Longitudinal Follow-Up of Non-Invasive Biomarkers for Laryngeal Squamous Cell Carcinoma: First Results of the BEAL-Study. Cancer Med 2025; 14:e70961. [PMID: 40365873 PMCID: PMC12076192 DOI: 10.1002/cam4.70961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 03/26/2025] [Accepted: 04/30/2025] [Indexed: 05/15/2025] Open
Abstract
INTRODUCTION Despite therapeutic and prognostic improvements in the early treatment of laryngeal squamous cell carcinoma (LSCC), screening for early detection of laryngeal cancer has not yet been established. METHODS A study has been designed to address this issue based on an analysis of exosomal serum biomarkers for LSCC. A three-step approach was used. Firstly, the serum biomarkers Nov and uPAR were validated in control and LSCC patients using a standardized enzyme-linked immunosorbent assay (ELISA). Subsequently, an immunohistochemical comparison was conducted. Secondly, the ELISA results were compared with patients with benign laryngeal lesions. Thirdly, a prospective study compared preoperative and postoperative values. The study is ongoing. RESULTS In the initial comparison of the control group with tumor patients at the time of diagnosis, Nov and uPAR demonstrated significant overexpression in LSCC patients' serum. In Step 2, the comparison with the cohort of benign laryngeal lesions revealed that both biomarkers were also significantly overexpressed here. Nevertheless, uPAR effectively differentiated between control, benign, and malignant lesions. In the third step, the observations in the postoperative course demonstrated that the serum concentrations of Nov and uPAR were elevated in both groups with laryngeal diseases but declined faster in patients with benign lesions. CONCLUSION uPAR and Nov may serve as valuable biomarkers for early detection and disease monitoring. Further investigation is required to ascertain their suitability, including an extended follow-up period and a larger study population. For this reason, this study is still ongoing, and only initial results are presented here. This study's objective is to examine the potential of Nov and uPAR as serum biomarkers for early detection and follow-up of LSCC. We compare them in a control group, tumor group, and first-time benign laryngeal diseases and monitor a long-term follow-up. This aims to deepen understanding of suitability for early detection and follow-up and provide future research insights. TRIAL REGISTRATION DRKS00033427.
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Affiliation(s)
- Ann‐Christin Winkelmann
- Department of Otolaryngology, Head and Neck SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität Erlangen‐NürnbergErlangenGermany
| | - Olaf Wendler
- Department of Otolaryngology, Head and Neck SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität Erlangen‐NürnbergErlangenGermany
| | - Johannes Schuster
- Department of Otolaryngology, Head and Neck SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität Erlangen‐NürnbergErlangenGermany
| | - Abbas Agaimy
- Department of PathologyUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität Erlangen‐NürnbergErlangenGermany
| | - Marlen Haderlein
- Department of Radiation OncologyUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität Erlangen‐NürnbergErlangenGermany
| | - Benjamin Frey
- Department of Radiation OncologyUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität Erlangen‐NürnbergErlangenGermany
| | - Sarina Katrin Mueller
- Department of Otolaryngology, Head and Neck SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität Erlangen‐NürnbergErlangenGermany
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Hu J, Weber JN, Fuess LE, Steinel NC, Bolnick DI, Wang M. A spectral framework to map QTLs affecting joint differential networks of gene co-expression. PLoS Comput Biol 2025; 21:e1012953. [PMID: 40245036 PMCID: PMC12040279 DOI: 10.1371/journal.pcbi.1012953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 04/29/2025] [Accepted: 03/11/2025] [Indexed: 04/19/2025] Open
Abstract
Studying the mechanisms underlying the genotype-phenotype association is crucial in genetics. Gene expression studies have deepened our understanding of the genotype → expression → phenotype mechanisms. However, traditional expression quantitative trait loci (eQTL) methods often overlook the critical role of gene co-expression networks in translating genotype into phenotype. This gap highlights the need for more powerful statistical methods to analyze genotype → network → phenotype mechanism. Here, we develop a network-based method, called spectral network quantitative trait loci analysis (snQTL), to map quantitative trait loci affecting gene co-expression networks. Our approach tests the association between genotypes and joint differential networks of gene co-expression via a tensor-based spectral statistics, thereby overcoming the ubiquitous multiple testing challenges in existing methods. We demonstrate the effectiveness of snQTL in the analysis of three-spined stickleback (Gasterosteus aculeatus) data. Compared to conventional methods, our method snQTL uncovers chromosomal regions affecting gene co-expression networks, including one strong candidate gene that would have been missed by traditional eQTL analyses. Our framework suggests the limitation of current approaches and offers a powerful network-based tool for functional loci discoveries.
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Affiliation(s)
- Jiaxin Hu
- Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Jesse N. Weber
- Department of Integrative Biology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Lauren E. Fuess
- Department of Biology, Texas State University, San Marcos, Texas, United States of America
| | - Natalie C. Steinel
- Department of Biological Sciences, University of Massachusetts Lowell, Lowell, Massachusetts, United States of America
| | - Daniel I. Bolnick
- Department of Ecology and Evolutionary Biology, University of Connecticut, Storrs, Connecticut, United States of America
| | - Miaoyan Wang
- Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Fan Y, Gao L, Huang Y, Zhao L, Zhao Y, Wang X, Mo D, Lu H, Wang D. Effects and Significance of Dicliptera chinensis Polysaccharide on the Expression of Transforming Growth Factor β1/Connective Tissue Growth Factor Pathway in the Masseter and Head and Neck Skin of Rats With Radiation-Induced Fibrosis. Int Dent J 2025; 75:784-796. [PMID: 38991877 PMCID: PMC11976479 DOI: 10.1016/j.identj.2024.06.011] [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: 04/12/2024] [Revised: 05/26/2024] [Accepted: 06/13/2024] [Indexed: 07/13/2024] Open
Abstract
PURPOSE To investigate whether Dicliptera chinensis polysaccharide (DCP) can alleviate radiation-induced fibrosis of masseter and head and neck skin. METHODS SD rats were divided into the control, the irradiation (IR), the IR + low dose DCP (200 mg/kg), and the IR + high dose DCP (400 mg/kg) groups. The head and neck of rats in the last 3 groups received a single dose of 18 Gy X-ray. At 1st, 2nd, 4th week (w) after radiation, haematoxylin and eosin staining were performed on masseter and skin to observe the histopathological changes; immunohistochemistry staining was performed to observe the pathological changes of the skin; Masson staining was performed on masseter and skin to observe the collagen deposition; western blot analysis was used on masseter to calculate the relative transforming growth factor β1 (TGF-β1), connective tissue growth factor (CTGF) expressions; ELISA was used to detect the contents of TGF-β1 and CTGF in skin and the contents of type I and type III collagens in masseter and skin. RESULTS In terms of skin, compared to the IR group, the IR + high-dose DCP group exhibited relatively smaller changes in skin structure, lower levels of TGF-β1 and CTGF; thinner skin thickness was observed at the 4th w after radiation; and the positive rates of collagen fibre and the optical densities of type I and type III collagens were lower at the 2nd and 4th w. For the masseter, compared to the IR group, the morphological changes were improved and the expression levels of TGF-β1 and CTGF proteins decreased in the 2 DCP dose groups at 2nd and 4th w. CONCLUSION DCP can reduce the formation and accumulation of type I and type III collagens after IR and ameliorate radiation-induced fibrosis of masseter and skin by down-regulating the expressions of TGF-β1 and CTGF.
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Affiliation(s)
- Yiyang Fan
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research, Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Deformity, Nanning, China; Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China
| | - Linjing Gao
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Yude Huang
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research, Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Deformity, Nanning, China
| | - Lixiang Zhao
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research, Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Deformity, Nanning, China
| | - Yanfei Zhao
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research, Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Deformity, Nanning, China
| | - Xian Wang
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research, Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Deformity, Nanning, China
| | - Dongqin Mo
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research, Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Deformity, Nanning, China
| | - Haoyu Lu
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research, Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Deformity, Nanning, China
| | - Daiyou Wang
- College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research, Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Deformity, Nanning, China.
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Hu J, Weber JN, Fuess LE, Steinel NC, Bolnick DI, Wang M. A spectral framework to map QTLs affecting joint differential networks of gene co-expression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.29.587398. [PMID: 38585912 PMCID: PMC10996691 DOI: 10.1101/2024.03.29.587398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Studying the mechanisms underlying the genotype-phenotype association is crucial in genetics. Gene expression studies have deepened our understanding of the genotype → expression → phenotype mechanisms. However, traditional expression quantitative trait loci (eQTL) methods often overlook the critical role of gene co-expression networks in translating genotype into phenotype. This gap highlights the need for more powerful statistical methods to analyze genotype → network → phenotype mechanism. Here, we develop a network-based method, called snQTL, to map quantitative trait loci affecting gene co-expression networks. Our approach tests the association between genotypes and joint differential networks of gene co-expression via a tensor-based spectral statistics, thereby overcoming the ubiquitous multiple testing challenges in existing methods. We demonstrate the effectiveness of snQTL in the analysis of three-spined stickleback (Gasterosteus aculeatus) data. Compared to conventional methods, our method snQTL uncovers chromosomal regions affecting gene co-expression networks, including one strong candidate gene that would have been missed by traditional eQTL analyses. Our framework suggests the limitation of current approaches and offers a powerful network-based tool for functional loci discoveries.
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Affiliation(s)
- Jiaxin Hu
- Department of Statistics, University of Wisconsin-Madison
| | - Jesse N. Weber
- Department of Integrative Biology, University of Wisconsin-Madison
| | | | | | - Daniel I. Bolnick
- Department of Ecology and Evolutionary Biology, University of Connecticut
| | - Miaoyan Wang
- Department of Statistics, University of Wisconsin-Madison
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Gogoi RP, Galoforo S, Fox A, Morris C, Ramos H, Gogoi VK, Chehade H, Adzibolosu NK, Shi C, Zhang J, Tedja R, Morris R, Alvero AB, Mor G. A Novel Role of Connective Tissue Growth Factor in the Regulation of the Epithelial Phenotype. Cancers (Basel) 2023; 15:4834. [PMID: 37835529 PMCID: PMC10571845 DOI: 10.3390/cancers15194834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/21/2023] [Accepted: 09/21/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) is a biological process where epithelial cells lose their adhesive properties and gain invasive, metastatic, and mesenchymal properties. Maintaining the balance between the epithelial and mesenchymal stage is essential for tissue homeostasis. Many of the genes promoting mesenchymal transformation have been identified; however, our understanding of the genes responsible for maintaining the epithelial phenotype is limited. Our objective was to identify the genes responsible for maintaining the epithelial phenotype and inhibiting EMT. METHODS RNA seq was performed using an vitro model of EMT. CTGF expression was determined via qPCR and Western blot analysis. The knockout of CTGF was completed using the CTGF sgRNA CRISPR/CAS9. The tumorigenic potential was determined using NCG mice. RESULTS The knockout of CTGF in epithelial ovarian cancer cells leads to the acquisition of functional characteristics associated with the mesenchymal phenotype such as anoikis resistance, cytoskeleton remodeling, increased cell stiffness, and the acquisition of invasion and tumorigenic capacity. CONCLUSIONS We identified CTGF is an important regulator of the epithelial phenotype, and its loss is associated with the early cellular modifications required for EMT. We describe a novel role for CTGF, regulating cytoskeleton and the extracellular matrix interactions necessary for the conservation of epithelial structure and function. These findings provide a new window into understanding the early stages of mesenchymal transformation.
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Affiliation(s)
- Radhika P. Gogoi
- Karmanos Cancer Institute, Wayne State University, 4100 John R St, Detroit, MI 48202, USA;
| | - Sandra Galoforo
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (S.G.); (A.F.); (C.M.); (H.R.); (V.K.G.); (H.C.); (N.K.A.); (R.T.); (A.B.A.)
| | - Alexandra Fox
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (S.G.); (A.F.); (C.M.); (H.R.); (V.K.G.); (H.C.); (N.K.A.); (R.T.); (A.B.A.)
| | - Colton Morris
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (S.G.); (A.F.); (C.M.); (H.R.); (V.K.G.); (H.C.); (N.K.A.); (R.T.); (A.B.A.)
| | - Harry Ramos
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (S.G.); (A.F.); (C.M.); (H.R.); (V.K.G.); (H.C.); (N.K.A.); (R.T.); (A.B.A.)
| | - Vir K. Gogoi
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (S.G.); (A.F.); (C.M.); (H.R.); (V.K.G.); (H.C.); (N.K.A.); (R.T.); (A.B.A.)
| | - Hussein Chehade
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (S.G.); (A.F.); (C.M.); (H.R.); (V.K.G.); (H.C.); (N.K.A.); (R.T.); (A.B.A.)
| | - Nicholas K. Adzibolosu
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (S.G.); (A.F.); (C.M.); (H.R.); (V.K.G.); (H.C.); (N.K.A.); (R.T.); (A.B.A.)
| | - Chenjun Shi
- Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, USA; (C.S.); (J.Z.)
| | - Jitao Zhang
- Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, USA; (C.S.); (J.Z.)
| | - Roslyn Tedja
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (S.G.); (A.F.); (C.M.); (H.R.); (V.K.G.); (H.C.); (N.K.A.); (R.T.); (A.B.A.)
| | - Robert Morris
- Karmanos Cancer Institute, Wayne State University, 4100 John R St, Detroit, MI 48202, USA;
| | - Ayesha B. Alvero
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (S.G.); (A.F.); (C.M.); (H.R.); (V.K.G.); (H.C.); (N.K.A.); (R.T.); (A.B.A.)
| | - Gil Mor
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (S.G.); (A.F.); (C.M.); (H.R.); (V.K.G.); (H.C.); (N.K.A.); (R.T.); (A.B.A.)
