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Li X, Luo X, Zhang X, Guo Y, Cheng L, Cheng M, Tang S, Gong Y. COL1A1 promotes cell proliferation, cell cycle progression, and anoikis resistance in granulosa cells of chicken pre-ovulatory follicles. Int J Biol Macromol 2025; 306:141524. [PMID: 40020834 DOI: 10.1016/j.ijbiomac.2025.141524] [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: 07/02/2024] [Revised: 02/25/2025] [Accepted: 02/25/2025] [Indexed: 03/03/2025]
Abstract
Chicken follicular granulosa cells (GCs) are the earliest differentiated follicular somatic cells, which play a crucial role throughout follicular growth and development. The extracellular matrix (ECM) plays a key role in maintaining cell-cell interactions and communication during follicular development. This study investigated the effects of the COL1A1 gene, a major component of ECM, on chicken pre-ovulatory follicular granulosa cells (PO-GCs) and the related regulatory mechanism. Transcriptomic analysis results showed that silencing COL1A1 significantly inhibited GCs proliferation, cell cycle, and anoikis-related biological functions and pathways. The overexpression of endogenous COL1A1 promoted the GCs proliferation through the ERK1/2 signaling pathway, increased the number of GCs in the S/G2 phase of the cell cycle, and enhanced anoikis resistance of GCs. The exogenous addition of collagen Ι (Col Ι) promoted GCs proliferation but did not affect the cell cycle progression and anoikis resistance of GCs. In addition, we identified multiple genes involved in COL1A1 knockdown-induced anoikis in GCs, of which 7 genes including PIK3CA, DAPK2, TSC2, BMF, SRC, NTRK2, and NOTCH1 were identified as the core anoikis genes. Our findings provide new perspectives for exploring the role of ECM in chicken follicle development and lay the foundation for further revealing the regulatory network of follicular development.
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Affiliation(s)
- Xuelian Li
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, Wuhan, Hubei, PR China; College of Animal Science and Technology and College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Xuliang Luo
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, Wuhan, Hubei, PR China; College of Animal Science and Technology and College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Xiaxia Zhang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, Wuhan, Hubei, PR China; College of Animal Science and Technology and College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Yan Guo
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, Wuhan, Hubei, PR China; College of Animal Science and Technology and College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Lu Cheng
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, Wuhan, Hubei, PR China; College of Animal Science and Technology and College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Manman Cheng
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, Wuhan, Hubei, PR China; College of Animal Science and Technology and College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Shuixin Tang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, Wuhan, Hubei, PR China; College of Animal Science and Technology and College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Yanzhang Gong
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, Wuhan, Hubei, PR China; College of Animal Science and Technology and College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China.
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Mancini F, Teveroni E, Cicchinelli M, Iavarone F, Astorri AL, Maulucci G, Serantoni C, Hatem D, Gallo D, Di Nardo C, Urbani A, Pontecorvi A, Milardi D, Di Nicuolo F. Secretory Profile Analysis of Human Granulosa Cell Line Following Gonadotropin Stimulation. Int J Mol Sci 2025; 26:4108. [PMID: 40362347 PMCID: PMC12072160 DOI: 10.3390/ijms26094108] [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: 02/27/2025] [Revised: 04/16/2025] [Accepted: 04/17/2025] [Indexed: 05/15/2025] Open
Abstract
Granulosa cell (GC) differentiation, stimulated by FSH and LH, drives oocyte maturation and follicle development. FSH promotes GC proliferation, and LH triggers ovulation. In clinical practice, hCG is used to mimic LH. Despite various controlled ovarian stimulation (COS) protocols employing exogenous gonadotropins and GnRH analogs to prevent premature ovulation, their effectiveness and safety remain debated. To identify markers predicting a positive treatment response, the secretome of gonadotropin-stimulated GC using the human granulosa-like tumor cell line (KGN) via proteomics was analyzed. Additionally, a novel 2D-FFT quantitative method was employed to assess cytoskeleton fiber aggregation and polymerization, which are critical processes for GC differentiation. Furthermore, the activation of key kinases, focal adhesion kinase (FAK), and Rho-associated coiled-coil-containing protein kinase 1 (ROCK-1), which are implicated in cytoskeleton dynamics and hormone signaling, was evaluated. The proteomic analysis revealed significant modulation of proteins involved in extracellular matrix organization, steroidogenesis, and cytoskeleton remodeling. Notably, the combined FSH/hCG treatment led to a dynamic upregulation of the semaphorin pathway, specifically semaphorin 7A. Finally, a significant reorganization of the cytoskeleton network and signaling was detected. These findings enhance our understanding of folliculogenesis and suggest potential novel molecular markers for predicting patient responses to gonadotropin stimulation.
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Affiliation(s)
- Francesca Mancini
- International Scientific Institute Paul VI, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.M.); (E.T.); (A.L.A.); (F.D.N.)
| | - Emanuela Teveroni
- International Scientific Institute Paul VI, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.M.); (E.T.); (A.L.A.); (F.D.N.)
| | - Michela Cicchinelli
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (M.C.); (F.I.); (A.U.)
| | - Federica Iavarone
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (M.C.); (F.I.); (A.U.)
- Clinical Chemistry, Biochemistry and Molecular Biology Operations (UOC), Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Anna Laura Astorri
- International Scientific Institute Paul VI, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.M.); (E.T.); (A.L.A.); (F.D.N.)
| | - Giuseppe Maulucci
- Department of Neuroscience, Section of Biophysics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (G.M.); (C.S.); (D.H.)
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Cassandra Serantoni
- Department of Neuroscience, Section of Biophysics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (G.M.); (C.S.); (D.H.)
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Duaa Hatem
- Department of Neuroscience, Section of Biophysics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (G.M.); (C.S.); (D.H.)
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Daniela Gallo
- Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Lgo A. Gemelli 8, 00168 Roma, Italy;
| | - Carla Di Nardo
- Division of Endocrinology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (C.D.N.); (A.P.)
| | - Andrea Urbani
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (M.C.); (F.I.); (A.U.)
- Clinical Chemistry, Biochemistry and Molecular Biology Operations (UOC), Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Alfredo Pontecorvi
- Division of Endocrinology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (C.D.N.); (A.P.)
| | - Domenico Milardi
- International Scientific Institute Paul VI, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.M.); (E.T.); (A.L.A.); (F.D.N.)
- Division of Endocrinology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (C.D.N.); (A.P.)
| | - Fiorella Di Nicuolo
- International Scientific Institute Paul VI, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.M.); (E.T.); (A.L.A.); (F.D.N.)
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Buraschi S, Pascal G, Liberatore F, Iozzo RV. Comprehensive investigation of proteoglycan gene expression in breast cancer: Discovery of a unique proteoglycan gene signature linked to the malignant phenotype. PROTEOGLYCAN RESEARCH 2025; 3:e70014. [PMID: 40066261 PMCID: PMC11893098 DOI: 10.1002/pgr2.70014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 12/06/2024] [Indexed: 03/14/2025]
Abstract
Solid tumors present a formidable challenge in oncology, necessitating innovative approaches to improve therapeutic outcomes. Proteoglycans, multifaceted molecules within the tumor microenvironment, have garnered attention due to their diverse roles in cancer progression. Their unique ability to interact with specific membrane receptors, growth factors, and cytokines provides a promising avenue for the development of recombinant proteoglycan-based therapies that could enhance the precision and efficacy of cancer treatment. In this study, we performed a comprehensive analysis of the proteoglycan gene landscape in human breast carcinomas. Leveraging the available wealth of genomic and clinical data regarding gene expression in breast carcinoma and using a machine learning model, we identified a unique gene expression signature composed of five proteoglycans differentially modulated in the tumor tissue: Syndecan-1 and asporin (upregulated) and decorin, PRELP and podocan (downregulated). Additional query of the breast carcinoma data revealed that serglycin, previously shown to be increased in breast carcinoma patients and mouse models and to correlate with a poor prognosis, was indeed decreased in the vast majority of breast cancer patients and its levels inversely correlated with tumor progression and invasion. This proteoglycan gene signature could provide novel diagnostic capabilities in breast cancer biology and highlights the need for further utilization of publicly available datasets for the clinical validation of preclinical experimental results.
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Affiliation(s)
- Simone Buraschi
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Gabriel Pascal
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Federico Liberatore
- School of Computer Science and Informatics, Cardiff University, Cardiff CF24 4AG, UK
| | - Renato V Iozzo
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
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Manou D, Golfinopoulou MA, Alharbi SND, Alghamdi HA, Alzahrani FM, Theocharis AD. The Expression of Serglycin Is Required for Active Transforming Growth Factor β Receptor I Tumorigenic Signaling in Glioblastoma Cells and Paracrine Activation of Stromal Fibroblasts via CXCR-2. Biomolecules 2024; 14:461. [PMID: 38672477 PMCID: PMC11048235 DOI: 10.3390/biom14040461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 03/25/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
Serglycin (SRGN) is a pro-tumorigenic proteoglycan expressed and secreted by various aggressive tumors including glioblastoma (GBM). In our study, we investigated the interplay and biological outcomes of SRGN with TGFβRI, CXCR-2 and inflammatory mediators in GBM cells and fibroblasts. SRGN overexpression is associated with poor survival in GBM patients. High SRGN levels also exhibit a positive correlation with increased levels of various inflammatory mediators including members of TGFβ signaling pathway, cytokines and receptors including CXCR-2 and proteolytic enzymes in GBM patients. SRGN-suppressed GBM cells show decreased expressions of TGFβRI associated with lower responsiveness to the manipulation of TGFβ/TGFβRI pathway and the regulation of pro-tumorigenic properties. Active TGFβRI signaling in control GBM cells promotes their proliferation, invasion, proteolytic and inflammatory potential. Fibroblasts cultured with culture media derived by control SRGN-expressing GBM cells exhibit increased proliferation, migration and overexpression of cytokines and proteolytic enzymes including CXCL-1, IL-8, IL-6, IL-1β, CCL-20, CCL-2, and MMP-9. Culture media derived by SRGN-suppressed GBM cells fail to induce the above properties to fibroblasts. Importantly, the activation of fibroblasts by GBM cells not only relies on the expression of SRGN in GBM cells but also on active CXCR-2 signaling both in GBM cells and fibroblasts.