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Luis TC, Barkas N, Carrelha J, Giustacchini A, Mazzi S, Norfo R, Wu B, Aliouat A, Guerrero JA, Rodriguez-Meira A, Bouriez-Jones T, Macaulay IC, Jasztal M, Zhu G, Ni H, Robson MJ, Blakely RD, Mead AJ, Nerlov C, Ghevaert C, Jacobsen SEW. Perivascular niche cells sense thrombocytopenia and activate hematopoietic stem cells in an IL-1 dependent manner. Nat Commun 2023; 14:6062. [PMID: 37770432 PMCID: PMC10539537 DOI: 10.1038/s41467-023-41691-y] [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] [Received: 03/31/2022] [Accepted: 09/11/2023] [Indexed: 09/30/2023] Open
Abstract
Hematopoietic stem cells (HSCs) residing in specialized niches in the bone marrow are responsible for the balanced output of multiple short-lived blood cell lineages in steady-state and in response to different challenges. However, feedback mechanisms by which HSCs, through their niches, sense acute losses of specific blood cell lineages remain to be established. While all HSCs replenish platelets, previous studies have shown that a large fraction of HSCs are molecularly primed for the megakaryocyte-platelet lineage and are rapidly recruited into proliferation upon platelet depletion. Platelets normally turnover in an activation-dependent manner, herein mimicked by antibodies inducing platelet activation and depletion. Antibody-mediated platelet activation upregulates expression of Interleukin-1 (IL-1) in platelets, and in bone marrow extracellular fluid in vivo. Genetic experiments demonstrate that rather than IL-1 directly activating HSCs, activation of bone marrow Lepr+ perivascular niche cells expressing IL-1 receptor is critical for the optimal activation of quiescent HSCs upon platelet activation and depletion. These findings identify a feedback mechanism by which activation-induced depletion of a mature blood cell lineage leads to a niche-dependent activation of HSCs to reinstate its homeostasis.
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Affiliation(s)
- Tiago C Luis
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK.
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK.
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, W12 0NN, London, UK.
- Department of Life Sciences, Imperial College London, SW7 2AZ, London, UK.
| | - Nikolaos Barkas
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
| | - Joana Carrelha
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
| | - Alice Giustacchini
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
- Human Technopole, Viale Rita Levi-Montalcini 1, 20157, Milan, Italy
| | - Stefania Mazzi
- Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, SE-141 86, Stockholm, Sweden
| | - Ruggiero Norfo
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
| | - Bishan Wu
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
| | - Affaf Aliouat
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
| | - Jose A Guerrero
- Department of Haematology, University of Cambridge, Cambridge, UK
- National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK
| | - Alba Rodriguez-Meira
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
| | - Tiphaine Bouriez-Jones
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
| | - Iain C Macaulay
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
- Earlham Institute, Norwich Research Park, NR4 7UZ, Norwich, UK
| | - Maria Jasztal
- Department of Haematology, University of Cambridge, Cambridge, UK
- National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK
| | - Guangheng Zhu
- Toronto Platelet Immunobiology Group and Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada
- CCOA Therapeutics Inc, Toronto, ON, M5B 1T8, Canada
| | - Heyu Ni
- Toronto Platelet Immunobiology Group and Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada
- CCOA Therapeutics Inc, Toronto, ON, M5B 1T8, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A1, Canada
- Canadian Blood Services Centre for Innovation, Toronto, ON, M5B 1W8, Canada
| | - Matthew J Robson
- Department of Biomedical Science, Charles E. Schmidt College of Medicine and Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter, FL, 33458, USA
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA
| | - Randy D Blakely
- Department of Biomedical Science, Charles E. Schmidt College of Medicine and Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter, FL, 33458, USA
| | - Adam J Mead
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
| | - Claus Nerlov
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK
| | - Cedric Ghevaert
- Department of Haematology, University of Cambridge, Cambridge, UK
- National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK
| | - Sten Eirik W Jacobsen
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK.
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS, Oxford, UK.
- Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, SE-141 86, Stockholm, Sweden.
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
- Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
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7
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Cazzola A, Calzón Lozano D, Menne DH, Dávila Pedrera R, Liu J, Peña-Jiménez D, Fontenete S, Halin C, Perez-Moreno M. Lymph Vessels Associate with Cancer Stem Cells from Initiation to Malignant Stages of Squamous Cell Carcinoma. Int J Mol Sci 2023; 24:13615. [PMID: 37686421 PMCID: PMC10488284 DOI: 10.3390/ijms241713615] [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] [Received: 08/08/2023] [Revised: 08/28/2023] [Accepted: 09/01/2023] [Indexed: 09/10/2023] Open
Abstract
Tumor-associated lymph vessels and lymph node involvement are critical staging criteria in several cancers. In skin squamous cell carcinoma, lymph vessels play a role in cancer development and metastatic spread. However, their relationship with the cancer stem cell niche at early tumor stages remains unclear. To address this gap, we studied the lymph vessel localization at the cancer stem cell niche and observed an association from benign skin lesions to malignant stages of skin squamous cell carcinoma. By co-culturing lymphatic endothelial cells with cancer cell lines representing the initiation and promotion stages, and conducting RNA profiling, we observed a reciprocal induction of cell adhesion, immunity regulation, and vessel remodeling genes, suggesting dynamic interactions between lymphatic and cancer cells. Additionally, imaging analyses of the cultured cells revealed the establishment of heterotypic contacts between cancer cells and lymph endothelial cells, potentially contributing to the observed distribution and maintenance at the cancer stem cell niche, inducing downstream cellular responses. Our data provide evidence for an association of lymph vessels from the early stages of skin squamous cell carcinoma development, opening new avenues for better comprehending their involvement in cancer progression.
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Affiliation(s)
- Anna Cazzola
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - David Calzón Lozano
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Dennis Hirsch Menne
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Raquel Dávila Pedrera
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Jingcheng Liu
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Daniel Peña-Jiménez
- Unidad de Investigación Biomédica, Universidad Alfonso X el Sabio (UAX), Avenida de la Universidad 1, Villanueva de la Cañada, 28691 Madrid, Spain
| | - Silvia Fontenete
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Cornelia Halin
- Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland;
| | - Mirna Perez-Moreno
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
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8
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Mekala S, Dugam P, Das A. Ephrin-Eph receptor tyrosine kinases for potential therapeutics against hepatic pathologies. J Cell Commun Signal 2023; 17:549-561. [PMID: 37103689 PMCID: PMC10409970 DOI: 10.1007/s12079-023-00750-1] [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: 11/14/2022] [Accepted: 04/14/2023] [Indexed: 04/28/2023] Open
Abstract
Hepatic fibrosis is the common pathological change that occurs due to increased synthesis and accumulation of extracellular matrix components. Chronic insult from hepatotoxicants leads to liver cirrhosis, which if not reversed timely using appropriate therapeutics, liver transplantation remains the only effective therapy. Often the disease further progresses into hepatic carcinoma. Although there is an increased advancement in understanding the pathological phenotypes of the disease, additional knowledge of the novel molecular signaling mechanisms involved in the disease progression would enable the development of efficacious therapeutics. Ephrin-Eph molecules belong to the largest family of receptor tyrosine kinases (RTKs) which are identified to play a crucial role in cellular migratory functions, during morphological and developmental stages. Additionally, they contribute to the growth of a multicellular organism as well as in pathological conditions like cancer, and diabetes. A wide spectrum of mechanistic studies has been performed on ephrin-Eph RTKs in various hepatic tissues under both normal and diseased conditions revealing their diverse roles in hepatic pathology. This systematic review summarizes the liver-specific ephrin-Eph RTK signaling mechanisms and recognizes them as druggable targets for mitigating hepatic pathology.
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Affiliation(s)
- Sowmya Mekala
- Department of Applied Biology, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad, TS, 500 007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP, 201 002, India
| | - Prachi Dugam
- Department of Applied Biology, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad, TS, 500 007, India
| | - Amitava Das
- Department of Applied Biology, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad, TS, 500 007, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP, 201 002, India.
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9
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Nam MW, Lee HK, Kim CW, Choi Y, Ahn D, Go RE, Choi KC. Effects of CCN6 overexpression on the cell motility and activation of p38/bone morphogenetic protein signaling pathways in pancreatic cancer cells. Biomed Pharmacother 2023; 163:114780. [PMID: 37105075 DOI: 10.1016/j.biopha.2023.114780] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/17/2023] [Accepted: 04/23/2023] [Indexed: 04/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancer types that is highly resistant to conventional treatments, such as chemotherapy and radiotherapy. As the demand for more effective therapeutics for PDAC treatment increases, various approaches have been studied to develop novel targets. The cellular communication network (CCN) family is a matricellular protein that modulates various cellular functions, including cell adhesion, proliferation, migration, and invasiveness. Despite this, little is known about the role of CCN6 in PDAC. The current study investigated the role of CCN6 in PDAC by generating CCN6-overexpressing PANC-1 cells (PANC-1-CCN6) by infecting lentivirus particles containing CCN6. PANC-1-CCN6 induces cell viability and tumorigenesis than PANC-1 cells with empty vector (control). The PANC-1-CCN6 formed more colonies, and the size of spheroids increased compared to the control. The upregulation of CCN6 enhances the expression of bone morphogenetic proteins (BMPs) genes and the upregulation of p38 mitogen-activated protein kinases (MAPKs). In PANC-1-CCN6 cells, the levels of N-cadherin, VEGF, and Snail expression were higher than the control, while E-cadherin expression was lower, which is associated with upregulation of epithelial-to-mesenchymal transition (EMT). Consistent with the changes in EMT-related proteins in PANC-1-CCN6, the migratory ability and invasiveness were enhanced in PANC-1-CCN6. Xenografted PANC-1-CCN6 in immunocompromised mice exhibited accelerated tumor growth than the control group. In immunohistochemistry (IHC), the PANC-1-CCN6 xenografted tumor showed an increased positive area of PCNA and Ki-67 than the control. These results suggest that CCN6 plays a tumorigenic role and induces the metastatic potential by the p38 MAPK and BMPs signaling pathways. Although the role of CCN6 has been introduced as an antitumor factor, there was evidence of CCN6 acting to cause tumorigenesis and invasion in PANC-1.
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Affiliation(s)
- Min-Woo Nam
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, the Republic of Korea
| | - Hong Kyu Lee
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, the Republic of Korea
| | - Cho-Won Kim
- Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
| | - Youngdong Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, the Republic of Korea
| | - Dohee Ahn
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, the Republic of Korea
| | - Ryeo-Eun Go
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, the Republic of Korea
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, the Republic of Korea.
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10
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Hu Y, Zhang R, Lu S, Zhang W, Wang D, Ge Y, Jiang F, Qin X, Liu Y. S100 Calcium Binding Protein A16 Promotes Cell Proliferation by triggering LATS1 ubiquitin degradation mediated by CUL4A ligase to inhibit Hippo pathway in Glioma development. Int J Biol Sci 2023; 19:2034-2052. [PMID: 37151881 PMCID: PMC10158029 DOI: 10.7150/ijbs.79924] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 03/08/2023] [Indexed: 05/09/2023] Open
Abstract
Background: S100 Calcium Binding Protein A16 (S100A16), a novel member of S100 protein family, is linked to tumorigenic processes and abundantly expressed in CNS tissues. Our study aimed to explore the biological function and possible mechanism of S100A16 in the progression of glioma. Methods: Sequence data of S100A16 and survival prognosis of glioma patients were initially analyzed using public databases. Glioma tissues were collected to examine S100A16 expression levels. Glioma cell lines and nude mice were subjected to in vitro and in vivo functional experiments. Western blot, immunofluorescence (IF), immunoprecipitation (IP) and ubiquitination assays were done to further elucidate the underlying mechanism. Results: This study firstly revealed that S100A16 was markedly up-regulated in glioma, and patients with higher S100A16 levels have a shorter survival time. S100A16 overexpression promoted the proliferation, invasion and migration of glioma cells, and the tumor formation of nude mice. Importantly, we identified S100A16 as a negative regulator of the Hippo pathway which could decrease LATS1 expression levels, promote the YAP nuclear import and initiate the downstream target genes CYR61 and CTGF. Moreover, our data showed that S100A16 destabilized LATS1 protein by inducing the CUL4A-mediated LATS1 ubiquitination degradation. Conclusions: This study demonstrated a vital biological role of S100A16 in glioma progression mechanism by promoting CUL4A-mediated LATS1 ubiquitination to inhibit Hippo signaling pathway. S100A16 could be a novel biomarker and treatment option for glioma patients.
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Affiliation(s)
- Yifang Hu
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rihua Zhang
- Department of Core Facility Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shan Lu
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wensong Zhang
- Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dan Wang
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yaoqi Ge
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Feng Jiang
- Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Xiaoxuan Qin
- Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yun Liu
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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11
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Maurya VK, Szwarc MM, Lonard DM, Gibbons WE, Wu SP, O’Malley BW, DeMayo FJ, Lydon JP. Decidualization of human endometrial stromal cells requires steroid receptor coactivator-3. FRONTIERS IN REPRODUCTIVE HEALTH 2022; 4:1033581. [PMID: 36505394 PMCID: PMC9730893 DOI: 10.3389/frph.2022.1033581] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/07/2022] [Indexed: 11/25/2022] Open
Abstract
Steroid receptor coactivator-3 (SRC-3; also known as NCOA3 or AIB1) is a member of the multifunctional p160/SRC family of coactivators, which also includes SRC-1 and SRC-2. Clinical and cell-based studies as well as investigations on mice have demonstrated pivotal roles for each SRC in numerous physiological and pathophysiological contexts, underscoring their functional pleiotropy. We previously demonstrated the critical involvement of SRC-2 in murine embryo implantation as well as in human endometrial stromal cell (HESC) decidualization, a cellular transformation process required for trophoblast invasion and ultimately placentation. We show here that, like SRC-2, SRC-3 is expressed in the epithelial and stromal cellular compartments of the human endometrium during the proliferative and secretory phase of the menstrual cycle as well as in cultured HESCs. We also found that SRC-3 depletion in cultured HESCs results in a significant attenuation in the induction of a wide-range of established biomarkers of decidualization, despite exposure of these cells to a deciduogenic stimulus and normal progesterone receptor expression. These molecular findings are supported at the cellular level by the inability of HESCs to morphologically transform from a stromal fibroblastoid cell to an epithelioid decidual cell when endogenous SRC-3 levels are markedly reduced. To identify genes, signaling pathways and networks that are controlled by SRC-3 and potentially important for hormone-dependent decidualization, we performed RNA-sequencing on HESCs in which SRC-3 levels were significantly reduced at the time of administering the deciduogenic stimulus. Comparing HESC controls with HESCs deficient in SRC-3, gene enrichment analysis of the differentially expressed gene set revealed an overrepresentation of genes involved in chromatin remodeling, cell proliferation/motility, and programmed cell death. These predictive bioanalytic results were confirmed by the demonstration that SRC-3 is required for the expansion, migratory and invasive activities of the HESC population, cellular properties that are required in vivo in the formation or functioning of the decidua. Collectively, our results support SRC-3 as an important coregulator in HESC decidualization. Since perturbation of normal homeostatic levels of SRC-3 is linked with common gynecological disorders diagnosed in reproductive age women, this endometrial coregulator-along with its new molecular targets described here-may open novel clinical avenues in the diagnosis and/or treatment of a non-receptive endometrium, particularly in patients presenting non-aneuploid early pregnancy loss.
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Affiliation(s)
- Vineet K. Maurya
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
| | - Maria M. Szwarc
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
| | - David M. Lonard
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
| | - William E. Gibbons
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, United States
| | - San-Pin Wu
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, United States
| | - Bert W. O’Malley
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
| | - Francesco J. DeMayo
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, United States
| | - John P. Lydon
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States,Correspondence: John P. Lydon
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12
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Guo WJ, Wang Y, Deng Y, Cheng LY, Liu X, Xi RF, Zhu SJ, Feng XY, Hua L, Ze K, Zhu JY, Guo DJ, Li FL. Therapeutic effects of the extract of Sancao Formula, a Chinese herbal compound, on imiquimod-induced psoriasis via cysteine-rich protein 61. JOURNAL OF INTEGRATIVE MEDICINE 2022; 20:376-384. [PMID: 35491357 DOI: 10.1016/j.joim.2022.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/16/2022] [Indexed: 06/14/2023]
Abstract
OBJECTIVE Psoriasis is a common chronic inflammatory skin disease that is prone to recurrence, and the proinflammatory factor, cysteine-rich protein 61 (Cyr61), is important in its pathophysiology. Long-term clinical practice has shown that Sancao Formula (SC), a Chinese herbal compound, is effective in the treatment of psoriasis, but the precise mechanism remains unknown. In this study, we investigate the mechanism by which SC extract alleviates imiquimod (IMQ)-induced psoriasis. METHODS The expression of Cyr61 in psoriatic lesions and normal healthy skin was detected using immunohistochemical analysis to investigate the biological role of Cyr61 in models of psoriatic inflammation. A psoriatic mouse model was established by topical application of IMQ, and the effect of topical application of SC extract was evaluated using the psoriasis area and severity index (PASI) score, hematoxylin-eosin staining, and histopathological features of the skin. Next, a HaCaT cell inflammation model was established using interferon-γ (IFN-γ), and the effect of SC extract on the mRNA and protein levels of Cyr61 and intercellular cell adhesion molecule-1 (ICAM-1) was confirmed using Western blot and quantitative real-time polymerase chain reaction analyses. RESULTS Immunohistochemical staining showed that the expression of Cyr61 in psoriatic lesions was higher than that in normal skin samples (78.26% vs 41.18%, P < 0.05), and the number of Cyr61-positive cells in psoriatic lesions was also significantly higher than in normal skin (18.66 ± 2.51 vs 4.33 ± 1.52, P < 0.05). Treatment in mice with IMQ-induced psoriasis showed that SC extract could significantly improve the inflammatory phenotype, PASI score (10.875 ± 0.744 vs 3.875 ± 0.582, P < 0.05), and pathological features compared with those in IMQ model group; SC treatment was also associated with decreased levels of Cyr61 and ICAM-1. In the IFN-γ-induced inflammatory cell model, the mRNA and protein levels of Cyr61 and ICAM-1 were upregulated, while the SC extract downregulated the levels of Cyr61 and ICAM-1. CONCLUSION The results provide a theoretical basis for the involvement of Cyr61 in the pathogenesis of psoriasis, and suggest that SC should be used to target Cyr61 for the prevention of psoriasis recurrence.
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Affiliation(s)
- Wan-Jun Guo
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Yi Wang
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Yu Deng
- School of Medicine, Chengdu University, Chengdu 610106, Sichuan Province, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106, Sichuan Province, China
| | - Lin-Yan Cheng
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Xin Liu
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Ruo-Fan Xi
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Sheng-Jie Zhu
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Xin-Yi Feng
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Liang Hua
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Kan Ze
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Jian-Yong Zhu
- Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Dong-Jie Guo
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
| | - Fu-Lun Li
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
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13
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Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge. Int J Mol Sci 2022; 23:ijms23116064. [PMID: 35682743 PMCID: PMC9181498 DOI: 10.3390/ijms23116064] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 05/24/2022] [Accepted: 05/26/2022] [Indexed: 12/23/2022] Open
Abstract
CTGF is upregulated in patients with idiopathic pulmonary fibrosis (IPF), characterized by the deposition of a pathological extracellular matrix (ECM). Additionally, many omics studies confirmed that aberrant cellular senescence-associated mitochondria dysfunction and metabolic reprogramming had been identified in different IPF lung cells (alveolar epithelial cells, alveolar endothelial cells, fibroblasts, and macrophages). Here, we reviewed the role of the CTGF in IPF lung cells to mediate anomalous senescence-related metabolic mechanisms that support the fibrotic environment in IPF.
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14
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Gopinath P, Natarajan A, Sathyanarayanan A, Veluswami S, Gopisetty G. The multifaceted role of Matricellular Proteins in health and cancer, as biomarkers and therapeutic targets. Gene 2022; 815:146137. [PMID: 35007686 DOI: 10.1016/j.gene.2021.146137] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/07/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023]
Abstract
The extracellular matrix (ECM) is composed of a mesh of proteins, proteoglycans, growth factors, and other secretory components. It constitutes the tumor microenvironment along with the endothelial cells, cancer-associated fibroblasts, adipocytes, and immune cells. The proteins of ECM can be functionally classified as adhesive proteins and matricellular proteins (MCP). In the tumor milieu, the ECM plays a major role in tumorigenesis and therapeutic resistance. The current review encompasses thrombospondins, osteonectin, osteopontin, tenascin C, periostin, the CCN family, laminin, biglycan, decorin, mimecan, and galectins. The matrix metalloproteinases (MMPs) are also discussed as they are an integral part of the ECM with versatile functions in the tumor stroma. In this review, the role of these proteins in tumor initiation, growth, invasion and metastasis have been highlighted, with emphasis on their contribution to tumor therapeutic resistance. Further, their potential as biomarkers and therapeutic targets based on existing evidence are discussed. Owing to the recent advancements in protein targeting, the possibility of agents to modulate MCPs in cancer as therapeutic options are discussed.
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Affiliation(s)
- Prarthana Gopinath
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India
| | - Aparna Natarajan
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India
| | | | - Sridevi Veluswami
- Deaprtment of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
| | - Gopal Gopisetty
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India.
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15
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Yeger H, Perbal B. The CCN axis in cancer development and progression. J Cell Commun Signal 2021; 15:491-517. [PMID: 33877533 PMCID: PMC8642525 DOI: 10.1007/s12079-021-00618-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 04/06/2021] [Indexed: 12/12/2022] Open
Abstract
Since the authors first reviewed this subject in 2016 significant progress has been documented in the CCN field with advances made in the understanding of how members of the CCN family of proteins, CCN1-6, contribute to the pathogenesis and progression, positive and negative, of a larger variety of cancers. As termed matricellular proteins, and more recently the connective communication network, it has become clearer that members of the CCN family interact complexly with other proteins in the extracellular microenvironment, membrane signaling proteins, and can also operate intracellularly at the transcriptional level. In this review we expand on this earlier information providing new detailed information and insights that appropriate a much greater involvement and importance of their role in multiple aspects of cancer. Despite all the new information many more questions have been raised and intriguing results generated that warrant greater investigation. In order to permit the reader to smoothly integrate the new information we discuss all relevant CCN members in the context of cancer subtypes. We have harmonized the nomenclature with CCN numbering for easier comparisons. Finally, we summarize what new has been learned and provide a perspective on how our knowledge about CCN1-6 is being used to drive new initiatives on cancer therapeutics.
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Affiliation(s)
- Herman Yeger
- Program in Developmental and Stem Cell Biology Research Institute, SickKids, Toronto, Canada
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16
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Kubota S, Kawaki H, Perbal B, Kawata K, Hattori T, Nishida T. Cellular communication network factor 3 in cartilage development and maintenance. J Cell Commun Signal 2021; 15:533-543. [PMID: 34125392 PMCID: PMC8642582 DOI: 10.1007/s12079-021-00629-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 05/27/2021] [Indexed: 12/30/2022] Open
Abstract
Cellular communication network factor (CCN) 3 is one of the classical members of the CCN family, which are characterized by common molecular structures and multiple functionalities. Although this protein was discovered as a gene product overexpressed in a truncated form in nephroblastoma, recent studies have revealed its physiological roles in the development and homeostasis of mammalian species, in addition to its pathological association with a number of diseases. Cartilage is a tissue that creates most of the bony parts and cartilaginous tissues that constitute the human skeleton, in which CCN3 is also differentially produced to exert its molecular missions therein. In this review article, after the summary of the molecular structure and function of CCN3, recent findings on the regulation of ccn3 expression and the roles of CCN3 in endochondral ossification, cartilage development, maintenance and disorders are introduced with an emphasis on the metabolic regulation and function of this matricellular multifunctional molecule.
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Affiliation(s)
- Satoshi Kubota
- Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School 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
| | | | - Kazumi Kawata
- Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School 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 Graduate School 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 Graduate School 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 Dental School, Okayama, Japan
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Ahmed KA, Hasib TA, Paul SK, Saddam M, Mimi A, Saikat ASM, Faruque HA, Rahman MA, Uddin MJ, Kim B. Potential Role of CCN Proteins in Breast Cancer: Therapeutic Advances and Perspectives. Curr Oncol 2021; 28:4972-4985. [PMID: 34940056 PMCID: PMC8700172 DOI: 10.3390/curroncol28060417] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 12/24/2022] Open
Abstract
CCNs are a specific type of matricellular protein, which are essential signaling molecules, and play multiple roles in multicellular eukaryotes. This family of proteins consists of six separate members, which exist only in vertebrates. The architecture of CCN proteins is multi-modular comprising four distinct modules. CCN Proteins achieve their primary functional activities by binding with several integrin7 receptors. The CCN family has been linked to cell adhesion, chemotaxis and migration, mitogenesis, cell survival, angiogenesis, differentiation, tumorigenesis, chondrogenesis, and wound healing, among other biological interactions. Breast cancer is the most commonly diagnosed cancer worldwide and CCN regulated breast cancer stands at the top. A favorable or unfavorable association between various CCNs has been reported in patients with breast carcinomas. The pro-tumorigenic CCN1, CCN2, CCN3, and CCN4 may lead to human breast cancer, although the anti-tumorigenic actions of CCN5 and CCN6 are also present. Several studies have been conducted on CCN proteins and cancer in recent years. CCN1 and CCN3 have been shown to exhibit a dual nature of tumor inhibition and tumor suppression to some extent in quiet recent time. Pharmacological advances in treating breast cancer by targeting CCN proteins are also reported. In our study, we intend to provide an overview of these research works while keeping breast cancer in focus. This information may facilitate early diagnosis, early prognosis and the development of new therapeutic strategies.
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Affiliation(s)
- Kazi Ahsan Ahmed
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.A.A.); (T.A.H.); (S.K.P.); (H.A.F.)
- Department of Biochemistry and Molecular Biology, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (M.S.); (A.M.); (A.S.M.S.)
- Bio-Science Research Initiative, Gopalganj 8100, Bangladesh
| | - Tasnin Al Hasib
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.A.A.); (T.A.H.); (S.K.P.); (H.A.F.)
- Department of Biochemistry and Molecular Biology, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (M.S.); (A.M.); (A.S.M.S.)
- Bio-Science Research Initiative, Gopalganj 8100, Bangladesh
| | - Shamrat Kumar Paul
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.A.A.); (T.A.H.); (S.K.P.); (H.A.F.)
- Department of Biochemistry and Molecular Biology, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (M.S.); (A.M.); (A.S.M.S.)
- Bio-Science Research Initiative, Gopalganj 8100, Bangladesh
| | - Md. Saddam
- Department of Biochemistry and Molecular Biology, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (M.S.); (A.M.); (A.S.M.S.)
- Bio-Science Research Initiative, Gopalganj 8100, Bangladesh
| | - Afsana Mimi
- Department of Biochemistry and Molecular Biology, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (M.S.); (A.M.); (A.S.M.S.)
| | - Abu Saim Mohammad Saikat
- Department of Biochemistry and Molecular Biology, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (M.S.); (A.M.); (A.S.M.S.)
| | - Hasan Al Faruque
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.A.A.); (T.A.H.); (S.K.P.); (H.A.F.)
- Companion Diagnostics and Medical Technology Research Group, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea
| | - Md. Ataur Rahman
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.A.A.); (T.A.H.); (S.K.P.); (H.A.F.)
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
- Correspondence: (M.A.R.); (M.J.U.); (B.K.)
| | - Md. Jamal Uddin
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.A.A.); (T.A.H.); (S.K.P.); (H.A.F.)
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Women’s University, Seoul 03760, Korea
- Correspondence: (M.A.R.); (M.J.U.); (B.K.)
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
- Correspondence: (M.A.R.); (M.J.U.); (B.K.)