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Affiliation(s)
- Dimitra Manou
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece; (D.M.); (M.-A.G.)
| | - Maria-Angeliki Golfinopoulou
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece; (D.M.); (M.-A.G.)
| | - Sara Naif D. Alharbi
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia; (S.N.D.A.); (H.A.A.); (F.M.A.)
| | - Hind A. Alghamdi
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia; (S.N.D.A.); (H.A.A.); (F.M.A.)
| | - Fatimah Mohammed Alzahrani
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia; (S.N.D.A.); (H.A.A.); (F.M.A.)
| | - Achilleas D. Theocharis
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece; (D.M.); (M.-A.G.)
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5
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Zhang S, Zhai M, Xu Y, Han J, Chen J, Xiong Y, Pan S, Wang Q, Yu C, Rao Z, Sun Q, Sui Y, Fan K, Li H, Guo W, Liu C, Bai Y, Zhou J, Quan D, Zhang X. Decellularised spinal cord matrix manipulates glial niche into repairing phase via serglycin-mediated signalling pathway. Cell Prolif 2023; 56:e13429. [PMID: 36807637 PMCID: PMC10472524 DOI: 10.1111/cpr.13429] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 02/01/2023] [Accepted: 02/06/2023] [Indexed: 02/20/2023] Open
Abstract
Astrocytes are the most abundant and widespread glial cells in the central nervous system. The heterogeneity of astrocytes plays an essential role in spinal cord injury (SCI) repair. Decellularised spinal cord matrix (DSCM) is advantageous for repairing SCI, but little is known regarding the exact mechanisms and niche alterations. Here, we investigated the DSCM regulatory mechanism of glial niche in the neuro-glial-vascular unit using single-cell RNA sequencing. Our single cell sequencing, molecular and biochemical experiments validated that DSCM facilitated the differentiation of neural progenitor cells through increasing the number of immature astrocytes. Upregulation of mesenchyme-related genes, which maintained astrocyte immaturity, causing insensitivity to inflammatory stimuli. Subsequently, we identified serglycin (SRGN) as a functional component of DSCM, which involves inducing CD44-AKT signalling to trigger human spinal cord-derived primary astrocytes (hspASCs) proliferation and upregulation of genes related to epithelial-mesenchymal transition, thus impeding astrocyte maturation. Finally, we verified that SRGN-COLI and DSCM had similar functions in the human primary cell co-culture system to mimic the glia niche. In conclusion, our work revealed that DSCM reverted astrocyte maturation and altered the glia niche into the repairing phase through the SRGN-mediated signalling pathway.
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Affiliation(s)
- Sheng Zhang
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and EngineeringSun Yat‐sen UniversityGuangzhouChina
| | - Man Zhai
- CAS Key Laboratory of Regenerative BiologyGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhouChina
| | - Yiwei Xu
- CAS Key Laboratory of Regenerative BiologyGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhouChina
| | - Jiandong Han
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and EngineeringSun Yat‐sen UniversityGuangzhouChina
| | - Jiaxin Chen
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and EngineeringSun Yat‐sen UniversityGuangzhouChina
| | - Yucui Xiong
- CAS Key Laboratory of Regenerative BiologyGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhouChina
| | - Shihua Pan
- GMU‐GIBH Joint School of Life SciencesGuangzhou Medical UniversityGuangzhouChina
| | - Qizheng Wang
- CAS Key Laboratory of Regenerative BiologyGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhouChina
| | - Chunlai Yu
- School of Life Science and TechnologyUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Zilong Rao
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and EngineeringSun Yat‐sen UniversityGuangzhouChina
| | - Qi Sun
- CAS Key Laboratory of Regenerative BiologyGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhouChina
| | - Yufei Sui
- CAS Key Laboratory of Regenerative BiologyGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhouChina
| | - Ke Fan
- CAS Key Laboratory of Regenerative BiologyGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhouChina
| | - Heying Li
- CAS Key Laboratory of Regenerative BiologyGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhouChina
| | - Wenjing Guo
- CAS Key Laboratory of Regenerative BiologyGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhouChina
| | - Cuicui Liu
- CAS Key Laboratory of Regenerative BiologyGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhouChina
| | - Ying Bai
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and EngineeringSun Yat‐sen UniversityGuangzhouChina
| | - Jing Zhou
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and EngineeringSun Yat‐sen UniversityGuangzhouChina
| | - Daping Quan
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and EngineeringSun Yat‐sen UniversityGuangzhouChina
| | - Xiao Zhang
- CAS Key Laboratory of Regenerative BiologyGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhouChina
- GMU‐GIBH Joint School of Life SciencesGuangzhou Medical UniversityGuangzhouChina
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Fakhari S, Jalili A, Nikkhoo B, Ghaderi B, Boshagh MA, Mirzaie S, Moradzad M. MT2-MMP is differentially expressed in multiple myeloma cells and mediates their growth and progression. Cell Signal 2022; 92:110248. [PMID: 35041985 DOI: 10.1016/j.cellsig.2022.110248] [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: 11/25/2021] [Revised: 01/08/2022] [Accepted: 01/11/2022] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Membrane type-matrix metalloproteinases (MT-MMPs) are known as key regulators of cancer progression/metastasis. However, their roles in the growth and progression of multiple myeloma (MM) have not been yet elucidated. METHODS AND MATERIALS The expression of 6 MT-MMPs in MM, B cell lines, and normal peripheral blood (PB) cells were measured by RT-PCR, qRT-PCR, flow cytometry, western blotting, and immunocytochemistry. B lymphocytes, CD19-/CD138-, and CD19-/CD138+ cells, known as malignant plasma cells (MPC), were sorted from bone marrow (BM) aspirations of 10 MM patients, and MT2-MMP expression was examined in these cells using qRT-PCR, flow cytometry and immunohistochemistry, and western blotting. Moreover, the expression of MT2-MMP in BM biopsies from 13 normal individuals and 14 MM patients was analyzed by immunohistochemistry. MT2-MMP was also knocked down in U266 cells using siRNA technology and the adhesion, invasion, migration abilities, and cell proliferation were determined and compared with scrambled ones in both in vitro and in vivo studies. RESULTS Our results showed that MT2-MMP expression is significantly higher in MM cell lines and MPC cells than B cell lines and other PB- or BM-derived cells. MT2-MMP is expressed in BM biopsies from all 14 patients with MM, and 67.85% ± 32.38 of BM cells were positive for MT2-MMP. In contrast, only 0.38 ± 0.76 of BM biopsies from normal individuals were positive for MT2-MMP. Importantly, MT2-MMP was expressed in all the patients' BM biopsies at the diagnosis, but not in the remission phase. MT2-MMP siRNA significantly decreased adhesion, invasion, migration, and 3D cell proliferation of U266 cells. Moreover, in the xenographic model, MT2-MMP siRNA prevented the growth and development of plasmacytoma. Taken together, these data demonstrate that MT2-MMP is strongly expressed in MM cells and plays important role in the growth and progression of these cells, suggesting that MT2-MMP is an appropriate biomarker in diagnosis and therapeutic interventions of MM.
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Affiliation(s)
- Shohreh Fakhari
- Cancer & Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
| | - Ali Jalili
- Cancer & Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
| | - Bahram Nikkhoo
- Cancer & Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Bayazid Ghaderi
- Cancer & Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Amin Boshagh
- Cancer & Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Sako Mirzaie
- Department of Biochemistry, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran
| | - Mohammad Moradzad
- Department of Clinical Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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7
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Saad AA. Targeting cancer-associated glycans as a therapeutic strategy in leukemia. ALL LIFE 2022. [DOI: 10.1080/26895293.2022.2049901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- Ashraf Abdullah Saad
- Unit of Pediatric Hematologic Oncology and BMT, Sultan Qaboos University Hospital, Muscat, Oman
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8
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Harmon KA, Roman S, Lancaster HD, Chowhury S, Cull E, Goodwin RL, Arce S, Fanning S. Structural and Ultrastructural Analysis of the Multiple Myeloma Cell Niche and a Patient-Specific Model of Plasma Cell Dysfunction. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2022; 28:254-264. [PMID: 34881690 DOI: 10.1017/s1431927621013805] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Multiple myeloma (MM) is a deadly, incurable malignancy in which antibody-secreting plasma cells (PCs) become neoplastic. Previous studies have shown that the PC niche plays a role cancer progression. Bone marrow (BM) cores from MM and a premalignant condition known as monoclonal gammopathy of unknown significance (MGUS) patients were analyzed with confocal and transmission electron microscopy. The BM aspirates from these patients were used to generate 3D PC cultures. These in vitro cultures were then assayed for the molecular, cellular, and ultrastructural hallmarks of dysfunctional PC at days 1 and 5. In vivo, evidence of PC endoplasmic reticulum stress was found in both MM and MGUS BM; however, evidence of PC autophagy was found only in MM BM. Analysis of in vitro cultures found that MM PC can survive and maintain a differentiated phenotype over an unprecedented 5 days, had higher levels of paraprotein production when compared to MGUS-derived cultures, and showed evidence of PC autophagy as well. Increased fibronectin deposition around PC associated with disease severity and autophagy dysregulation was also observed. 3D cultures constructed from BM aspirates from MGUS and MM patients allow for long-term culture of functional PC while maintaining their distinct morphological phenotypes.