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18
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Jia Q, Zhang Y, Xu B, Liao X, Bu Y, Xu Z, Duan X, Zhang Q. Dual roles of WISP2 in the progression of hepatocellular carcinoma: implications of the fibroblast infiltration into the tumor microenvironment. Aging (Albany NY) 2021; 13:21216-21231. [PMID: 34497155 PMCID: PMC8457598 DOI: 10.18632/aging.203424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 07/08/2021] [Indexed: 12/24/2022]
Abstract
The dismal outcome of hepatocellular carcinoma (HCC) patients is attributable to high frequency of metastasis and. Identification of effective biomarkers is a key strategy to inform prognosis and improve survival. Previous studies reported inconsistent roles of WISP2 in carcinogenesis, while the role of WISP2 in HCC progression also remains unclear. In this study, we confirmed that WISP2 was downregulated in HCC tissues, and WISP2 was acting as a protective factor, especially in patients without alcohol intake using multiple online datasets. In addition, we reported that upregulation of WISP2 in HCC was related to inhibition of the malignant phenotype in vitro, but these alterations were not observed in vivo. WISP2 also negatively correlated with tumour purity, and increased infiltration of fibroblasts promoted malignant progression in HCC tissues. The enhanced infiltration ability of fibroblasts was related to upregulated HMGB1 after overexpression of WISP2 in HCC. The findings shed light on the anticancer role of WISP2, and HMGB1 is one of the key factors involved in the inhibition of the efficiency of WISP2 through reducing the tumour purity with fibroblast infiltration.
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Affiliation(s)
- Qingan Jia
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China
| | - Yaoyao Zhang
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China
| | - Binghui Xu
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China
| | - Xia Liao
- Department of Nutrition, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Yang Bu
- Department of Hepatobiliary Surgery, General Hospital, Ningxia Medical University, Yinchuan 750001, China
| | - Zihan Xu
- Department of Burns and Plastic Surgery, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an 710068, China
| | - Xianglong Duan
- Second Department of General Surgery, Shaanxi Provincial People's Hospital Affiliated Hospital of Northwestern Polytechnical University, Xi'an 710068, China
| | - Qiangbo Zhang
- Cheeloo College of Medicine, Shandong University, Jinan 250012, China.,Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
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19
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Yang C, Li F, Zhou W, Huang J. Knockdown of long non-coding RNA CCAT2 suppresses growth and metastasis of esophageal squamous cell carcinoma by inhibiting the β-catenin/WISP1 signaling pathway. J Int Med Res 2021; 49:3000605211019938. [PMID: 34057837 PMCID: PMC8753796 DOI: 10.1177/03000605211019938] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective Long non-coding RNA (lncRNA) colon cancer-associated transcript 2 (CCAT2) plays oncogenic roles in several cancers, including esophageal squamous cell carcinoma (ESCC). However, the specific mechanism of how CCAT2 influences ESCC tumorigenesis is still unknown. Methods Using RT-qPCR, the mRNA expression levels of CCAT2 in 33 paired ESCC and adjacent non-cancer tissues and cell lines were measured. Lentiviral vector sh-CCAT2 was designed and transfected into TE10 cells. CCK-8 and transwell assays were employed to detect the effects of CCAT2 knockdown on cell proliferation and invasion, respectively. RT-qPCR and western blots were used to detect the effects of CCAT2 knockdown. Results CCAT2 was overexpressed in ESCC tissues compared with corresponding adjacent tissues. CCAT2 knockdown could suppress cell proliferation and invasion in vitro. Furthermore, knockdown of CCAT2 could suppress the mRNA and protein levels of β-catenin and Wnt-induced-secreted-protein-1 (WISP1), as well as the mRNA levels of their downstream targets VEGF-A, MMP2, and ICAM-1. High expression of CCAT2 and WISP1 were associated with poor prognosis of ESCC patients. Conclusions In conclusion, a novel CCAT2/β-catenin/WISP1 axis was revealed in ESCC progression and may provide a promising therapeutic target against ESCC. CCAT2 and WISP1 are potential molecular biomarkers for predicting prognosis of ESCC.
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Affiliation(s)
- Canlin Yang
- Department of Oncology, Taizhou People's Hospital, Affiliated with Nanjing University of Chinese Medicine, Taizhou, Jiangsu, P.R. China
| | - Fei Li
- Department of Oncology, Taizhou People's Hospital, Affiliated with Nanjing University of Chinese Medicine, Taizhou, Jiangsu, P.R. China
| | - Wenbiao Zhou
- Department of Oncology, Taizhou People's Hospital, Affiliated with Nanjing University of Chinese Medicine, Taizhou, Jiangsu, P.R. China
| | - Junxing Huang
- Department of Oncology, Taizhou People's Hospital, Affiliated with Nanjing University of Chinese Medicine, Taizhou, Jiangsu, P.R. China
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20
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Jia Q, Xu B, Zhang Y, Ali A, Liao X. CCN Family Proteins in Cancer: Insight Into Their Structures and Coordination Role in Tumor Microenvironment. Front Genet 2021; 12:649387. [PMID: 33833779 PMCID: PMC8021874 DOI: 10.3389/fgene.2021.649387] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/03/2021] [Indexed: 12/19/2022] Open
Abstract
The crosstalk between tumor cells and the tumor microenvironment (TME), triggers a variety of critical signaling pathways and promotes the malignant progression of cancer. The success rate of cancer therapy through targeting single molecule of this crosstalk may be extremely low, whereas co-targeting multiple components could be complicated design and likely to have more side effects. The six members of cellular communication network (CCN) family proteins are scaffolding proteins that may govern the TME, and several studies have shown targeted therapy of CCN family proteins may be effective for the treatment of cancer. CCN protein family shares similar structures, and they mutually reinforce and neutralize each other to serve various roles that are tightly regulated in a spatiotemporal manner by the TME. Here, we review the current knowledge on the structures and roles of CCN proteins in different types of cancer. We also analyze CCN mRNA expression, and reasons for its diverse relationship to prognosis in different cancers. In this review, we conclude that the discrepant functions of CCN proteins in different types of cancer are attributed to diverse TME and CCN truncated isoforms, and speculate that targeting CCN proteins to rebalance the TME could be a potent anti-cancer strategy.
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Affiliation(s)
- Qingan Jia
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China
| | - Binghui Xu
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China
| | - Yaoyao Zhang
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China
| | - Arshad Ali
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Xia Liao
- Department of Nutrition, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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21
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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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22
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Chen S, Su X, Liu J, Shi Y, Wu M, Xu M, Zhang F, Tang M. [Regulatory effect of CCN3 on proliferation of mouse embryonic fibroblasts and its mechanism]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2021; 41:79-86. [PMID: 33509757 DOI: 10.12122/j.issn.1673-4254.2021.01.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To investigate the role of NOV/CCN3 in regulating the proliferation of mesenchymal stem cells (MSCs) and its regulatory mechanism and assess the value of CCN3 as a proliferative factor in bone tissue engineering. METHODS Mouse embryonic fibroblasts (MEFs) were used as the MSC model, in which CCN3 expression was up-regulated and downregulated by transfection with the recombinant adenovirus vectors Ad-CCN3 and Ad-siCCN3, respectively. Flow cytometry was used to analyze the changes in cell cycle and apoptosis of the transfected cells. Western blotting was used to detect the expression levels of the proliferation indicators (PCNA, cyclin E, and cyclin B1) and the apoptosis indicators (Bax and Bcl-2) to assess the effect of modulation of CCN3 expression on MEF proliferation and apoptosis. CCN3 protein secretion by the cells was detected using ELISA. RT-qPCR and Western blotting were employed to analyze the changes in the expressions of Notch1, ligand DLL1, the downstream key proteins or genes (Hey1, P300, H3K9) and MAPK pathway-related proteins ERK1+2 and p-ERK1+2. RESULTS Flow cytometry showed that compared with the control cells, MEFs transfected with Ad-CCN3 exhibited significantly increased cell proliferation index (P < 0.01) and lowered cell apoptosis rate (P < 0.05) with obviously enhanced expressions of PCNA, cyclin E and Bcl-2 proteins (P < 0.05). The results of RT-qPCR and Western blotting demonstrated that CCN3 overexpression significantly promoted the expression of Notch1 in the Notch signaling pathway (P < 0.001), inhibited the expressions of DLL1, Hey1, P300, and H3K9 (P < 0.05), and increased the protein expressions of ERK1+2 and P-ERk1+2 in the MAPK pathway (P < 0.01). CONCLUSIONS CCN3 over-expression promotes the proliferation and inhibits apoptosis of MEFs possibly by inhibiting the classical Notch signaling pathway and activating the MAPK pathway via binding to Notch1, suggesting the potential value of CCN3 as a proliferative factor of MSCs in bone tissue engineering.
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Affiliation(s)
- Shiyu Chen
- College of Laboratory Medicine, Chongqing Medical University//Key Laboratory of Clinical Laboratory Diagnostics of Ministry of Education, Chongqing 400016, China
| | - Xin Su
- College of Laboratory Medicine, Chongqing Medical University//Key Laboratory of Clinical Laboratory Diagnostics of Ministry of Education, Chongqing 400016, China
| | - Junping Liu
- College of Laboratory Medicine, Chongqing Medical University//Key Laboratory of Clinical Laboratory Diagnostics of Ministry of Education, Chongqing 400016, China
| | - Yutong Shi
- College of Laboratory Medicine, Chongqing Medical University//Key Laboratory of Clinical Laboratory Diagnostics of Ministry of Education, Chongqing 400016, China
| | - Minmin Wu
- College of Laboratory Medicine, Chongqing Medical University//Key Laboratory of Clinical Laboratory Diagnostics of Ministry of Education, Chongqing 400016, China
| | - Mengqi Xu
- College of Laboratory Medicine, Chongqing Medical University//Key Laboratory of Clinical Laboratory Diagnostics of Ministry of Education, Chongqing 400016, China
| | - Fengmei Zhang
- College of Laboratory Medicine, Chongqing Medical University//Key Laboratory of Clinical Laboratory Diagnostics of Ministry of Education, Chongqing 400016, China
| | - Min Tang
- College of Laboratory Medicine, Chongqing Medical University//Key Laboratory of Clinical Laboratory Diagnostics of Ministry of Education, Chongqing 400016, China
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23
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Song Y, Kang Y, Lin Z, Zeng M, Shi P, Lin J, Lu P, Luo L, Cao Y, Zhu X. Cyr61 mediates oxaliplatin resistance in colorectal cancer cells by regulating Bcl-xL expression. J Cancer 2021; 12:1952-1959. [PMID: 33753993 PMCID: PMC7974528 DOI: 10.7150/jca.48891] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 01/06/2021] [Indexed: 01/07/2023] Open
Abstract
Although the clinical application of oxaliplatin (L-OHP) has improved the survival of colorectal cancer (CRC) patients, approximately half of patients with CRC fail to achieve good clinical outcomes, indicating resistance to L-OHP therapy. Cysteine-rich protein 61 (Cyr61), a multifunctional extracellular matrix protein, is highly expressed in a variety of tumors; increased Cyr61 expression is known to be closely involved in the chemotherapeutic resistance of many tumors, but its role in the L-OHP resistance of CRC cells has not been studied. In this study, we aimed to investigate the role of Cyr61 in the L-OHP resistance of CRC cells and examine the underlying mechanism. Our findings showed that the mRNA and protein levels of Cyr61 in L-OHP-resistant cells were significantly increased compared with those in nonresistant cells. Knockdown of Cyr61 enhanced the chemosensitivity of L-OHP-resistant cells to L-OHP. Mechanistically, we found that overexpression of Cyr61 decreased L-OHP-induced apoptosis in drug-resistant CRC cells through the regulation of Bcl-xL. Collectively, our results revealed for the first time that Cyr61 plays a crucial role in the resistance of CRC cells to L-OHP and indicated that targeting Cyr61 may be a promising therapeutic strategy to overcome L-OHP resistance in CRC.
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Affiliation(s)
- Yanfang Song
- Department of Clinical Laboratory, Affiliated People Hospital of Fujian University of Traditional Chinese Medicine, 602 Bayiqi Road, Fuzhou, Fujian 350001, China
| | - Yanli Kang
- Department of Clinical Laboratory, Fujian Provincial Hospital, 134 Dongjie Road, Fuzhou, Fujian 350001, China
| | - Zhen Lin
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China
| | - Menglu Zeng
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China
| | - Pengchong Shi
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China
| | - Jia Lin
- Department of Clinical Laboratory, Affiliated People Hospital of Fujian University of Traditional Chinese Medicine, 602 Bayiqi Road, Fuzhou, Fujian 350001, China
| | - Pingxia Lu
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China
| | - Li Luo
- Department of Clinical Laboratory, Affiliated People Hospital of Fujian University of Traditional Chinese Medicine, 602 Bayiqi Road, Fuzhou, Fujian 350001, China
| | - Yingping Cao
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China
| | - Xianjin Zhu
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China
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Videira A, Beckedorff FC, daSilva LF, Verjovski-Almeida S. PVT1 signals an androgen-dependent transcriptional repression program in prostate cancer cells and a set of the repressed genes predicts high-risk tumors. Cell Commun Signal 2021; 19:5. [PMID: 33430890 PMCID: PMC7798249 DOI: 10.1186/s12964-020-00691-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 12/01/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Androgen receptor (AR) and polycomb repressive complex 2 (PRC2) are known to co-occupy the loci of genes that are downregulated by androgen-stimulus. Long intergenic non-coding RNA (lincRNA) PVT1 is an overexpressed oncogene that is associated with AR in LNCaP prostate cancer cells, and with PRC2 in HeLa and many other types of cancer cells. The possible involvement of PVT1 in mediating androgen-induced gene expression downregulation in prostate cancer has not been explored. METHODS LNCaP cell line was used. Native RNA-binding-protein immunoprecipitation with anti-AR or anti-EZH2 was followed by RT-qPCR with primers for PVT1. Knockdown of PVT1 with specific GapmeRs (or a control with scrambled GapmeR) was followed by differentially expressed genes (DEGs) determination with Agilent microarrays and with Significance Analysis of Microarrays statistical test. DEGs were tested as a tumor risk classifier with a machine learning Random Forest algorithm run with gene expression data from all TCGA-PRAD (prostate adenocarcinoma) tumors as input. ChIP-qPCR was performed for histone marks at the promoter of one DEG. RESULTS We show that PVT1 knockdown in androgen-stimulated LNCaP cells caused statistically significant expression upregulation/downregulation of hundreds of genes. Interestingly, PVT1 knockdown caused upregulation of 160 genes that were repressed by androgen, including a significantly enriched set of tumor suppressor genes, and among them FAS, NOV/CCN3, BMF, HRK, IFIT2, AJUBA, DRAIC and TNFRSF21. A 121-gene-set (out of the 160) was able to correctly predict the classification of all 293 intermediate- and high-risk TCGA-PRAD tumors, with a mean ROC area under the curve AUC = 0.89 ± 0.04, pointing to the relevance of these genes in cancer aggressiveness. Native RIP-qPCR in LNCaP showed that PVT1 was associated with EZH2, a component of PRC2. PVT1 knockdown followed by ChIP-qPCR showed significant epigenetic remodeling at the enhancer and promoter regions of tumor suppressor gene NOV, one of the androgen-repressed genes that were upregulated upon PVT1 silencing. CONCLUSIONS Overall, we provide first evidence that PVT1 was involved in signaling a genome-wide androgen-dependent transcriptional repressive program of tumor suppressor protein-coding genes in prostate cancer cells. Identification of transcriptional inhibition of tumor suppressor genes by PVT1 highlights the pathway to the investigation of mechanisms that lie behind the oncogenic role of PVT1 in cancer. Video Abstract.
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Affiliation(s)
- Alexandre Videira
- Laboratório de Expressão Gênica Em Eucariotos, Instituto Butantan, Av. Vital Brasil 1500, São Paulo, SP 05503-900 Brazil
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508-900 Brazil
| | - Felipe C. Beckedorff
- Laboratório de Expressão Gênica Em Eucariotos, Instituto Butantan, Av. Vital Brasil 1500, São Paulo, SP 05503-900 Brazil
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508-900 Brazil
- Present Address: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL USA
| | - Lucas F. daSilva
- Laboratório de Expressão Gênica Em Eucariotos, Instituto Butantan, Av. Vital Brasil 1500, São Paulo, SP 05503-900 Brazil
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508-900 Brazil
- Present Address: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL USA
| | - Sergio Verjovski-Almeida
- Laboratório de Expressão Gênica Em Eucariotos, Instituto Butantan, Av. Vital Brasil 1500, São Paulo, SP 05503-900 Brazil
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508-900 Brazil
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25
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Pommier A, Varilh J, Bleuse S, Delétang K, Bonini J, Bergougnoux A, Brochiero E, Koenig M, Claustres M, Taulan-Cadars M. miRNA repertoires of cystic fibrosis ex vivo models highlight miR-181a and miR-101 that regulate WISP1 expression. J Pathol 2020; 253:186-197. [PMID: 33095908 DOI: 10.1002/path.5571] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 09/24/2020] [Accepted: 10/19/2020] [Indexed: 12/14/2022]
Abstract
Cystic fibrosis (CF), a genetic disorder, is characterized by chronic lung disease. Small non-coding RNAs are key regulators of gene expression and participate in various processes, which are dysregulated in CF; however, they remain poorly studied. Here, we determined the complete microRNAs (miRNAs) expression pattern in three CF ex vivo models. The miRNA profiles of air-liquid interface cultures of airway epithelia (bronchi, nasal cells, and nasal polyps) samples from patients with CF and non-CF controls were obtained by deep sequencing. Compared with non-CF controls, several miRNAs were deregulated in CF samples; for instance, miR-181a-5p and the miR-449 family were upregulated. Moreover, mature miRNAs often showed variations (i.e. isomiRs) relative to their reference sequence, such as miR-101, suggesting that miRNAs consist of heterogeneous repertoires of multiple isoforms with different effects on gene expression. Analysis of miR-181a-5p and miR-101-3p roles indicated that they regulate the expression of WISP1, a key component of cell proliferation/migration programs. We showed that miR-101 and miR-181a-5p participated in aberrant recapitulation of wound healing programs by controlling WISP1 mRNA and protein level. Our miRNA expression data bring new insights into CF physiopathology and define new potential therapeutic targets in CF. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Alexandra Pommier
- Université de Montpellier, Laboratoire de Génétique de Maladies Rares EA7402, Montpellier, France
| | - Jessica Varilh
- Université de Montpellier, Laboratoire de Génétique de Maladies Rares EA7402, Montpellier, France
| | - Solenne Bleuse
- Université de Montpellier, Laboratoire de Génétique de Maladies Rares EA7402, Montpellier, France
| | - Karine Delétang
- Université de Montpellier, Laboratoire de Génétique de Maladies Rares EA7402, Montpellier, France
| | - Jennifer Bonini
- Université de Montpellier, Laboratoire de Génétique de Maladies Rares EA7402, Montpellier, France
| | - Anne Bergougnoux
- Université de Montpellier, Laboratoire de Génétique de Maladies Rares EA7402, Montpellier, France.,CHU de Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France
| | - Emmanuelle Brochiero
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.,Département de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Michel Koenig
- Université de Montpellier, Laboratoire de Génétique de Maladies Rares EA7402, Montpellier, France.,CHU de Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France
| | - Mireille Claustres
- Université de Montpellier, Laboratoire de Génétique de Maladies Rares EA7402, Montpellier, France
| | - Magali Taulan-Cadars
- Université de Montpellier, Laboratoire de Génétique de Maladies Rares EA7402, Montpellier, France
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26
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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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Li G, Guan C, Xu L, Wang L, Yang C, Zhao L, Zhou B, Luo C, Luan H, Jiang W, Li C, Xu Y. Scutellarin Ameliorates Renal Injury via Increasing CCN1 Expression and Suppressing NLRP3 Inflammasome Activation in Hyperuricemic Mice. Front Pharmacol 2020; 11:584942. [PMID: 33192525 PMCID: PMC7641948 DOI: 10.3389/fphar.2020.584942] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 09/21/2020] [Indexed: 11/17/2022] Open
Abstract
Considerable evidences have indicated that elevated uric acid (UA) was involved in renal tubular injury leading to hyperuricemic nephropathy (HN). Scutellarin is a biologically active flavonoid derived from the Chinese traditional herb Erigeron breviscapus Hand-Mazz, which has been widely used in the treatment of cardiovascular and cerebrovascular diseases. In the present study, we analyzed the effect of scutellarin on HN, by using C57BL/6 mice and human renal tubular epithelial cell line HK-2 which was subjected to adenine/potassium oxonate and UA to mimic a HN injury. The HN mice showed a significant decrease in renal function with the increased SCr and blood urea nitrogen (BUN) (p < 0.05). Hematoxylin–eosin staining results showed a histological injury in HN mice kidney tissues with severe tubular damage. Scutellarin dose dependently alleviated the renal injury of the HN model (p < 0.05), and a dose of 20 mg/kg/day remarkably reduced the Scr level (26.10 ± 3.23 μmol/ml vs. 48.39 ± 7.51 μmol/ml, p < 0.05) and BUN (151.12 ± 30.24 mmol/L vs. 210.43 ± 45.67 mmol/L, p < 0.05) compared with the HN model group. Similarly, scutellarin decreased NGAL, Kim-1, cystatin C, and IL-18 protein expression levels in HN mouse (p < 0.05). Overexpressed CCN1 could not induce NLRP3 inflammasome activation, with no change of mRNA and protein expression levels of NLRP3, ASC, and pro-caspase-1 compared with the control HK-2. However, HK-2 showed a significant NLRP3 inflammasome activation and apoptosis. Importantly, knockdown of CCN1 not only aggravated NLRP3 inflammasome activation and apoptosis but also abrogated the protective effect of scutellarin in UA-induced HK-2 injury. Thus, scutellarin might alleviate HN progression via a mechanism involved in CCN1 regulation on NLRP3 inflammasome activation.
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Affiliation(s)
- Guozheng Li
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chen Guan
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lingyu Xu
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lin Wang
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chengyu Yang
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Long Zhao
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bin Zhou
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Congjuan Luo
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hong Luan
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wei Jiang
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chenyu Li
- The Affiliated Hospital of Qingdao University, Qingdao, China.,Medizinische Klinik und Poliklinik IV, Klinikum der Universität, LMU München, München, German
| | - Yan Xu
- The Affiliated Hospital of Qingdao University, Qingdao, China
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28
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Liu D, Wang X, Zhang M, Tian J, Liu M, Jin T, Pan J, Gao M, An F. WISP1 alleviates lipid deposition in macrophages via the PPARγ/CD36 pathway in the plaque formation of atherosclerosis. J Cell Mol Med 2020; 24:11729-11741. [PMID: 32851768 PMCID: PMC7579692 DOI: 10.1111/jcmm.15783] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/30/2020] [Accepted: 07/30/2020] [Indexed: 12/22/2022] Open
Abstract
Lipid deposition in macrophages plays an important role in atherosclerosis. The WNT1-inducible signalling pathway protein 1(WISP1) can promote proliferation and migration of smooth muscle cells. Its expression is up-regulated in obesity, which is associated with atherosclerosis, but the effect of WISP1 on atherosclerosis remains unclear. Thus, the objective of our study was to elucidate the role of WISP and its mechanism of action in atherosclerosis via in vivo and in vitro experiments. In our experiment, ApoE-/- mice were divided into 5 groups: control, high-fat diet (HFD), null lentivirus (HFD + NC), lentivirus WISP1 (HFD + IvWISP1) and WISP1-shRNA (HFD + shWISP1). Oil Red O staining, immunofluorescence and immunohistochemistry of the aortic sinuses were conducted. Macrophages (RAW264.7 cell lines and peritoneal macrophages) were stimulated with 50 μg/mL oxidized low-density lipoprotein (ox-LDL); then, the reactive oxygen species (ROS) level was measured. Oil Red O staining and Dil-ox-LDL (ox-LDL with Dil dye) uptake measurements were used to test lipid deposition of peritoneal macrophages. WISP1, CD36, SR-A and PPARγ expression levels were measured via Western blotting and ELISA. The results showed that HFD mice had increased WISP1, CD36 and SR-A levels. The plaque lesion area increased when WISP1 was down-regulated, and lipid uptake and foam cell formation were inhibited when WISP1 was up-regulated. Treatment of RAW264.7 cell lines with ox-LDL increased WISP1 expression via activation of the Wnt5a/β-catenin pathway, whereas ROS inhibition reduced WISP1 expression. Moreover, WISP1 down-regulated CD36 and SR-A expression, and Oil Red O staining and Dil-ox-LDL uptake measurement showed that WISP1 down-regulated lipid deposition in macrophages. These results clearly demonstrate that WISP1 is activated by ox-LDL at high ROS levels and can alleviate lipid deposition in atherosclerosis through the PPARγ/CD36 pathway.
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Affiliation(s)
- Dian Liu
- The Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineDepartment of CardiologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Xuyang Wang
- The Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineDepartment of CardiologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Mingjun Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineDepartment of CardiologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Jingjing Tian
- The Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineDepartment of CardiologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Ming Liu
- The Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineDepartment of CardiologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Tao Jin
- The Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineDepartment of CardiologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Jinyu Pan
- Department of CardiologyShandong Provincial The First Affiliated Hospital of Shandong First Medical UniversityJinanChina
| | | | - Fengshuang An
- The Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineDepartment of CardiologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
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29
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Chen W, Lv X, Wang Y, Zhang X, Wang S, Hussain Z, Chen L, Su R, Sun W. Transcriptional Profiles of Long Non-coding RNA and mRNA in Sheep Mammary Gland During Lactation Period. Front Genet 2020; 11:946. [PMID: 33101361 PMCID: PMC7546800 DOI: 10.3389/fgene.2020.00946] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 07/28/2020] [Indexed: 12/13/2022] Open
Abstract
Sheep milk and related products have been growing in popularity around the world in recent years. However, the sheep milk industry is limited by low milk yield, and the molecular regulators of ovine lactation remain largely unknown. To investigate the transcriptomic basis of sheep lactation, RNA-Sequencing was used to explore the expression profiles of lncRNA and mRNA of the mammary gland in Hu sheep at three key time points during the lactation stage: 5 days before the expected date of parturition perinatal period (PP), 6 days after parturition early lactation (EL), and 25 days after parturition peak lactation (PL). A total of 1111, 688, and 54 differentially expressed (DE) lncRNAs as well as 1360, 660, and 17 DE mRNAs were detected in the EL vs PP, PL vs PP, and PL vs EL comparisons, respectively. Several prominent mRNAs (e.g., CSN1S1, CSN1S2, PAEP, CSN2, CSN3, and COL3A1) and lncRNAs (e.g., LNC_018483, LNC_005678, LNC_012936, and LNC_004856) were identified. Functional enrichment analysis revealed that several DE mRNAs and target genes of DE lncRNAs were involved in lactation-related pathways, such as MAPK, PPAR, and ECM-receptor interaction. This study enhances our understanding of how transcriptomic profiles change during the lactation period and pave the way for future studies examining sheep lactation.
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Affiliation(s)
- Weihao Chen
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Xiaoyang Lv
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Yue Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Xinjun Zhang
- Animal Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Shanhe Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Zahid Hussain
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Ling Chen
- Animal Science and Veterinary Medicine Bureau of Suzhou City, Suzhou, China
| | - Rui Su
- Suzhou Taihu Dongshang Sheep Industry Development Co., Ltd., Suzhou, China
| | - Wei Sun
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou, China.,College of Veterinary Medicine, Yangzhou University, Yangzhou, China
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30
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Mpilla GB, Philip PA, El-Rayes B, Azmi AS. Pancreatic neuroendocrine tumors: Therapeutic challenges and research limitations. World J Gastroenterol 2020; 26:4036-4054. [PMID: 32821069 PMCID: PMC7403797 DOI: 10.3748/wjg.v26.i28.4036] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/10/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine tumors (PNETs) are known to be the second most common epithelial malignancy of the pancreas. PNETs can be listed among the slowest growing as well as the fastest growing human cancers. The prevalence of PNETs is deceptively low; however, its incidence has significantly increased over the past decades. According to the American Cancer Society's estimate, about 4032 (> 7% of all pancreatic malignancies) individuals will be diagnosed with PNETs in 2020. PNETs often cause severe morbidity due to excessive secretion of hormones (such as serotonin) and/or overall tumor mass. Patients can live for many years (except for those patients with poorly differentiated G3 neuroendocrine tumors); thus, the prevalence of the tumors that is the number of patients actually dealing with the disease at any given time is fairly high because the survival is much longer than pancreatic ductal adenocarcinoma. Due to significant heterogeneity, the management of PNETs is very complex and remains an unmet clinical challenge. In terms of research studies, modest improvements have been made over the past decades in the identification of potential oncogenic drivers in order to enhance the quality of life and increase survival for this growing population of patients. Unfortunately, the majority of systematic therapies approved for the management of advanced stage PNETs lack objective response or at most result in modest benefits in survival. In this review, we aim to discuss the broad challenges associated with the management and the study of PNETs.