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Affiliation(s)
| | | | - Harrison D Lancaster
- School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
| | - Saeeda Chowhury
- School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
- Department of Internal Medicine, Prisma Health System Upstate, Greenville, SC29605, USA
- Prisma Health Cancer Institute, Greenville, SC29605, USA
| | - Elizabeth Cull
- School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
- Department of Internal Medicine, Prisma Health System Upstate, Greenville, SC29605, USA
- Prisma Health Cancer Institute, Greenville, SC29605, USA
| | - Richard L Goodwin
- School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
| | - Sergio Arce
- School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
- Prisma Health Cancer Institute, Greenville, SC29605, USA
| | - Suzanne Fanning
- School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
- Department of Internal Medicine, Prisma Health System Upstate, Greenville, SC29605, USA
- Prisma Health Cancer Institute, Greenville, SC29605, USA
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9
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Zhu Y, Cheung ALM. Proteoglycans and their functions in esophageal squamous cell carcinoma. World J Clin Oncol 2021; 12:507-521. [PMID: 34367925 PMCID: PMC8317653 DOI: 10.5306/wjco.v12.i7.507] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/13/2021] [Accepted: 06/02/2021] [Indexed: 02/06/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a highly malignant disease that has a poor prognosis. Its high lethality is mainly due to the lack of symptoms at early stages, which culminates in diagnosis at a late stage when the tumor has already metastasized. Unfortunately, the common cancer biomarkers have low sensitivity and specificity in esophageal cancer. Therefore, a better understanding of the molecular mechanisms underlying ESCC progression is needed to identify novel diagnostic markers and therapeutic targets for intervention. The invasion of cancer cells into the surrounding tissue is a crucial step for metastasis. During metastasis, tumor cells can interact with extracellular components and secrete proteolytic enzymes to remodel the surrounding tumor microenvironment. Proteoglycans are one of the major components of extracellular matrix. They are involved in multiple processes of cancer cell invasion and metastasis by interacting with soluble bioactive molecules, surrounding matrix, cell surface receptors, and enzymes. Apart from having diverse functions in tumor cells and their surrounding microenvironment, proteoglycans also have diagnostic and prognostic significance in cancer patients. However, the functional significance and underlying mechanisms of proteoglycans in ESCC are not well understood. This review summarizes the proteoglycans that have been studied in ESCC in order to provide a comprehensive view of the role of proteoglycans in the progression of this cancer type. A long term goal would be to exploit these molecules to provide new strategies for therapeutic intervention.
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Affiliation(s)
- Yun Zhu
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
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10
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Chanzu H, Lykins J, Wigna-Kumar S, Joshi S, Pokrovskaya I, Storrie B, Pejler G, Wood JP, Whiteheart SW. Platelet α-granule cargo packaging and release are affected by the luminal proteoglycan, serglycin. J Thromb Haemost 2021; 19:1082-1095. [PMID: 33448622 DOI: 10.1111/jth.15243] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 12/16/2020] [Accepted: 01/04/2021] [Indexed: 01/27/2023]
Abstract
BACKGROUND Serglycin (SRGN) is an intragranular, sulfated proteoglycan in hematopoietic cells that affects granule composition and function. OBJECTIVE To understand how SRGN affects platelet granule packaging, cargo release, and extra-platelet microenvironments. METHODS Platelets and megakaryocytes from SRGN-/- mice were assayed for secretion kinetics, cargo levels, granule morphology upon activation, and receptor shedding. RESULTS Metabolic, 35 SO4 labeling identified SRGN as a major sulfated macromolecule in megakaryocytes. SRGN colocalized with α-granule markers (platelet factor 4 [PF4], von Willebrand factor [VWF], and P-selectin), but its deletion did not affect α-granule morphology or number. Platelet α-granule composition was altered, with a reduction in basic proteins (pI ≥8; e.g., PF4, SDF-1, angiogenin) and constitutive release of PF4 from SRGN-/- megakaryocytes. P-Selectin, VWF, and fibrinogen were unaffected. Serotonin (5-HT) uptake and β-hexosaminidase (HEXB) were slightly elevated. Thrombin-induced exocytosis of PF4 from platelets was defective; however, release of RANTES/CCL5 was normal and osteopontin secretion was more rapid. Release of 5-HT and HEXB (from dense granules and lysosomes, respectively) were unaffected. Ultrastructural studies showed distinct morphologies in activated platelets. The α-granule lumen of SRGN-/- platelet had a grainy staining pattern, whereas that of wild-type granules had only fibrous material remaining. α-Granule swelling and decondensation were reduced in SRGN-/- platelets. Upon stimulation of platelets, a SRGN/PF4 complex was released in a time- and agonist-dependent manner. Shedding of GPVI from SRGN-/- platelets was modestly enhanced. Shedding of GP1b was unaffected. CONCLUSION The polyanionic proteoglycan SRGN influences α-granule packaging, cargo release, and shedding of platelet membrane proteins.
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Affiliation(s)
- Harry Chanzu
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Joshua Lykins
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Subershan Wigna-Kumar
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Smita Joshi
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
- Lexington VA Medical Center, Lexington, KY, USA
| | - Irina Pokrovskaya
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Brian Storrie
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Gunnar Pejler
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Jeremy P Wood
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
- Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, USA
| | - Sidney W Whiteheart
- Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
- Lexington VA Medical Center, Lexington, KY, USA
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11
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Zhu Y, Lam AK, Shum DK, Cui D, Zhang J, Yan DD, Li B, Xu WW, Lee NP, Chan KT, Law S, Tsao SW, Cheung AL. Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer. Theranostics 2021; 11:2722-2741. [PMID: 33456569 PMCID: PMC7806492 DOI: 10.7150/thno.49547] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 12/08/2020] [Indexed: 12/20/2022] Open
Abstract
Rationale: Little is known about the roles of proteoglycans in esophageal cancer. This study aims to investigate the roles and mechanisms of serglycin (SRGN) proteoglycan in promoting metastasis of esophageal squamous cell carcinoma (ESCC). Methods: Reverse phase protein array analysis was used to identify activated signaling pathways in SRGN-overexpressing cells. Chemokine array was used to identify differentially secreted factors from SRGN-overexpressing cells. Binding between SRGN and potential interacting partners was evaluated using proximity ligation assay and co-immunoprecipitation. The glycosaminoglycan (GAG) chains of SRGN were characterized using fluorophore-assisted carbohydrate electrophoresis. Tissue microarray and serum samples were used to determine the correlation of SRGN expression with clinicopathological parameters and patient survival. Results: In vitro and in vivo experiments showed that SRGN promoted invasion and metastasis in ESCC via activating ERK pathway, stabilizing c-Myc and upregulating the secretion of matrix metalloproteinases. SRGN-knockdown suppressed tumorigenic hallmarks. These SRGN-elicited functions were carried out in an autocrine manner by inducing the secretion of midkine (MDK), which was further identified as a novel binding partner of SRGN for the formation of a SRGN/MDK/CD44 complex. In addition, SRGN interacted with MDK and matrix metalloproteinase 2 in ESCC via its GAG chains, which were mainly decorated with chondroitin sulfate comprising of ∆di-4S and ∆di-6S CS. Clinically, high expression of serum SRGN in serum of patients with ESCC was an independent prognostic marker for poor survival. Conclusions: This study provides the first evidence that elevated serum SRGN has prognostic significance in patients with ESCC, and sheds light on the molecular mechanism by which elevated circulating SRGN in cancer patients might promote cancer progression.
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Affiliation(s)
- Yun Zhu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Alfred K.Y. Lam
- Department of Pathology, Griffith Medical School, Queensland, Gold Coast, QLD, Australia
| | - Daisy K.Y. Shum
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Di Cui
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Jun Zhang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Dong Dong Yan
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Bin Li
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou, China
| | - Wen Wen Xu
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Nikki P.Y. Lee
- Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Kin Tak Chan
- Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Simon Law
- Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Sai Wah Tsao
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Annie L.M. Cheung
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
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12
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Salinas-Marín R, Villanueva-Cabello TM, Martínez-Duncker I. Biology of Proteoglycans and Associated Glycosaminoglycans. COMPREHENSIVE GLYCOSCIENCE 2021:63-102. [DOI: 10.1016/b978-0-12-819475-1.00065-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Su H, Wang M, Pang X, Guan F, Li X, Cheng Y. When Glycosylation Meets Blood Cells: A Glance of the Aberrant Glycosylation in Hematological Malignancies. Rev Physiol Biochem Pharmacol 2021; 180:85-117. [PMID: 34031738 DOI: 10.1007/112_2021_60] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Among neoplasia-associated epigenetic alterations, changes in cellular glycosylation have recently received attention as a key component of hematological malignancy progression. Alterations in glycosylation appear to not only directly impact cell growth and survival, but also alter the adhesion of tumor cells and their interactions with the microenvironment, facilitating cancer-induced immunomodulation and eventual metastasis. Changes in glycosylation arise from altered expression of glycosyltransferases, enzymes that catalyze the transfer of saccharide moieties to a wide range of acceptor substrates, such as proteins, lipids, and other saccharides in the endoplasmic reticulum (ER) and Golgi apparatus. Novel glycan structures in hematological malignancies represent new targets for the diagnosis and treatment of blood diseases. This review summarizes studies of the aberrant expression of glycans commonly found in hematological malignancies and their potential mechanisms and defines the specific roles of glycans as drivers or passengers in the development of hematological malignancies.