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Affiliation(s)
- Gabriel Benyomo Mpilla
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States
| | - Philip Agop Philip
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States
| | - Bassel El-Rayes
- Department of Hematology Oncology, Emory Winship Institute, Atlanta, GA 30322, United States
| | - Asfar Sohail Azmi
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States
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31
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Ohkawara B, Kobayakawa A, Kanbara S, Hattori T, Kubota S, Ito M, Masuda A, Takigawa M, Lyons KM, Ishiguro N, Ohno K. CTGF/CCN2 facilitates LRP4-mediated formation of the embryonic neuromuscular junction. EMBO Rep 2020; 21:e48462. [PMID: 32558157 DOI: 10.15252/embr.201948462] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 05/20/2020] [Accepted: 05/27/2020] [Indexed: 12/12/2022] Open
Abstract
At the neuromuscular junction (NMJ), lipoprotein-related receptor 4 (LRP4) mediates agrin-induced MuSK phosphorylation that leads to clustering of acetylcholine receptors (AChRs) in the postsynaptic region of the skeletal muscle. Additionally, the ectodomain of LRP4 is necessary for differentiation of the presynaptic nerve terminal. However, the molecules regulating LRP4 have not been fully elucidated yet. Here, we show that the CT domain of connective tissue growth factor (CTGF/CCN2) directly binds to the third beta-propeller domain of LRP4. CTGF/CCN2 enhances the binding of LRP4 to MuSK and facilitates the localization of LRP4 on the plasma membrane. CTGF/CCN2 enhances agrin-induced MuSK phosphorylation and AChR clustering in cultured myotubes. Ctgf-deficient mouse embryos (Ctgf-/- ) have small AChR clusters and abnormal dispersion of synaptic vesicles along the motor axon. Ultrastructurally, the presynaptic nerve terminals have reduced numbers of active zones and mitochondria. Functionally, Ctgf-/- embryos exhibit impaired NMJ signal transmission. These results indicate that CTGF/CCN2 interacts with LRP4 to facilitate clustering of AChRs at the motor endplate and the maturation of the nerve terminal.
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Affiliation(s)
- Bisei Ohkawara
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akinori Kobayakawa
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shunsuke Kanbara
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takako Hattori
- Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Satoshi Kubota
- Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Mikako Ito
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akio Masuda
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masaharu Takigawa
- Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan
| | - Karen M Lyons
- Department of Orthopedic Surgery, UCLA, Los Angeles, CA, USA
| | - Naoki Ishiguro
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kinji Ohno
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Sgalla G, Franciosa C, Simonetti J, Richeldi L. Pamrevlumab for the treatment of idiopathic pulmonary fibrosis. Expert Opin Investig Drugs 2020; 29:771-777. [PMID: 32447983 DOI: 10.1080/13543784.2020.1773790] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
INTRODUCTION The two available therapies for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, slow down but do not halt IPF progression. As such, in the last few years several agents with specific molecular targets have been investigated to find a cure forIPF. Pamrevlumab, a recombinant human antibody that binds to connective tissue growth factor (CTGF) has emerged as a potential therapy for IPF and has advanced to phase 3 clinical trials. AREAS COVERED The authors offer a backdrop to the current IPF treatment market and describe the chemistry, pharmacokinetics and pharmacodynamics of pamrevlumab. They summarize the preclinical and early clinical evidence on pamrevlumab and propose ways of progressing this agent further as a potential IPF treatment. EXPERT OPINION Pamrevlumab was effective and safe in patients in a placebo-controlled phase 2 trial, demonstrating its potential to become an alternative therapeutic option for IPF; however, the feasibility of intravenous administration in clinical practice may be a hurdle to its use as a first-line treatment. Further studies are necessary to assess its effects when administered with pirfenidone or nintedanib and this could open up a new era of combined therapeutic approaches for IPF.
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Affiliation(s)
- Giacomo Sgalla
- UOC Pneumologia, Dipartimento Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS , Rome, Italy
| | - Claudia Franciosa
- UOC Pneumologia, Dipartimento Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS , Rome, Italy
| | - Jacopo Simonetti
- UOC Pneumologia, Dipartimento Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS , Rome, Italy
| | - Luca Richeldi
- UOC Pneumologia, Dipartimento Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS , Rome, Italy.,Istituto di Medicina Interna, Università Cattolica del Sacro Cuore , Rome, Italy
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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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34
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Liao X, Bu Y, Xu Z, Jia F, Chang F, Liang J, Jia Q, Lv Y. WISP1 Predicts Clinical Prognosis and Is Associated With Tumor Purity, Immunocyte Infiltration, and Macrophage M2 Polarization in Pan-Cancer. Front Genet 2020; 11:502. [PMID: 32523603 PMCID: PMC7261883 DOI: 10.3389/fgene.2020.00502] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 04/23/2020] [Indexed: 12/30/2022] Open
Abstract
Cancer is becoming the leading cause of death and a major public health problem. Although many advanced treatment strategies are currently in use, the general prognosis of cancer patients remains dismal due to the high frequency of recurrence, metastasis. The identification of effective biomarkers is important for predicting survival of cancer patients and improving treatment efficacy. In this study, we comprehensively analyzed WNT1-inducible-signaling pathway protein 1 (WISP1) expression and explored its correlation with prognosis in pan-cancer using tumor IMmune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2). We also examined correlations between WISP1 and immunocyte infiltration using TIMER. We identified genes co-expressed with WISP1 using the LinkedOmics database and analyzed associated gene ontology using Metascape. Finally, we constructed protein-protein interaction networks and examined correlations between genes co-expressed with WISP1 and immunocyte infiltration in pan-cancer. WISP1 level differed between human pan-cancer tissues and normal tissues, indicating its potential as a prognostic biomarker. WISP1 expression was correlated with tumor purity and immunocyte infiltration, especially monocyte-macrophage trafficking and M2 polarization. Genes co-expressed with WISP1 were mainly associated with extracellular matrix organization, with collagen members COL6A3, COL5A1, and COL8A1 being key genes correlated with macrophage infiltration and M2 polarization in pan-cancer. Conversely, in certain types of cancer with better prognoses, WISP1 was associated with low M2 macrophage infiltration. These results suggest that WISP1 affect clinical prognosis through associations with tumor purity, immune cell infiltration, and macrophage M2 polarization in pan-cancer, with collagen member proteins may serving as effector molecules of WISP1.
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Affiliation(s)
- Xia Liao
- Department of Nutrition, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yang Bu
- Department of Hepatobiliary Surgery, General Hospital, Ningxia Medical University, Yinchuan, China
| | - Zihan Xu
- Department of Burns and Plastic Surgery, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Fengan Jia
- Metabolite Research Center, Shaanxi Institute of Microbiology, Xi'an, China
| | - Fan Chang
- Metabolite Research Center, Shaanxi Institute of Microbiology, Xi'an, China
| | - Junrong Liang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Qingan Jia
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Leask A. Breathe, breathe in the air: the anti-CCN2 antibody pamrevlumab (FG-3019) completes a successful phase II clinical trial for idiopathic pulmonary fibrosis. J Cell Commun Signal 2019; 13:441-442. [PMID: 31811619 DOI: 10.1007/s12079-019-00542-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Pirfenidone and nintedanib have been approved for idiopathic pulmonary fibrosis (IPF) due to their ability to statistically slow, over a year, the rate of decline in lung forced vital capacity (FVC), neither drug has been reported to have o positive effects on high-resolution computed tomography (HRCT) of the chest, symptoms, or quality of life. Moreover, pirfenidone and nintedanib have substantial gastrointestinal tolerability issues. Overall, these data highly suggest that novel therapeutic approached are needed. CCN2 has been shown to be a mediator of fibrosis in many preclinical models. Anti-CCN2 strategies are in clinical development for IPF, A recent study by Richeldi and colleagues described the recent Phase II clinical trial for FG-3019 in IPF, and the results were highly encouraging. This commentary contextualizes and summarizes these exciting findings.
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Affiliation(s)
- Andrew Leask
- College of Dentistry, University of Saskatchewan, 105 Wiggins Road, Saskatoon, SK, S7N 5E4, Canada.
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36
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Shoji M, Ueda M, Nishioka M, Minato H, Seki M, Harada K, Kubo M, Fukuyama Y, Suzuki Y, Aoyama E, Takigawa M, Kuzuhara T. Jiadifenolide induces the expression of cellular communication network factor (CCN) genes, and CCN2 exhibits neurotrophic activity in neuronal precursor cells derived from human induced pluripotent stem cells. Biochem Biophys Res Commun 2019; 519:309-315. [PMID: 31506177 DOI: 10.1016/j.bbrc.2019.09.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 09/02/2019] [Indexed: 01/27/2023]
Abstract
Jiadifenolide has been reported to have neurotrophin-like activity in primary rat cortical neurons, and also possesses neurotrophic effects in neuronal precursor cells derived from human induced pluripotent stem cells (hiPSCs), as we have previously reported. However, the molecular mechanisms by which jiadifenolide exerts its neurotrophic effects in rat and human neurons are unknown. Thus, we aimed to investigate the molecular mechanisms and pathways by which jiadifenolide promotes neurotrophic effects. Here, we found that jiadifenolide activated cellular communication network factor (CCN) signaling pathways by up-regulating mRNA level expression of CCN genes in human neuronal cells. We also found that CCN2 (also known as connective tissue growth factor, CTGF) protein promotes neurotrophic effects through activation of the p44/42 mitogen-activated protein kinase signaling pathway. This is the first discovery which links neurotrophic activity with CCN signaling.
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Affiliation(s)
- Masaki Shoji
- Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
| | - Masako Ueda
- Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
| | - Megumi Nishioka
- Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
| | - Hiroki Minato
- Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
| | - Masahide Seki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan
| | - Kenichi Harada
- Laboratory of Biophysical Chemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
| | - Miwa Kubo
- Laboratory of Biophysical Chemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
| | - Yoshiyasu Fukuyama
- Laboratory of Biophysical Chemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
| | - Yutaka Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan
| | - Eriko Aoyama
- Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School/Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masaharu Takigawa
- Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School/Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Takashi Kuzuhara
- Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
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Sidahmed-Adrar N, Ottavi JF, Benzoubir N, Ait Saadi T, Bou Saleh M, Mauduit P, Guettier C, Desterke C, Le Naour F. Tspan15 Is a New Stemness-Related Marker in Hepatocellular Carcinoma. Proteomics 2019; 19:e1900025. [PMID: 31390680 DOI: 10.1002/pmic.201900025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 07/15/2019] [Indexed: 12/19/2022]
Abstract
Hepatocellular carcinoma (HCC) is the second cause of cancer-related deaths worldwide. A clearer understanding of the molecular mechanisms underlying tumor growth and invasiveness remains crucial for developing new therapies. Here, the expression of tetraspanins, a family of plasma membrane organizers involved in tumor progression, has been addressed. Integrative approaches combining transcriptomics and bioinformatics allow demonstrating the induced and heterogeneous expression of Tspan15 in HCC. Tspan15 positive tumors exhibit signatures related to hepatic progenitor cells as well as recurrence of cancer. Immunohistochemistry experiments confirm Tspan15 expression in the subset of HCC expressing stemness-related markers such as EpCAM and Cytokeratin-19. Functional networks reveal that most of these genes expressed in correlation to Tspan15 support cell proliferation. Furthermore, Tspan15 overexpression in the hepatoma cell line HepG2 significantly increases cell proliferation. A quantitative proteomic analysis of the secretome reveals a higher abundance of the protein connective tissue growth factor (CTGF), a pleiotropic matricellular signaling protein. Proteomic profiling of Tspan15 complexes allows identifying numerous membrane proteins including several growth factor receptors. Finally, Tspan15 increases ERK1/2 phosphorylation that directly controls CTGF expression and secretion. In conclusion, Tspan15 is a new stemness-related marker in HCC which exhibits high potential of tumor growth and recurrence.