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Affiliation(s)
- Huining Su
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Mimi Wang
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Xingchen Pang
- Key Laboratory of Resource Biology and Biotechnology Western China, College of Life Science, Northwest University, Xi'an, China
| | - Feng Guan
- Key Laboratory of Resource Biology and Biotechnology Western China, College of Life Science, Northwest University, Xi'an, China
| | - Xiang Li
- Key Laboratory of Resource Biology and Biotechnology Western China, College of Life Science, Northwest University, Xi'an, China.
| | - Ying Cheng
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
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14
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Wang X, Xiong H, Liang D, Chen Z, Li X, Zhang K. The role of SRGN in the survival and immune infiltrates of skin cutaneous melanoma (SKCM) and SKCM-metastasis patients. BMC Cancer 2020; 20:378. [PMID: 32370744 PMCID: PMC7201763 DOI: 10.1186/s12885-020-06849-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 04/12/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Skin cutaneous melanoma (SKCM) is one of most aggressive type of cancers worldwide. Serglycin (SRGN) is an intracellular proteoglycan that playing an important role in various tumors. However, its effect on immune infiltrates and whether it associates with survival of SKCM and SKCM-metastasis patients has not been explored. METHODS We evaluated SRGN expression via the databases of Oncomine, Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA). The influence of SRGN expression on survival of SKCM and SKCM-metastasis patients was analyzed using TIMER database. Furthermore, the correlations between SRGN expression and immune infiltrates or gene marker sets of immune infiltrates were also analyzed via TIMER database. RESULTS We found that the expression of SRGN in SKCM and SKCM-metastasis tissues was significantly increased compared to the normal skin tissues (P < 0.001). Interestingly, it was showed that lower level of SRGN expression and lower immune infiltrates of B cell, CD8+ T cell, Neutrophil, and Dendritic cell were correlated with poor survival rate of SKCM and SKCM-metastasis patients (P < 0.001) but not SKCM primary patients. We also demonstrated that SRGN expression was positively associated with the immune infiltrates and diverse immune marker sets in SKCM and SKCM-metastasis. CONCLUSIONS Our findings indicated that SRGN was associated with the survival of SKCM and SKCM-metastasis patients. SRGN may be a new immune therapy target for treating SKCM and SKCM-metastasis.
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Affiliation(s)
- Xiaofang Wang
- Department of Dermatology and Venerology, University of Chinese Academy of Sciences-Shenzhen Hospital, Shenzhen, China
| | - Hui Xiong
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Daning Liang
- Department of Dermatology and Venerology, University of Chinese Academy of Sciences-Shenzhen Hospital, Shenzhen, China
| | - Zhenzhen Chen
- Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Xiqing Li
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kun Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
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15
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Manou D, Bouris P, Kletsas D, Götte M, Greve B, Moustakas A, Karamanos NK, Theocharis AD. Serglycin activates pro-tumorigenic signaling and controls glioblastoma cell stemness, differentiation and invasive potential. Matrix Biol Plus 2020; 6-7:100033. [PMID: 33543029 PMCID: PMC7852318 DOI: 10.1016/j.mbplus.2020.100033] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 03/06/2020] [Accepted: 03/06/2020] [Indexed: 12/11/2022] Open
Abstract
Despite the functional role of serglycin as an intracellular proteoglycan, a variety of malignant cells depends on its expression and constitutive secretion to advance their aggressive behavior. Serglycin arose to be a biomarker for glioblastoma, which is the deadliest and most treatment-resistant form of brain tumor, but its role in this disease is not fully elucidated. In our study we suppressed the endogenous levels of serglycin in LN-18 glioblastoma cells to decipher its involvement in their malignant phenotype. Serglycin suppressed LN-18 (LN-18shSRGN) glioblastoma cells underwent astrocytic differentiation characterized by induced expression of GFAP, SPARCL-1 and SNAIL, with simultaneous loss of their stemness capacity. In particular, LN-18shSRGN cells presented decreased expression of glioma stem cell-related genes and ALDH1 activity, accompanied by reduced colony formation ability. Moreover, the suppression of serglycin in LN-18shSRGN cells retarded the proliferative and migratory rate, the invasive potential in vitro and the tumor burden in vivo. The lack of serglycin in LN-18shSRGN cells was followed by G2 arrest, with subsequent reduction of the expression of cell-cycle regulators. LN-18shSRGN cells also exhibited impaired expression and activity of proteolytic enzymes such as MMPs, TIMPs and uPA, both in vitro and in vivo. Moreover, suppression of serglycin in LN-18shSRGN cells eliminated the activation of pro-tumorigenic signal transduction. Of note, LN-18shSRGN cells displayed lower expression and secretion levels of IL-6, IL-8 and CXCR-2. Concomitant, serglycin suppressed LN-18shSRGN cells demonstrated repressed phosphorylation of ERK1/2, p38, SRC and STAT-3, which together with PI3K/AKT and IL-8/CXCR-2 signaling control LN-18 glioblastoma cell aggressiveness. Collectively, the absence of serglycin favors an astrocytic fate switch and a less aggressive phenotype, characterized by loss of pluripotency, block of the cell cycle, reduced ability for ECM proteolysis and pro-tumorigenic signaling attenuation.
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Key Words
- ALDH1, aldehyde dehydrogenase 1
- Astrocytic differentiation
- CXCR, C-X-C chemokine receptor
- ECM, extracellular matrix
- EMT, epithelial to mesenchymal transition
- ERK, extracellular-signal-regulated kinase
- GFAP, glial fibrillary acid protein
- Glioblastoma
- IL, interleukin
- Interleukins
- MAPK, mitogen-activated protein kinase
- MMPs, metalloproteinases
- PGs, proteoglycans
- PI3K, phosphoinositide 3-kinase
- Proteoglycans
- Proteolytic enzymes
- SRGN, serglycin
- STAT-3, signal transducer and activator of transcription 3
- Serglycin
- Signaling
- Stemness
- TIMPs, tissue inhibitors of metalloproteinases
- uPA, urokinase plasminogen activator
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Affiliation(s)
- Dimitra Manou
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Panagiotis Bouris
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Dimitris Kletsas
- Laboratory of Cell Proliferation & Ageing, Institute of Biosciences & Applications, National Centre for Scientific Research ‘Demokritos’, Athens, Greece
| | - Martin Götte
- Department of Gynecology and Obstetrics, University Hospital, Muenster, Germany
| | - Burkhard Greve
- Department of Radiotherapy-Radiooncology, University Hospital, Muenster, Germany
| | - Aristidis Moustakas
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Sweden
| | - Nikos K. Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Achilleas D. Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
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16
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Iozzo RV, Theocharis AD, Neill T, Karamanos NK. Complexity of matrix phenotypes. Matrix Biol Plus 2020; 6-7:100038. [PMID: 33543032 PMCID: PMC7852209 DOI: 10.1016/j.mbplus.2020.100038] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 05/11/2020] [Indexed: 02/06/2023] Open
Abstract
The extracellular matrix is engaged in an ever-evolving and elegant ballet of dynamic reciprocity that directly and bi-directionally regulates cell behavior. Homeostatic and pathophysiological changes in cell-matrix signaling cascades manifest as complex matrix phenotypes. Indeed, the extracellular matrix can be implicated in virtually every known human disease, thus, making it the most critical and dynamic "organ" in the human body. The overall goal of this Special Issue is to provide an accurate and inclusive functional definition that addresses the inherent complexity of matrix phenotypes. This goal is summarily achieved via a corpus of expertly written articles, reviews and original research, focused at answering this question empirically and fundamentally via state-of-the-art methods and research strategies.
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Key Words
- ADAM, a disintegrin and metalloproteinases
- AGE, advanced glycation end products
- Angiogenesis
- Cancer
- Collagen
- DDR1, discoidin domain receptor 1
- ECM, extracellular matrix
- EGF, epidermal growth factor
- EGFR, epidermal growth factor receptor
- EMILIN1, elastin microfibril interfacer 1
- EMILIN2, elastin microfibril interfacer 2
- EMT, epithelial-mesenchymal transition
- ERα, estrogen receptor α
- ERβ, estrogen receptor β
- GBM, glioblastoma
- HA, hyaluronan
- HAS2, hyaluronan synthase 2
- HAS2-AS1, HAS2 antisense 1
- HB-EGF, heparin binding EGF
- HMGA2, high-mobility group AT-Hook 2
- IBC, inflammatory breast cancer
- IGF-IR, insulin growth factor I receptor
- IR-A, insulin receptor A
- LEKTI, lympho-epithelial Kazal-type inhibitor
- LOX, lysyl oxidases
- LTBP, latent TGFβ-binding proteins
- MAGP, microfibril-associated glycoproteins
- MET, mesenchymal-epithelial transition
- MMP, matrix metalloproteinases
- Methodologies
- OB, osteoblast
- OI, osteogenesis imperfecta
- PARs, protease activated receptors
- PG, proteoglycans
- PLL, poly-l-lysine
- Proteoglycans
- ROS, reactive oxygen species
- RTK, receptor tyrosine kinase
- SLRP, small leucine rich proteoglycans
- SSR, solar-simulated radiation
- TGFβ, transforming growth factor β
- TNT, tunneling nanotubes
- UVR, ultraviolet radiation
- VEGF, vascular endothelial growth factor
- miR, microRNA
- tPA, tissue-type plasminogen activator
- uPA, urokinase-type plasminogen activator
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Affiliation(s)
- Renato V. Iozzo
- Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States of America
| | - Achilleas D. Theocharis
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Thomas Neill
- Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States of America
| | - Nikos K. Karamanos
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
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Jin J, Cheng S, Wang Y, Wang T, Zeng D, Li Z, Li X, Wang J. SRC3 expressed in bone marrow mesenchymal stem cells promotes the development of multiple myeloma. Acta Biochim Biophys Sin (Shanghai) 2019; 51:1258-1266. [PMID: 31769473 DOI: 10.1093/abbs/gmz130] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/30/2019] [Accepted: 09/30/2019] [Indexed: 12/13/2022] Open
Abstract
SRC3 plays critical roles in various biological processes of diseases, including proliferation, apoptosis, migration, and cell cycle arrest. However, the effect of SRC3 expression in mesenchymal stem cells (MSCs) on multiple myeloma (MM) is not clear yet. In our study, MSCs (MSC-SRC3, MSC-SRC3-/-) and MM cells were co-cultured in a direct or indirect way. The proliferation of MM cells was studied by CCK-8 and colony formation assays. The apoptosis and cell cycle of MM cells were detected by flow cytometry. In addition, the expressions of proteins in MM cells were detected by western blot analysis and the secretions of cytokines were measured by ELISA. Our data showed that the expression of SRC3 in bone marrow mesenchymal stem cells (BM-MSCs) could promote cell proliferation and colony formation of MM cells through accelerating the transformation of the G1/S phase, no matter what kind of culture method was adopted. Meanwhile, SRC3 expressed in BM-MSCs could inhibit the apoptosis of MM cells through the caspase apoptosis pathway and mitochondrial apoptosis pathway. Moreover, SRC3 could enhance the adhesion ability of MM cells through up-regulating the expression of adhesion molecules including CXCL4, ICAM1, VLA4, and syndecan-1. SRC3 also played a regulatory role in the progress of MM through the NF-κB and PI-3K/Akt pathways. SRC3 expressed in MSCs was found to promote the growth and survival of MM cells, while SRC3 silencing in MSCs could inhibit the development of MM. These results would be useful for developing a more effective new strategy for MM treatment.