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Affiliation(s)
- Nazha Sidahmed-Adrar
- Inserm, Unité 1193, Villejuif, F-94800, France.,Université Paris-Sud, Institut André Lwoff, Villejuif, F-94800, France
| | - Jean-François Ottavi
- Inserm, Unité 1193, Villejuif, F-94800, France.,Université Paris-Sud, Institut André Lwoff, Villejuif, F-94800, France
| | - Nassima Benzoubir
- Inserm, Unité 1193, Villejuif, F-94800, France.,Université Paris-Sud, Institut André Lwoff, Villejuif, F-94800, France
| | - Taous Ait Saadi
- Inserm, Unité 1193, Villejuif, F-94800, France.,Université Paris-Sud, Institut André Lwoff, Villejuif, F-94800, France
| | - Mohamed Bou Saleh
- Inserm, Unité 1193, Villejuif, F-94800, France.,Université Paris-Sud, Institut André Lwoff, Villejuif, F-94800, France
| | - Philippe Mauduit
- Université Paris-Sud, Institut André Lwoff, Villejuif, F-94800, France.,Inserm, Unité 1197, Villejuif, F-94800, France
| | - Catherine Guettier
- Inserm, Unité 1193, Villejuif, F-94800, France.,Université Paris-Sud, Institut André Lwoff, Villejuif, F-94800, France.,AP-HP Hôpital Bicêtre, Service d'Anatomopathologie, Le Kremlin-Bicêtre, F-94275, France
| | - Christophe Desterke
- Université Paris-Sud, Institut André Lwoff, Villejuif, F-94800, France.,Inserm, US33, Villejuif, F-94800, France
| | - François Le Naour
- Inserm, Unité 1193, Villejuif, F-94800, France.,Université Paris-Sud, Institut André Lwoff, Villejuif, F-94800, France.,Inserm, US33, Villejuif, F-94800, France
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38
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Systems Biology Approaches to Investigate Genetic and Epigenetic Molecular Progression Mechanisms for Identifying Gene Expression Signatures in Papillary Thyroid Cancer. Int J Mol Sci 2019; 20:ijms20102536. [PMID: 31126066 PMCID: PMC6566633 DOI: 10.3390/ijms20102536] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 05/15/2019] [Accepted: 05/21/2019] [Indexed: 12/20/2022] Open
Abstract
Thyroid cancer is the most common endocrine cancer. Particularly, papillary thyroid cancer (PTC) accounts for the highest proportion of thyroid cancer. Up to now, there are few researches discussing the pathogenesis and progression mechanisms of PTC from the viewpoint of systems biology approaches. In this study, first we constructed the candidate genetic and epigenetic network (GEN) consisting of candidate protein–protein interaction network (PPIN) and candidate gene regulatory network (GRN) by big database mining. Secondly, system identification and system order detection methods were applied to prune candidate GEN via next-generation sequencing (NGS) and DNA methylation profiles to obtain the real GEN. After that, we extracted core GENs from real GENs by the principal network projection (PNP) method. To investigate the pathogenic and progression mechanisms in each stage of PTC, core GEN was denoted in respect of KEGG pathways. Finally, by comparing two successive core signaling pathways of PTC, we not only shed light on the causes of PTC progression, but also identified essential biomarkers with specific gene expression signature. Moreover, based on the identified gene expression signature, we suggested potential candidate drugs to prevent the progression of PTC with querying Connectivity Map (CMap).
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Li C, Zhao L, Wang Y, Che L, Luan H, Luo C, Xu Y. Cysteine‐rich protein 61, a specific ultra‐early biomarker in kidney ischemia/reperfusion injury. Nephrology (Carlton) 2019; 24:798-805. [PMID: 30328178 DOI: 10.1111/nep.13513] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2018] [Indexed: 01/03/2023]
Affiliation(s)
- Chenyu Li
- Department of NephrologyThe Affiliated Hospital of Qingdao University Qingdao China
| | - Long Zhao
- Department of NephrologyThe Affiliated Hospital of Qingdao University Qingdao China
| | - Yanfei Wang
- Department of NephrologyThe Affiliated Hospital of Qingdao University Qingdao China
| | - Lin Che
- Department of NephrologyThe Affiliated Hospital of Qingdao University Qingdao China
| | - Hong Luan
- Department of NephrologyThe Affiliated Hospital of Qingdao University Qingdao China
| | - Congjuan Luo
- Department of NephrologyThe Affiliated Hospital of Qingdao University Qingdao China
| | - Yan Xu
- Department of NephrologyThe Affiliated Hospital of Qingdao University Qingdao China
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40
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Maguire LH, Handelman SK, Du X, Chen Y, Pers TH, Speliotes EK. Genome-wide association analyses identify 39 new susceptibility loci for diverticular disease. Nat Genet 2018; 50:1359-1365. [PMID: 30177863 PMCID: PMC6168378 DOI: 10.1038/s41588-018-0203-z] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 07/23/2018] [Indexed: 12/31/2022]
Abstract
Diverticular disease is common and has a high morbidity. Treatments are limited owing to the poor understanding of its pathophysiology. Here, to elucidate its etiology, we performed a genome-wide association study of diverticular disease (27,444 cases; 382,284 controls) from the UK Biobank and tested for replication in the Michigan Genomics Initiative (2,572 cases; 28,649 controls). We identified 42 loci associated with diverticular disease; 39 of these loci are novel. Using data-driven expression-prioritized integration for complex traits (DEPICT), we show that genes in these associated regions are significantly enriched for expression in mesenchymal stem cells and multiple connective tissue cell types and are co-expressed with genes that have a role in vascular and mesenchymal biology. Genes in these associated loci have roles in immunity, extracellular matrix biology, cell adhesion, membrane transport and intestinal motility. Phenome-wide association analysis of the 42 variants shows a common etiology of diverticular disease with obesity and hernia. These analyses shed light on the genomic landscape of diverticular disease.
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Affiliation(s)
- Lillias H Maguire
- Department of Surgery, Division of Colorectal Surgery, University of Michigan, Ann Arbor, MI, USA.
| | - Samuel K Handelman
- Department of Internal Medicine, Division of Gastroenterology, Ann Arbor, MI, USA
| | - Xiaomeng Du
- Department of Internal Medicine, Division of Gastroenterology, Ann Arbor, MI, USA
| | - Yanhua Chen
- Department of Internal Medicine, Division of Gastroenterology, Ann Arbor, MI, USA
| | - Tune H Pers
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
| | - Elizabeth K Speliotes
- Department of Internal Medicine, Division of Gastroenterology, Ann Arbor, MI, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
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41
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Abstract
CCN proteins are secreted into the extracellular environment where they interact with both components of the extracellular matrix and with cell surface receptors to regulate cellular function. Through these interactions, CCNs act as extracellular ligands to activate intracellular signal transduction pathways. CCN4/WISP-1, like other CCNs, plays multiple physiologic roles in development and also participates in pathogenesis. CCN4 is of particular interest with respect to cancer, showing promise as a biomarker or prognostic factor as well as a potential therapeutic target. This review focuses on recent work addressing the role of CCN4 in cancer. While CCN4 has been identified as an oncogene in a number of cancers, where it enhances cell migration and promoting epithelial-mesenchymal transition, there are other cancers where CCN4 appears to play an inhibitory role. The mechanisms underlying these differences in cellular response have not yet been delineated, but are an active area of investigation. The expression and activities of CCN4 splice variants are likewise an emerging area for study. CCN4 acts as an autocrine factor that regulates the cancer cells from which it is secreted. However, CCN4 is also a paracrine factor that is secreted by stromal fibroblasts, and can affect the function of vascular endothelial cells. In summary, current evidence is abundant in regard to establishing potential roles for CCN4 in oncogenesis, but much remains to be learned about the functions of this fascinating protein as both an autocrine and paracrine regulator in the tumor microenvironment.
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Affiliation(s)
- Mary P Nivison
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA,
| | - Kathryn E Meier
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA,
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42
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Ramazani Y, Knops N, Elmonem MA, Nguyen TQ, Arcolino FO, van den Heuvel L, Levtchenko E, Kuypers D, Goldschmeding R. Connective tissue growth factor (CTGF) from basics to clinics. Matrix Biol 2018; 68-69:44-66. [DOI: 10.1016/j.matbio.2018.03.007] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 03/05/2018] [Accepted: 03/06/2018] [Indexed: 02/07/2023]
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43
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Dong QQ, Wang QT, Wang L, Jiang YX, Liu ML, Hu HJ, Liu Y, Zhou H, He HP, Zhang TC, Luo XG. SMYD3-associated pathway is involved in the anti-tumor effects of sulforaphane on gastric carcinoma cells. Food Sci Biotechnol 2018; 27:1165-1173. [PMID: 30263847 PMCID: PMC6085256 DOI: 10.1007/s10068-018-0337-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 12/26/2017] [Accepted: 02/11/2018] [Indexed: 12/13/2022] Open
Abstract
Sulforaphane (SFN), a natural compound derived from cruciferous vegetables, has been proved to possess potent anti-cancer activity. SMYD3 is a histone methyltransferase which is closely related to the proliferation and migration of cancer cells. This study showed that SFN could dose-dependently induce cell cycle arrest, stimulate apoptosis, and inhibit proliferation and migration of gastric carcinoma cells. Accompanied with these anti-cancer effects, SMYD3 and its downstream genes, myosin regulatory light chain 9, and cysteine-rich angiogenic inducer 61, was downregulated by SFN. Furthermore, overexpression of SMYD3 via transfection could abolish the effects of SFN, suggesting that SMYD3 might be an important mediator of SFN. To the best of our knowledge, this is the first report describing the role of SMYD3 in the anti-cancer of SFN. These findings might throw light on the development of novel anti-cancer drugs and functional food using SFN-rich cruciferous vegetables.
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Affiliation(s)
- Qing-Qing Dong
- State Key Laboratory of Food Nutrition and Safety & Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology) of the Ministry of Education, Tianjin, 300457 People’s Republic of China
- Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457 People’s Republic of China
| | - Qiu-Tong Wang
- State Key Laboratory of Food Nutrition and Safety & Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology) of the Ministry of Education, Tianjin, 300457 People’s Republic of China
- Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457 People’s Republic of China
| | - Lei Wang
- State Key Laboratory of Food Nutrition and Safety & Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology) of the Ministry of Education, Tianjin, 300457 People’s Republic of China
- Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457 People’s Republic of China
| | - Ya-Xin Jiang
- State Key Laboratory of Food Nutrition and Safety & Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology) of the Ministry of Education, Tianjin, 300457 People’s Republic of China
- Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457 People’s Republic of China
| | - Mei-Ling Liu
- State Key Laboratory of Food Nutrition and Safety & Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology) of the Ministry of Education, Tianjin, 300457 People’s Republic of China
- Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457 People’s Republic of China
| | - Hai-Jie Hu
- State Key Laboratory of Food Nutrition and Safety & Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology) of the Ministry of Education, Tianjin, 300457 People’s Republic of China
- Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457 People’s Republic of China
| | - Yong Liu
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060 China
| | - Hao Zhou
- State Key Laboratory of Food Nutrition and Safety & Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology) of the Ministry of Education, Tianjin, 300457 People’s Republic of China
- Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457 People’s Republic of China
| | - Hong-Peng He
- State Key Laboratory of Food Nutrition and Safety & Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology) of the Ministry of Education, Tianjin, 300457 People’s Republic of China
- Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457 People’s Republic of China
| | - Tong-Cun Zhang
- State Key Laboratory of Food Nutrition and Safety & Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology) of the Ministry of Education, Tianjin, 300457 People’s Republic of China
- Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457 People’s Republic of China
| | - Xue-Gang Luo
- State Key Laboratory of Food Nutrition and Safety & Key Lab of Industrial Fermentation Microbiology (Tianjin University of Science and Technology) of the Ministry of Education, Tianjin, 300457 People’s Republic of China
- Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457 People’s Republic of China
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44
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Hutchenreuther J, Vincent K, Norley C, Racanelli M, Gruber SB, Johnson TM, Fullen DR, Raskin L, Perbal B, Holdsworth DW, Postovit LM, Leask A. Activation of cancer-associated fibroblasts is required for tumor neovascularization in a murine model of melanoma. Matrix Biol 2018; 74:52-61. [PMID: 29885461 DOI: 10.1016/j.matbio.2018.06.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 05/10/2018] [Accepted: 06/05/2018] [Indexed: 01/08/2023]
Abstract
Metastatic melanoma is highly fatal. Within the tumor microenvironment, the role of cancer-associated fibroblasts (CAFs) in melanoma metastasis and progression is relatively understudied. The matricellular protein CCN2 (formerly termed connective tissue growth factor, CTGF) is overexpressed, in a fashion independent of BRAF mutational status, by CAFs in melanoma. Herein, we find, in human melanoma patients, that CCN2 expression negatively correlates with survival and positively correlates with expression of neovascularization markers. To assess the role of CAFs in melanoma progression, we used C57BL/6 mice expressing a tamoxifen-dependent cre recombinase expressed under the control of a fibroblast-specific promoter/enhancer (COL1A2) to delete CCN2 postnatally in fibroblasts. Mice deleted or not for CCN2 in fibroblasts were injected subcutaneously with B16-F10 melanoma cells. Loss of CCN2 in CAFs resulted in reduced CAF activation, as detected by staining with anti-α-smooth muscle actin antibodies, and reduced tumor-induced neovascularization, as detected by micro-computed tomography (micro-CT) and staining with anti-CD31 antibodies. CCN2-deficient B16(F10) cells were defective in a tubule formation/vasculogenic mimicry assay in vitro. Mice deleted for CCN2 in CAFs also showed impaired vasculogenic mimicry of subcutaneously-injected B16-F10 cells in vivo. Our results provide new insights into the cross-talk among different cell types in the tumor microenvironment and suggest CAFs play a heretofore unappreciated role by being essential for tumor neovascularization via the production of CCN2. Our data are consistent with the hypothesis that activated CAFs are essential for melanoma metastasis and that, due to its role in this process, CCN2 is a therapeutic target for melanoma.
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Affiliation(s)
- James Hutchenreuther
- Departments of Physiology and Pharmacology, University of Western Ontario, London N6A 5C1, ON, Canada
| | - Krista Vincent
- Departments of Anatomy and Cell Biology, University of Western Ontario, London N6A 5C1, ON, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada
| | - Chris Norley
- Robarts Research Institute, University of Western Ontario, London, ON, Canada
| | - Michael Racanelli
- Departments of Physiology and Pharmacology, University of Western Ontario, London N6A 5C1, ON, Canada
| | - Stephen B Gruber
- Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Timothy M Johnson
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Douglas R Fullen
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Leon Raskin
- Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | | | - David W Holdsworth
- Robarts Research Institute, University of Western Ontario, London, ON, Canada
| | | | - Andrew Leask
- Departments of Physiology and Pharmacology, University of Western Ontario, London N6A 5C1, ON, Canada; Departments of Dentistry, University of Western Ontario, London N6A 5C1, ON, Canada.