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Affiliation(s)
- Jie Jin
- Department of Hematology, the Third affiliated Daping Hospital, Army Medical University, Chongqing 400038, China
| | - Shidi Cheng
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, College of Preventive Medicine, Army Medical University, Chongqing 400038, China
| | - Yu Wang
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, College of Preventive Medicine, Army Medical University, Chongqing 400038, China
| | - Tao Wang
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, College of Preventive Medicine, Army Medical University, Chongqing 400038, China
| | - Dongfeng Zeng
- Department of Hematology, the Third affiliated Daping Hospital, Army Medical University, Chongqing 400038, China
| | - Zheng Li
- Department of Hematology, the Third affiliated Daping Hospital, Army Medical University, Chongqing 400038, China
| | - Xiang Li
- Department of Hematology, the Third affiliated Daping Hospital, Army Medical University, Chongqing 400038, China
| | - Jin Wang
- Department of Hematology, the Third affiliated Daping Hospital, Army Medical University, Chongqing 400038, China
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18
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Zeng M, Liu J, Yang W, Zhang S, Liu F, Dong Z, Peng Y, Sun L, Xiao L. Multiple-microarray analysis for identification of hub genes involved in tubulointerstial injury in diabetic nephropathy. J Cell Physiol 2019; 234:16447-16462. [PMID: 30761531 DOI: 10.1002/jcp.28313] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Revised: 01/19/2019] [Accepted: 01/24/2019] [Indexed: 01/24/2023]
Abstract
Diabetic nephropathy (DN) is a primary cause of renal failure. However, studies providing renal gene expression profiles of diabetic tubulointerstitial injury are scarce and its molecular mechanisms still await clarification. To identify vital genes involved in the diabetic tubulointerstitial injury, three microarray data sets from gene expression omnibus (GEO) were downloaded. A total of 127 differentially expressed genes (DEGs) were identified by limma package. Gene set enrichment analysis (GSEA) plots showed that sister chromatid cohesion was the most significant enriched gene set positively correlated with the DN group while retinoid X receptor binding was the most significant enriched gene set positively correlated with the control group. Enriched Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of DEGs mostly included extracellular matrix organization, extracellular space, extracellular matrix structural constituent, and Staphylococcus aureus infection. Twenty hub genes from three significant modules were ascertained by Cytoscape. Correlation analysis and subgroup analysis between hub genes and clinical features of DN showed that ALB, ANXA1, APOH, C3, CCL19, COL1A2, COL3A1, COL4A1, COL6A3, CXCL6, DCN, EGF, HRG, KNG1, LUM, SERPINA3, SPARC, SRGN, and TIMP1 may involve in diabetic tubulointerstitial injury. ConnectivityMap analysis indicated the most significant three compounds are 5182598, thapsigargin and 5224221. In conclusion, this study may provide new insights into the molecular mechanisms underlying diabetic tubulointerstitial injury as well as potential targets for diagnosis and therapeutics of DN.
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Affiliation(s)
- Mengru Zeng
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jialu Liu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wenxia Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shumin Zhang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fuyou Liu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zheng Dong
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Youming Peng
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Li Xiao
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Manou D, Karamanos NK, Theocharis AD. Tumorigenic functions of serglycin: Regulatory roles in epithelial to mesenchymal transition and oncogenic signaling. Semin Cancer Biol 2019; 62:108-115. [PMID: 31279836 DOI: 10.1016/j.semcancer.2019.07.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 06/24/2019] [Accepted: 07/03/2019] [Indexed: 02/07/2023]
Abstract
Numerous studies point out serglycin as an important regulator of tumorigenesis in a variety of malignancies. Serglycin expression correlates with the aggressive phenotype of tumor cells and serves as a poor prognostic indicator for disease progression. Although serglycin is considered as an intracellular proteoglycan, it is also secreted in the extracellular matrix by tumor cells affecting cell properties, oncogenic signaling and exosomes cargo. Serglycin directly interacts with CD44 and possibly other cell surface receptors including integrins, evoking cell adhesion and signaling. Serglycin also creates a pro-inflammatory and pro-angiogenic tumor microenvironment by regulating the secretion of proteolytic enzymes, IL-8, TGFβ2, CCL2, VEGF and HGF. Hence, serglycin activates multiple signaling cascades that drive angiogenesis, tumor cell growth, epithelial to mesenchymal transition, cancer cell stemness and metastasis. The interference with the tumorigenic functions of serglycin emerges as an attractive prospect to target malignancies.
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Affiliation(s)
- Dimitra Manou
- Biochemistry, Biochemical Analysis & Matrix Pathobiochemistry Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Nikos K Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiochemistry Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Achilleas D Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiochemistry Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
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20
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Theocharis AD, Manou D, Karamanos NK. The extracellular matrix as a multitasking player in disease. FEBS J 2019; 286:2830-2869. [PMID: 30908868 DOI: 10.1111/febs.14818] [Citation(s) in RCA: 277] [Impact Index Per Article: 46.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 02/06/2019] [Accepted: 03/22/2019] [Indexed: 12/12/2022]
Abstract
Extracellular matrices (ECMs) are highly specialized and dynamic three-dimensional (3D) scaffolds into which cells reside in tissues. ECM is composed of a variety of fibrillar components, such as collagens, fibronectin, and elastin, and non-fibrillar molecules as proteoglycans, hyaluronan, and glycoproteins including matricellular proteins. These macromolecular components are interconnected forming complex networks that actively communicate with cells through binding to cell surface receptors and/or matrix effectors. ECMs exert diverse roles, either providing tissues with structural integrity and mechanical properties essential for tissue functions or regulating cell phenotype and functions to maintain tissue homeostasis. ECM molecular composition and structure vary among tissues, and is markedly modified during normal tissue repair as well as during the progression of various diseases. Actually, abnormal ECM remodeling occurring in pathologic circumstances drives disease progression by regulating cell-matrix interactions. The importance of matrix molecules to normal tissue functions is also highlighted by mutations in matrix genes that give rise to genetic disorders with diverse clinical phenotypes. In this review, we present critical and emerging issues related to matrix assembly in tissues and the multitasking roles for ECM in diseases such as osteoarthritis, fibrosis, cancer, and genetic diseases. The mechanisms underlying the various matrix-based diseases are also discussed. Research focused on the highly dynamic 3D ECM networks will help to discover matrix-related causative abnormalities of diseases as well as novel diagnostic tools and therapeutic targets.
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Affiliation(s)
- Achilleas D Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiochemistry Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Dimitra Manou
- Biochemistry, Biochemical Analysis & Matrix Pathobiochemistry Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Nikos K Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiochemistry Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
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21
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Pudełko A, Wisowski G, Olczyk K, Koźma EM. The dual role of the glycosaminoglycan chondroitin-6-sulfate in the development, progression and metastasis of cancer. FEBS J 2019; 286:1815-1837. [PMID: 30637950 PMCID: PMC6850286 DOI: 10.1111/febs.14748] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 11/14/2018] [Accepted: 01/10/2019] [Indexed: 12/16/2022]
Abstract
The remarkable structural heterogeneity of chondroitin sulfate (CS) and dermatan sulfate (DS) generates biological information that can be unique to each of these glycosaminoglycans (GAGs), and changes in their composition are translated into alterations in the binding profiles of these molecules. CS/DS can bind to various cytokines and growth factors, cell surface receptors, adhesion molecules, enzymes and fibrillar glycoproteins of the extracellular matrix, thereby influencing both cell behavior and the biomechanical and biochemical properties of the matrix. In this review, we summarize the current knowledge concerning CS/DS metabolism in the human cancer stroma. The remodeling of the GAG profile in the tumor niche is manifested as a substantial increase in the CS content and a gradual decrease in the proportion between DS and CS. Furthermore, the composition of CS and DS is also affected, which results in a substantial increase in the 6‐O‐sulfated and/or unsulfated disaccharide content, which is concomitant with a decrease in the 4‐O‐sulfation level. Here, we discuss the possible impact of alterations in the CS/DS sulfation pattern on the binding capacity and specificity of these GAGs. Moreover, we propose potential consequences of the stromal accumulation of chondroitin‐6‐sulfate for the progression and metastasis of cancer.
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Affiliation(s)
- Adam Pudełko
- Department of Clinical Chemistry and Laboratory Diagnostics, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Grzegorz Wisowski
- Department of Clinical Chemistry and Laboratory Diagnostics, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Krystyna Olczyk
- Department of Clinical Chemistry and Laboratory Diagnostics, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Ewa Maria Koźma
- Department of Clinical Chemistry and Laboratory Diagnostics, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland
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22
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Karamanos NK, Piperigkou Z, Theocharis AD, Watanabe H, Franchi M, Baud S, Brézillon S, Götte M, Passi A, Vigetti D, Ricard-Blum S, Sanderson RD, Neill T, Iozzo RV. Proteoglycan Chemical Diversity Drives Multifunctional Cell Regulation and Therapeutics. Chem Rev 2018; 118:9152-9232. [PMID: 30204432 DOI: 10.1021/acs.chemrev.8b00354] [Citation(s) in RCA: 253] [Impact Index Per Article: 36.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Nikos K. Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
- Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras 26110, Greece
| | - Zoi Piperigkou
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
- Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras 26110, Greece
| | - Achilleas D. Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Hideto Watanabe
- Institute for Molecular Science of Medicine, Aichi Medical University, Aichi 480-1195, Japan
| | - Marco Franchi
- Department for Life Quality Studies, University of Bologna, Rimini 47100, Italy
| | - Stéphanie Baud
- Université de Reims Champagne-Ardenne, Laboratoire SiRMa, CNRS UMR MEDyC 7369, Faculté de Médecine, 51 rue Cognacq Jay, Reims 51100, France
| | - Stéphane Brézillon
- Université de Reims Champagne-Ardenne, Laboratoire de Biochimie Médicale et Biologie Moléculaire, CNRS UMR MEDyC 7369, Faculté de Médecine, 51 rue Cognacq Jay, Reims 51100, France
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster 48149, Germany
| | - Alberto Passi
- Department of Medicine and Surgery, University of Insubria, Varese 21100, Italy
| | - Davide Vigetti
- Department of Medicine and Surgery, University of Insubria, Varese 21100, Italy
| | - Sylvie Ricard-Blum
- University Claude Bernard Lyon 1, CNRS, UMR 5246, Institute of Molecular and Supramolecular Chemistry and Biochemistry, Villeurbanne 69622, France
| | - Ralph D. Sanderson
- Department of Pathology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Thomas Neill
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 10107, United States
| | - Renato V. Iozzo
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 10107, United States
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23
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Pang X, Li H, Guan F, Li X. Multiple Roles of Glycans in Hematological Malignancies. Front Oncol 2018; 8:364. [PMID: 30237983 PMCID: PMC6135871 DOI: 10.3389/fonc.2018.00364] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 08/17/2018] [Indexed: 01/05/2023] Open
Abstract
The three types of blood cells (red blood cells for carrying oxygen, white blood cells for immune protection, and platelets for wound clotting) arise from hematopoietic stem/progenitor cells in the adult bone marrow, and function in physiological regulation and communication with local microenvironments to maintain systemic homeostasis. Hematological malignancies are relatively uncommon malignant disorders derived from the two major blood cell lineages: myeloid (leukemia) and lymphoid (lymphoma). Malignant clones lose their regulatory mechanisms, resulting in production of a large number of dysfunctional cells and destruction of normal hematopoiesis. Glycans are one of the four major types of essential biological macromolecules, along with nucleic acids, proteins, and lipids. Major glycan subgroups are N-glycans, O-glycans, glycosaminoglycans, and glycosphingolipids. Aberrant expression of glycan structures, resulting from dysregulation of glycan-related genes, is associated with cancer development and progression in terms of cell signaling and communication, tumor cell dissociation and invasion, cell-matrix interactions, tumor angiogenesis, immune modulation, and metastasis formation. Aberrant glycan expression occurs in most hematological malignancies, notably acute myeloid leukemia, myeloproliferative neoplasms, and multiple myeloma, etc. Here, we review recent research advances regarding aberrant glycans, their related genes, and their roles in hematological malignancies. Our improved understanding of the mechanisms that underlie aberrant patterns of glycosylation will lead to development of novel, more effective therapeutic approaches targeted to hematological malignancies.
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Affiliation(s)
- Xingchen Pang
- School of Biotechnology, Jiangnan University, Wuxi, China
| | - Hongjiao Li
- College of Life Science, Northwest University, Xi'an, China
| | - Feng Guan
- School of Biotechnology, Jiangnan University, Wuxi, China.,College of Life Science, Northwest University, Xi'an, China
| | - Xiang Li
- College of Life Science, Northwest University, Xi'an, China.,Wuxi Medical School, Jiangnan University, Wuxi, China
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24
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Bouris P, Manou D, Sopaki-Valalaki A, Kolokotroni A, Moustakas A, Kapoor A, Iozzo RV, Karamanos NK, Theocharis AD. Serglycin promotes breast cancer cell aggressiveness: Induction of epithelial to mesenchymal transition, proteolytic activity and IL-8 signaling. Matrix Biol 2018; 74:35-51. [PMID: 29842969 DOI: 10.1016/j.matbio.2018.05.011] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 05/23/2018] [Accepted: 05/24/2018] [Indexed: 12/20/2022]
Abstract
Serglycin is an intracellular proteoglycan that is expressed and constitutively secreted by numerous malignant cells, especially prominent in the highly-invasive, triple-negative MDA-MB-231 breast carcinoma cells. Notably, de novo expression of serglycin in low aggressive estrogen receptor α (ERα)-positive MCF7 breast cancer cells promotes an aggressive phenotype. In this study, we discovered that serglycin promoted epithelial to mesenchymal transition (EMT) in MCF7 cells as shown by increased expression of mesenchymal markers vimentin, fibronectin and EMT-related transcription factor Snail2. These phenotypic traits were also associated with the development of drug resistance toward various chemotherapy agents and induction of their proteolytic potential as shown by the increased expression of matrix metalloproteinases, including MMP-1, MMP-2, MMP-9, MT1-MMP and up-regulation of urokinase-type plasminogen activator. Knockdown of serglycin markedly reduced the expression of these proteolytic enzymes in MDA-MB-231 cells. In addition, serglycin expression was closely linked to a pro-inflammatory gene signature including the chemokine IL-8 in ERα-negative breast cancer cells and tumors. Notably, serglycin regulated the secretion of IL-8 in breast cancer cells independently of their ERα status and promoted their proliferation, migration and invasion by triggering IL-8/CXCR2 downstream signaling cascades including PI3K, Src and Rac activation. Thus, serglycin promotes the establishment of a pro-inflammatory milieu in breast cancer cells that evokes an invasive mesenchymal phenotype via autocrine activation of IL-8/CXCR2 signaling axis.
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Affiliation(s)
- Panagiotis Bouris
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Dimitra Manou
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Anastasia Sopaki-Valalaki
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Anthi Kolokotroni
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Aristidis Moustakas
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, SE 75123 Uppsala, Sweden
| | - Aastha Kapoor
- Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Renato V Iozzo
- Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Nikos K Karamanos
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Achilleas D Theocharis
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
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25
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Meng C, He Y, Wei Z, Lu Y, Du F, Ou G, Wang N, Luo XG, Ma W, Zhang TC, He H. MRTF-A mediates the activation of COL1A1 expression stimulated by multiple signaling pathways in human breast cancer cells. Biomed Pharmacother 2018; 104:718-728. [PMID: 29807221 DOI: 10.1016/j.biopha.2018.05.092] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 05/19/2018] [Accepted: 05/20/2018] [Indexed: 12/29/2022] Open
Abstract
Deposition of type I collage in ECM is an important property of various fibrotic diseases including breast cancer. The excessive expression of type I collagen contributes to the rigidity of cancer tissue and increases the mechanical stresses which facilitate metastasis and proliferation of cancer cells via the activation of TGF-β signaling pathway. The increased mechanical stresses also cause the compression of blood vessels and result in hypoperfusion and impaired drug delivery in cancer tissue. Additionally, type I collage functions as the ligand of α2β1-integrin and DDR1/2 receptors on the membrane of cancer cells to initiate signal transduction leading to metastasis. The expression of type I collage in cancer cells is previously shown to be inducible by TGF-β however the detailed mechanism by which the synthesis of type I collagen is regulated in breast cancer cells remains unclear. Herein, we report that MRTF-A, a co-activator of SRF, is important for the regulation of type I collagen gene COL1A1 in breast cancer cells. MRTF-A physically interacted with the promoter of COL1A1 to facilitate histone acetylation and RNA polymerase II recruitment. The RhoC-ROCK signaling pathway which controls the nuclear localization of MRTF-A regulated the transcription of COL1A1 in human breast cancer cells. TGF-β and Wnt signaling increased the expression of both MRTF-A and COL1A1. Furthermore, depletion of MRTF-A abolished the upregulation of COL1A1 in response to the TGF-β or Wnt signaling, indicating the importance of MRTF-A in the synthesis of type I collagen in breast cancer. Given the crucial roles of type I collagen in the formation of metastasis-prone and hypoperfusion microenvironment, MRTF-A would be a potential target for the development of anti-breast cancer activities.
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Affiliation(s)
- Chao Meng
- Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China
| | - Yongping He
- Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China
| | - Zhaoqiang Wei
- Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China
| | - Yulin Lu
- Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China
| | - Fu Du
- Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China
| | - Guofang Ou
- Chongqing Business Vocational College, Chongqing, 401331, PR China
| | - Nan Wang
- Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China
| | - Xue-Gang Luo
- Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China
| | - Wenjian Ma
- Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China
| | - Tong-Cun Zhang
- Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China; College of Life Sciences, Wuhan University of Science and Technology, Wuhan, 430081, PR China
| | - Hongpeng He
- Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China.
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26
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Piperigkou Z, Götte M, Theocharis AD, Karamanos NK. Insights into the key roles of epigenetics in matrix macromolecules-associated wound healing. Adv Drug Deliv Rev 2018; 129:16-36. [PMID: 29079535 DOI: 10.1016/j.addr.2017.10.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/14/2017] [Accepted: 10/20/2017] [Indexed: 02/08/2023]
Abstract
Extracellular matrix (ECM) is a dynamic network of macromolecules, playing a regulatory role in cell functions, tissue regeneration and remodeling. Wound healing is a tissue repair process necessary for the maintenance of the functionality of tissues and organs. This highly orchestrated process is divided into four temporally overlapping phases, including hemostasis, inflammation, proliferation and tissue remodeling. The dynamic interplay between ECM and resident cells exerts its critical role in many aspects of wound healing, including cell proliferation, migration, differentiation, survival, matrix degradation and biosynthesis. Several epigenetic regulatory factors, such as the endogenous non-coding microRNAs (miRNAs), are the drivers of the wound healing response. microRNAs have pivotal roles in regulating ECM composition during wound healing and dermal regeneration. Their expression is associated with the distinct phases of wound healing and they serve as target biomarkers and targets for systematic regulation of wound repair. In this article we critically present the importance of epigenetics with particular emphasis on miRNAs regulating ECM components (i.e. glycoproteins, proteoglycans and matrix proteases) that are key players in wound healing. The clinical relevance of miRNA targeting as well as the delivery strategies designed for clinical applications are also presented and discussed.