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45
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Campbell JD, Yau C, Bowlby R, Liu Y, Brennan K, Fan H, Taylor AM, Wang C, Walter V, Akbani R, Byers LA, Creighton CJ, Coarfa C, Shih J, Cherniack AD, Gevaert O, Prunello M, Shen H, Anur P, Chen J, Cheng H, Hayes DN, Bullman S, Pedamallu CS, Ojesina AI, Sadeghi S, Mungall KL, Robertson AG, Benz C, Schultz A, Kanchi RS, Gay CM, Hegde A, Diao L, Wang J, Ma W, Sumazin P, Chiu HS, Chen TW, Gunaratne P, Donehower L, Rader JS, Zuna R, Al-Ahmadie H, Lazar AJ, Flores ER, Tsai KY, Zhou JH, Rustgi AK, Drill E, Shen R, Wong CK, Stuart JM, Laird PW, Hoadley KA, Weinstein JN, Peto M, Pickering CR, Chen Z, Van Waes C. Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas. Cell Rep 2018; 23:194-212.e6. [PMID: 29617660 PMCID: PMC6002769 DOI: 10.1016/j.celrep.2018.03.063] [Citation(s) in RCA: 229] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 02/26/2018] [Accepted: 03/15/2018] [Indexed: 12/23/2022] Open
Abstract
This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.
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Affiliation(s)
- Joshua D Campbell
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Boston University School of Medicine, Boston, MA 02118, USA
| | - Christina Yau
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94115, USA; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
| | - Reanne Bowlby
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
| | - Yuexin Liu
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kevin Brennan
- Department of Medicine-Biomedical Informatics Research, Stanford University, Stanford, CA 94305, USA
| | - Huihui Fan
- Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Alison M Taylor
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
| | - Chen Wang
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Vonn Walter
- Department of Public Health Sciences, Penn State Milton Hershey Medical Center, Hershey, PA 17033, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Rehan Akbani
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lauren Averett Byers
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Chad J Creighton
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Medicine and Dan L Duncan Comprehensive Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Cristian Coarfa
- Department of Molecular & Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Juliann Shih
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
| | - Andrew D Cherniack
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
| | - Olivier Gevaert
- Department of Medicine-Biomedical Informatics Research, Stanford University, Stanford, CA 94305, USA
| | - Marcos Prunello
- Department of Medicine-Biomedical Informatics Research, Stanford University, Stanford, CA 94305, USA
| | - Hui Shen
- Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Pavana Anur
- Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97201, USA
| | - Jianhong Chen
- Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA
| | - Hui Cheng
- Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA
| | - D Neil Hayes
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Susan Bullman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
| | - Chandra Sekhar Pedamallu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
| | - Akinyemi I Ojesina
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Hudson Alpha Institute for Biotechnology, Huntsville, AL 35806, USA
| | - Sara Sadeghi
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
| | - Karen L Mungall
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
| | - A Gordon Robertson
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
| | - Christopher Benz
- Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
| | - Andre Schultz
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rupa S Kanchi
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Carl M Gay
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Apurva Hegde
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lixia Diao
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Wencai Ma
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Pavel Sumazin
- Department of Medicine-Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hua-Sheng Chiu
- Department of Medicine-Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ting-Wen Chen
- Department of Medicine-Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Preethi Gunaratne
- Department of Biology & Biochemistry, UH-SeqNEdit Core, University of Houston, Houston, TX 77204, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Larry Donehower
- Center for Comparative Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Janet S Rader
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Rosemary Zuna
- University of Oklahoma Health Sciences Center, Department of Pathology, Oklahoma City, OK 73104, USA
| | - Hikmat Al-Ahmadie
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Alexander J Lazar
- Departments of Pathology, Genomic Medicine, Dermatology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77401, USA
| | - Elsa R Flores
- Molecular Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Kenneth Y Tsai
- Departments of Anatomic Pathology and Tumor Biology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Jane H Zhou
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Anil K Rustgi
- Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Esther Drill
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ronglei Shen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Christopher K Wong
- Department of Biomolecular Engineering, Center for Biomolecular Sciences and Engineering University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Joshua M Stuart
- Department of Biomolecular Engineering, Center for Biomolecular Sciences and Engineering University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Peter W Laird
- Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Katherine A Hoadley
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - John N Weinstein
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Myron Peto
- Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97201, USA
| | - Curtis R Pickering
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhong Chen
- Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
| | - Carter Van Waes
- Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
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46
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Wu W, Hu X, Zhou X, Klenotic PA, Zhou Q, Lin Z. Myeloid deficiency of CCN3 exacerbates liver injury in a mouse model of nonalcoholic fatty liver disease. J Cell Commun Signal 2017; 12:389-399. [PMID: 29214510 DOI: 10.1007/s12079-017-0432-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 10/28/2017] [Indexed: 11/28/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a condition in which fat accumulates in the liver of patients without a prior history of alcohol abuse. The most severe form, nonalcoholic steatohepatitis (NASH), often leads to hepatic fibrosis and cirrhosis with ensuing complications. To date, there is no pharmacologic treatment for NASH. The biological effects of CCN3, specifically its role in the regulation of inflammation, reactive oxygen species production and angiogenesis, have been recently established. Additional data suggests that CCN3 is associated with the development of tumors in the liver yet may be protective of liver fibrogenesis. Currently, the role of CCN3 in NAFLD/NASH remains unexplored. Therefore, the objective of our investigation was to decipher the role of myeloid-deficient CCN3 in the pathogenesis of NASH and the underlying mechanisms of CCN3 in modulation of hepatic function. Wild type and myeloid CCN3-deficient mice were fed a methionine- and choline-deficient diet to induced NASH. Increased lipid, cholesterol, and cholesterol ester accumulation was observed in myeloid CCN3-deficient mice when compared to the control group. This disease state was associated with alterations of key genes involved in lipid synthesis, β-oxidation and lipid uptake. Additionally, the levels of important molecules critical for inflammation, ROS generation, ER stress and liver injury were significantly elevated; as was the observed severity of hepatic apoptosis and necroptosis. Therefore, CCN3 is critical for protection from hepatic apoptosis and necroptosis in our induced NASH model and our findings suggest that CCN3 can be exploited as a therapeutic target for the treatment of NASH.
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Affiliation(s)
- Wenconghui Wu
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, 2103 Cornell Road, Room 4-541, Cleveland, OH, 44106, USA.,Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, Hubei Province, 430030, China.,Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, China
| | - Xingjian Hu
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, 2103 Cornell Road, Room 4-541, Cleveland, OH, 44106, USA.,Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xianming Zhou
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, 2103 Cornell Road, Room 4-541, Cleveland, OH, 44106, USA.,Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Philip A Klenotic
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, 2103 Cornell Road, Room 4-541, Cleveland, OH, 44106, USA
| | - Qi Zhou
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, Hubei Province, 430030, China
| | - Zhiyong Lin
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, 2103 Cornell Road, Room 4-541, Cleveland, OH, 44106, USA.
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47
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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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48
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Mayer S, Erbes T, Timme-Bronsert S, Jaeger M, Rücker G, Kuf F, Stickeler E, Gitsch G, Hirschfeld M. Clinical relevance of Cyr61 expression in patients with hormone-dependent breast cancer. Oncol Lett 2017; 14:2334-2340. [PMID: 28789451 PMCID: PMC5529991 DOI: 10.3892/ol.2017.6406] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 04/07/2017] [Indexed: 01/13/2023] Open
Abstract
Tumor resistance to endocrine therapy triggers estrogen-independent cancer progression, which is a major obstacle to the successful treatment of hormone receptor positive breast cancer (BC). The underlying molecular mechanisms of endocrine resistance are not fully understood yet. The matricellular protein cysteine-rich angiogenic inducer 61 (Cyr61) is associated with tumor invasiveness and the induction of tumorigenesis in various malignancies in vivo and the induction of estrogen-independence and endocrine therapy resistance in BC. The present study evaluated the potential effects and clinical relevance of Cyr61 expression levels in 67 patients with primary non-metastatic BC. Immunohistochemical analysis of formalin-fixed paraffin-embedded tissue sections was performed, and the association between Cyr61 protein expression and clinicopathological factors and survival was analyzed. Cyr61 overexpression was revealed to be significantly associated with a positive estrogen receptor (ER)/progesterone receptor (PR) status (P=0.016) and to the molecular subtype of BC (P=0.039). Compared with patients without Cyr61 overexpression, patients with Cyr61 overexpression exhibited an increased recurrence rate (30.6 vs. 22.6%) and decreased long-term survival (10-year overall survival, 62.9 vs. 69.7%); however, these associations did not reach statistically significant levels in Cox regression model analysis. Similar results were identified in the subgroup analysis of patients with ER/PR positive BC. These results indicate that Cyr61 serves a role in the development of endocrine therapy resistance in BC and is thus a potential therapeutic target to overcome endocrine therapy resistance. However, additional long-term survival analyses with large patient populations are required.
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Affiliation(s)
- Sebastian Mayer
- Department of Obstetrics and Gynecology, Medical Center - University of Freiburg, D-79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, D-79106 Freiburg, Germany
| | - Thalia Erbes
- Department of Obstetrics and Gynecology, Medical Center - University of Freiburg, D-79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, D-79106 Freiburg, Germany
| | - Sylvia Timme-Bronsert
- Faculty of Medicine, University of Freiburg, D-79106 Freiburg, Germany
- Institute of Surgical Pathology, Department of Pathology, Medical Center - University of Freiburg, D-79106 Freiburg, Germany
| | - Markus Jaeger
- Department of Obstetrics and Gynecology, Medical Center - University of Freiburg, D-79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, D-79106 Freiburg, Germany
| | - Gerta Rücker
- Faculty of Medicine, University of Freiburg, D-79106 Freiburg, Germany
- Institute for Medical Biometry and Statistics, Medical Center - University of Freiburg, D-79106 Freiburg, Germany
| | - Franciska Kuf
- Department of Obstetrics and Gynecology, Medical Center - University of Freiburg, D-79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, D-79106 Freiburg, Germany
| | - Elmar Stickeler
- Department of Gynecology and Obstetrics, University Medical Center RWTH Aachen, D-52062 Aachen, Germany
| | - Gerald Gitsch
- Department of Obstetrics and Gynecology, Medical Center - University of Freiburg, D-79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, D-79106 Freiburg, Germany
| | - Marc Hirschfeld
- Department of Obstetrics and Gynecology, Medical Center - University of Freiburg, D-79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, D-79106 Freiburg, Germany
- Institute of Veterinary Medicine, University of Göttingen, D-37073 Göttingen, Germany
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49
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Jeinsen N, Mägel L, Jonigk D, Klingenberg M, Haverich A, Wilhelmi M, Böer U. Biocompatibility of Intensified Decellularized Equine Carotid Arteries in a Rat Subcutaneous Implantation Model and in a Human In Vitro Model. Tissue Eng Part A 2017; 24:310-321. [PMID: 28530164 DOI: 10.1089/ten.tea.2016.0542] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Limited biocompatibility of decellularized scaffolds is an ongoing challenge in tissue engineering. We recently demonstrated that intensified detergent-based decellularization of equine carotid artery (dEACintens) removed residual cellular molecules from the scaffold more efficiently than a conventional decellularization (dEACcon), although this approach did not eliminate its immunogenicity entirely. CCN1 has been shown to improve biocompatibility of dEACcon in a sheep model. In this study, we tested the biocompatibility of dEACintens and dEACcon with or without CCN1 coating after subcutaneous implantation in rats for up to 12 weeks. Explants were assessed by conventional histopathology and immunostaining for infiltrating M2 macrophages. Moreover, human macrophages derived from monocytes (MDM) or THP-1 cells (THP-derived macrophages [TDM]) were seeded onto dEACcon and dEACintens, and activation was assessed either by cytokine expression or matrix metalloprotease 2 and 7 staining. dEACintens showed a significantly reduced inflammatory infiltration (52%; p < 0.0001), as well as an earlier and denser neovascularization (1.4-fold, p < 0.0001) independent of CCN1 coating, which, however, reduced fibrosis exclusively with dEACintens (26-53%; p < 0.05). Human MDM seeded for 48 h onto dEACintens showed higher transcript levels for anti-inflammatory IL-10 (2.3-fold), proinflammatory TNFα (2.2-fold), and macrophage/monocyte recruiting MIP1α (3.5-fold; all p < 0.05) and MCP (2.7-fold; p < 0.01), whereas 1.92-fold more TDM on dEACintens showed staining for MMP2 (p > 0.001). Thus, although being advantageous in regard to fibrosis, CCN1 coating of dEACintens does not appear to be necessary for further improving dEACintens excellent biocompatibility in rats. In humans, the unspecific cellular immune response toward dEACintens seemed to be more complex, but generally comparable to the mild acute inflammatory tissue reaction with high remodeling activity as observed after rat subcutaneous implantation.
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Affiliation(s)
- Niklas Jeinsen
- 1 Lower Saxony Centre of Biotechnology, Implant Research and Development (NIFE), Hannover Medical School , Hannover, Germany
| | - Lavinia Mägel
- 2 Institute of Pathology , Hannover Medical School, Hannover, Germany
| | - Danny Jonigk
- 2 Institute of Pathology , Hannover Medical School, Hannover, Germany
| | - Melanie Klingenberg
- 1 Lower Saxony Centre of Biotechnology, Implant Research and Development (NIFE), Hannover Medical School , Hannover, Germany .,3 Division for Cardiothoracic-, Transplantation- and Vascular Surgery, Hannover Medical School , Hannover, Germany
| | - Axel Haverich
- 1 Lower Saxony Centre of Biotechnology, Implant Research and Development (NIFE), Hannover Medical School , Hannover, Germany .,3 Division for Cardiothoracic-, Transplantation- and Vascular Surgery, Hannover Medical School , Hannover, Germany
| | - Mathias Wilhelmi
- 1 Lower Saxony Centre of Biotechnology, Implant Research and Development (NIFE), Hannover Medical School , Hannover, Germany .,3 Division for Cardiothoracic-, Transplantation- and Vascular Surgery, Hannover Medical School , Hannover, Germany
| | - Ulrike Böer
- 1 Lower Saxony Centre of Biotechnology, Implant Research and Development (NIFE), Hannover Medical School , Hannover, Germany .,3 Division for Cardiothoracic-, Transplantation- and Vascular Surgery, Hannover Medical School , Hannover, Germany
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