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27
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DNA methylation profiling of asbestos-treated MeT5A cell line reveals novel pathways implicated in asbestos response. Arch Toxicol 2018. [PMID: 29523930 DOI: 10.1007/s00204-018-2179-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Occupational and environmental asbestos exposure is the main determinant of malignant pleural mesothelioma (MPM), however, the mechanisms by which its fibres contribute to cell toxicity and transformation are not completely clear. Aberrant DNA methylation is a common event in cancer but epigenetic modifications involved specifically in MPM carcinogenesis need to be better clarified. To investigate asbestos-induced DNA methylation and gene expression changes, we treated Met5A mesothelial cells with different concentrations of crocidolite and chrysotile asbestos (0.5 ÷ 5.0 µg/cm2, 72 h incubation). Overall, we observed 243 and 302 differentially methylated CpGs (≥ 10%) between the asbestos dose at 5 µg/cm2 and untreated control, in chrysotile and crocidolite treatment, respectively. To examine the dose-response effect, Spearman's correlation test was performed and significant CpGs located in genes involved in migration/cell adhesion processes were identified in both treatments. Moreover, we found that both crocidolite and chrysotile exposure induced a significant up-regulation of CA9 and SRGN (log2 fold change > 1.5), previously reported as associated with a more aggressive MPM phenotype. However, we found no correlation between methylation and gene expression changes, except for a moderate significant inverse correlation at the promoter region of DKK1 (Spearman rho = - 1, P value = 0.02) after chrysotile exposure. These results describe for the first time the relationship between DNA methylation modifications and asbestos exposure. Our findings provide a basis to further explore and validate asbestos-induced DNA methylation changes, that could influence MPM carcinogenesis and possibly identifying new chemopreventive target.
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28
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Gruber HE, Hanley Jr EN. Expression of serglycin in human disc is increased in degenerated discs and up-regulated in vitro by exposure to IL-1ß or TNF-α. Biotech Histochem 2018; 93:109-117. [DOI: 10.1080/10520295.2017.1399464] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- HE Gruber
- Department of Orthopaedic Surgery, Carolinas Medical Center, Charlotte, North Carolina
| | - EN Hanley Jr
- Department of Orthopaedic Surgery, Carolinas Medical Center, Charlotte, North Carolina
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29
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Theocharis AD, Karamanos NK. Proteoglycans remodeling in cancer: Underlying molecular mechanisms. Matrix Biol 2017; 75-76:220-259. [PMID: 29128506 DOI: 10.1016/j.matbio.2017.10.008] [Citation(s) in RCA: 148] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 10/23/2017] [Accepted: 10/24/2017] [Indexed: 02/07/2023]
Abstract
Extracellular matrix is a highly dynamic macromolecular network. Proteoglycans are major components of extracellular matrix playing key roles in its structural organization and cell signaling contributing to the control of numerous normal and pathological processes. As multifunctional molecules, proteoglycans participate in various cell functions during morphogenesis, wound healing, inflammation and tumorigenesis. Their interactions with matrix effectors, cell surface receptors and enzymes enable them with unique properties. In malignancy, extensive remodeling of tumor stroma is associated with marked alterations in proteoglycans' expression and structural variability. Proteoglycans exert diverse functions in tumor stroma in a cell-specific and context-specific manner and they mainly contribute to the formation of a permissive provisional matrix for tumor growth affecting tissue organization, cell-cell and cell-matrix interactions and tumor cell signaling. Proteoglycans also modulate cancer cell phenotype and properties, the development of drug resistance and tumor stroma angiogenesis. This review summarizes the proteoglycans remodeling and their novel biological roles in malignancies with particular emphasis to the underlying molecular mechanisms.
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Affiliation(s)
- Achilleas D Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiochemistry Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece.
| | - Nikos K Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiochemistry Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece.
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30
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Nastase MV, Janicova A, Wygrecka M, Schaefer L. Signaling at the Crossroads: Matrix-Derived Proteoglycan and Reactive Oxygen Species Signaling. Antioxid Redox Signal 2017; 27:855-873. [PMID: 28510506 DOI: 10.1089/ars.2017.7165] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
SIGNIFICANCE Proteoglycans (PGs), besides their structural contribution, have emerged as dynamic components that mediate a multitude of cellular events. The various roles of PGs are attributed to their structure, spatial localization, and ability to act as ligands and receptors. Reactive oxygen species (ROS) are small mediators that are generated in physiological and pathological conditions. Besides their reactivity and ability to induce oxidative stress, a growing body of data suggests that ROS signaling is more relevant than direct radical damage in development of human pathologies. Recent Advances: Cell surface transmembrane PGs (syndecans, cluster of differentiation 44) represent receptors in diverse and complex transduction networks, which involve redox signaling with implications in cancer, fibrosis, renal dysfunction, or Alzheimer's disease. Through NADPH oxidase (NOX)-dependent ROS, the extracellular PG, hyaluronan is involved in osteoclastogenesis and cancer. The ROS sources, NOX1 and NOX4, increase biglycan-induced inflammation, while NOX2 is a negative regulator. CRITICAL ISSUES The complexity of the mechanisms that bring ROS into the light of PG biology might be the foundation of a new research area with significant promise for understanding health and disease. Important aspects need to be investigated in PG/ROS signaling: the discovery of specific targets of ROS, the precise ROS-induced chemical modifications of these targets, and the study of their pathological relevance. FUTURE DIRECTIONS As we become more and more aware of the interactions between PG and ROS signaling underlying intracellular communication and cell fate decisions, it is quite conceivable that this field will allow to identify new therapeutic targets.-Antioxid. Redox Signal. 27, 855-873.
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Affiliation(s)
- Madalina-Viviana Nastase
- 1 Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität , Frankfurt am Main, Germany .,2 National Institute for Chemical-Pharmaceutical Research and Development , Bucharest, Romania
| | - Andrea Janicova
- 1 Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität , Frankfurt am Main, Germany
| | - Malgorzata Wygrecka
- 3 Department of Biochemistry, Faculty of Medicine, Justus Liebig University , Giessen, Germany
| | - Liliana Schaefer
- 1 Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität , Frankfurt am Main, Germany
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31
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Paiva KBS, Granjeiro JM. Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 148:203-303. [PMID: 28662823 DOI: 10.1016/bs.pmbts.2017.05.001] [Citation(s) in RCA: 143] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Matrix metalloproteinases (MMPs) are the major protease family responsible for the cleavage of the matrisome (global composition of the extracellular matrix (ECM) proteome) and proteins unrelated to the ECM, generating bioactive molecules. These proteins drive ECM remodeling, in association with tissue-specific and cell-anchored inhibitors (TIMPs and RECK, respectively). In the bone, the ECM mediates cell adhesion, mechanotransduction, nucleation of mineralization, and the immobilization of growth factors to protect them from damage or degradation. Since the first description of an MMP in bone tissue, many other MMPs have been identified, as well as their inhibitors. Numerous functions have been assigned to these proteins, including osteoblast/osteocyte differentiation, bone formation, solubilization of the osteoid during bone resorption, osteoclast recruitment and migration, and as a coupling factor in bone remodeling under physiological conditions. In turn, a number of pathologies, associated with imbalanced bone remodeling, arise mainly from MMP overexpression and abnormalities of the ECM, leading to bone osteolysis or bone formation. In this review, we will discuss the functions of MMPs and their inhibitors in bone cells, during bone remodeling, pathological bone resorption (osteoporosis and bone metastasis), bone repair/regeneration, and emergent roles in bone bioengineering.
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Affiliation(s)
- Katiucia B S Paiva
- Laboratory of Extracellular Matrix Biology and Cellular Interaction (LabMec), Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
| | - José M Granjeiro
- National Institute of Metrology, Quality and Technology (InMetro), Bioengineering Laboratory, Duque de Caxias, RJ, Brazil; Fluminense Federal University, Dental School, Niterói, RJ, Brazil
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Asimakopoulos F, Hope C, Johnson MG, Pagenkopf A, Gromek K, Nagel B. Extracellular matrix and the myeloid-in-myeloma compartment: balancing tolerogenic and immunogenic inflammation in the myeloma niche. J Leukoc Biol 2017; 102:265-275. [PMID: 28254840 DOI: 10.1189/jlb.3mr1116-468r] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 02/06/2017] [Accepted: 02/09/2017] [Indexed: 12/14/2022] Open
Abstract
The last 10-15 years have witnessed a revolution in treating multiple myeloma, an incurable cancer of Ab-producing plasma cells. Advances in myeloma therapy were ushered in by novel agents that remodel the myeloma immune microenvironment. The first generation of novel agents included immunomodulatory drugs (thalidomide analogs) and proteasome inhibitors that target crucial pathways that regulate immunity and inflammation, such as NF-κB. This paradigm continued with the recent regulatory approval of mAbs (elotuzumab, daratumumab) that impact both tumor cells and associated immune cells. Moreover, recent clinical data support checkpoint inhibition immunotherapy in myeloma. With the success of these agents has come the growing realization that the myeloid infiltrate in myeloma lesions-what we collectively call the myeloid-in-myeloma compartment-variably sustains or deters tumor cells by shaping the inflammatory milieu of the myeloma niche and by promoting or antagonizing immune-modulating therapies. The myeloid-in-myeloma compartment includes myeloma-associated macrophages and granulocytes, dendritic cells, and myeloid-derived-suppressor cells. These cell types reflect variable states of differentiation and activation of tumor-infiltrating cells derived from resident myeloid progenitors in the bone marrow-the canonical myeloma niche-or myeloid cells that seed both canonical and extramedullary, noncanonical niches. Myeloma-infiltrating myeloid cells engage in crosstalk with extracellular matrix components, stromal cells, and tumor cells. This complex regulation determines the composition, activation state, and maturation of the myeloid-in-myeloma compartment as well as the balance between immunogenic and tolerogenic inflammation in the niche. Redressing this balance may be a crucial determinant for the success of antimyeloma immunotherapies.
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Affiliation(s)
- Fotis Asimakopoulos
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA; .,University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Chelsea Hope
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Michael G Johnson
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Adam Pagenkopf
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Kimberly Gromek
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Bradley Nagel
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
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Piperigkou Z, Bouris P, Onisto M, Franchi M, Kletsas D, Theocharis AD, Karamanos NK. Estrogen receptor beta modulates breast cancer cells functional properties, signaling and expression of matrix molecules. Matrix Biol 2016; 56:4-23. [DOI: 10.1016/j.matbio.2016.05.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 05/08/2016] [Accepted: 05/09/2016] [Indexed: 02/07/2023]
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Serglycin in tumor microenvironment promotes non-small cell lung cancer aggressiveness in a CD44-dependent manner. Oncogene 2016; 36:2457-2471. [PMID: 27819672 PMCID: PMC5415946 DOI: 10.1038/onc.2016.404] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 08/20/2016] [Accepted: 09/19/2016] [Indexed: 02/06/2023]
Abstract
Tumor microenvironment (TME) plays an active role in promoting tumor progression. To further understand the communication between TME and tumor cells, this study aimed at investigating the involvement of CD44, a type I cell surface receptor, in the crosstalk between tumor cells and TME. We have previously shown that chondroitin sulfate proteoglycan serglycin (SRGN), a CD44-interacting factor, was preferentially secreted by cancer-associated fibroblasts (CAFs) for promoting tumor growth in breast cancer patients. In this study, we show that SRGN is overexpressed in primary non-small cell lung cancers (NSCLCs), by both carcinoma and stromal cells. Using gain-of-function and loss-of-function approaches, we show that SRGN promotes NSCLC cell migration and invasion as well as colonization in the lung and liver in a CD44-dependent manner. SRGN induces lung cancer cell stemness, as demonstrated by its ability to enhance NSCLC cell sphere formation via Nanog induction, accompanied with increased chemoresistance and anoikis-resistance. SRGN promotes epithelial-mesenchymal transition by enhancing vimentin expression via CD44/NF-κB/claudin-1 (CLDN1) axis. In support, CLDN1 and SRGN expression are tightly linked together in primary NSCLC. Most importantly, increased expression of SRGN and/or CLDN1 predicts poor prognosis in primary lung adenocarcinomas. In summary, we demonstrate that SRGN secreted by tumor cells and stromal components in the TME promotes malignant phenotypes through interacting with tumor cell receptor CD44, suggesting that a combined therapy targeting both CD44 and its ligands in the TME may be an attractive approach for cancer therapy.
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Roy A, Femel J, Huijbers EJM, Spillmann D, Larsson E, Ringvall M, Olsson AK, Åbrink M. Targeting Serglycin Prevents Metastasis in Murine Mammary Carcinoma. PLoS One 2016; 11:e0156151. [PMID: 27223472 PMCID: PMC4880347 DOI: 10.1371/journal.pone.0156151] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 05/10/2016] [Indexed: 01/13/2023] Open
Abstract
In hematopoietic cells, serglycin proteoglycans mainly contribute to proper storage and secretion of inflammatory mediators via their negatively charged glycosaminoglycans. Serglycin proteoglycans are also expressed in cancer cells where increased expression has been linked to poor prognosis. However, the serglycin-dependent mediators promoting cancer progression remain to be determined. In the present study we report that genetic ablation of serglycin proteoglycan completely blocks lung metastasis in the MMTV-PyMT-driven mouse breast cancer model, while serglycin-deficiency did not affect primary tumour growth or number of mammary tumours. Although E-cadherin expression was higher in the serglycin-deficient primary tumour tissue, indicating reduced invasiveness, serglycin-deficient tumour cells were still detected in the circulation. These data suggest that serglycin proteoglycans play a role in extravasation as well as colonization and growth of metastatic cells. A microarray expression analysis and functional annotation of differentially expressed genes identified several biological pathways where serglycin may be important. Our results suggest that serglycin and serglycin-dependent mediators are potential drug targets to prevent metastatic disease/dissemination of cancer.
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Affiliation(s)
- Ananya Roy
- Swedish University of Agricultural Sciences, Department of Biomedical Sciences and Veterinary Public Health, Box 7028, 75007, Uppsala, Sweden
- Uppsala University, Department of Medical Biochemistry and Microbiology, Box 582, 75123, Uppsala, Sweden
| | - Julia Femel
- Uppsala University, Department of Medical Biochemistry and Microbiology, Box 582, 75123, Uppsala, Sweden
| | - Elisabeth J. M. Huijbers
- VUMC—Cancer Center Amsterdam, Angiogenesis Laboratory, Dept. of Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Dorothe Spillmann
- Uppsala University, Department of Medical Biochemistry and Microbiology, Box 582, 75123, Uppsala, Sweden
| | - Erik Larsson
- Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck laboratory, 751 85, Uppsala, Sweden
| | - Maria Ringvall
- Uppsala University, Department of Medical Biochemistry and Microbiology, Box 582, 75123, Uppsala, Sweden
| | - Anna-Karin Olsson
- Uppsala University, Department of Medical Biochemistry and Microbiology, Box 582, 75123, Uppsala, Sweden
| | - Magnus Åbrink
- Swedish University of Agricultural Sciences, Department of Biomedical Sciences and Veterinary Public Health, Box 7028, 75007, Uppsala, Sweden
- * E-mail:
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Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK. Extracellular matrix structure. Adv Drug Deliv Rev 2016; 97:4-27. [PMID: 26562801 DOI: 10.1016/j.addr.2015.11.001] [Citation(s) in RCA: 1547] [Impact Index Per Article: 171.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 10/30/2015] [Accepted: 11/02/2015] [Indexed: 12/12/2022]
Abstract
Extracellular matrix (ECM) is a non-cellular three-dimensional macromolecular network composed of collagens, proteoglycans/glycosaminoglycans, elastin, fibronectin, laminins, and several other glycoproteins. Matrix components bind each other as well as cell adhesion receptors forming a complex network into which cells reside in all tissues and organs. Cell surface receptors transduce signals into cells from ECM, which regulate diverse cellular functions, such as survival, growth, migration, and differentiation, and are vital for maintaining normal homeostasis. ECM is a highly dynamic structural network that continuously undergoes remodeling mediated by several matrix-degrading enzymes during normal and pathological conditions. Deregulation of ECM composition and structure is associated with the development and progression of several pathologic conditions. This article emphasizes in the complex ECM structure as to provide a better understanding of its dynamic structural and functional multipotency. Where relevant, the implication of the various families of ECM macromolecules in health and disease is also presented.
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Affiliation(s)
- Achilleas D Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece
| | - Spyros S Skandalis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece
| | - Chrysostomi Gialeli
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece; Division of Medical Protein Chemistry, Department of Translational Medicine Malmö, Lund University, S-20502 Malmö, Sweden
| | - Nikos K Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece.
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Cohen K, Flint N, Shalev S, Erez D, Baharal T, Davis PJ, Hercbergs A, Ellis M, Ashur-Fabian O. Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via αvβ3 integrin in myeloma cells. Oncotarget 2015; 5:6312-22. [PMID: 25071016 PMCID: PMC4171632 DOI: 10.18632/oncotarget.2205] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Thyroid hormone (3,5,3′-triiodothyronine, T3; L-thyroxine, T4) enhances cancer cell proliferation, invasion and angiogenesis via a discrete receptor located near the RGD recognition site on αvβ3 integrin. Tetraiodothyroacetic acid (tetrac) and its nanoparticulate formulation interfere with binding of T3/T4 to the integrin. This integrin is overexpressed in multiple myeloma (MM) and other cancers. MM cells interact with αvβ3 integrin to support growth and invasion. Matrix metalloproteinases (MMPs) are a family of enzymes active in tissue remodeling and cancer. The association between integrins and MMPs secretion and action is well established. In the current study, we examined the effects of thyroid hormone on myeloma cell adhesion, migration and MMP activity. We show that T3 and T4 increased myeloma adhesion to fibronectin and induced αvβ3 clustering. In addition, the hormones induced MMP-9 expression and activation via αvβ3 and MAPK induction. Bortezomib, a standard myeloma treatment, caused a decrease in activity/quantity of MMPs and thyroid hormone opposed this effect. RGD peptide and tetrac impaired the production of MMP-9 in cell lines and in primary BM cells from myeloma patients. In conclusion, thyroid hormone-dependent regulation via αvβ3 of myeloma cell adhesion and MMP-9 production may play a role in myeloma migration and progression.
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Affiliation(s)
- Keren Cohen
- Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel; Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nir Flint
- Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shachar Shalev
- Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Daniel Erez
- Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tal Baharal
- Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Paul J Davis
- Department of Medicine, Albany Medical College, Albany, NY, USA
| | | | - Martin Ellis
- Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Osnat Ashur-Fabian
- Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel; Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Increased Expression of Serglycin in Specific Carcinomas and Aggressive Cancer Cell Lines. BIOMED RESEARCH INTERNATIONAL 2015; 2015:690721. [PMID: 26581653 PMCID: PMC4637082 DOI: 10.1155/2015/690721] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 07/10/2015] [Accepted: 07/14/2015] [Indexed: 12/15/2022]
Abstract
In the present pilot study, we examined the presence of serglycin in lung, breast, prostate, and colon cancer and evaluated its expression in cell lines and tissues. We found that serglycin was expressed and constitutively secreted in culture medium in high levels in more aggressive cancer cells. It is worth noticing that aggressive cancer cells that harbor KRAS or EGFR mutations secreted serglycin constitutively in elevated levels. Furthermore, we detected the transcription of an alternative splice variant of serglycin lacking exon 2 in specific cell lines. In a limited number of tissue samples analyzed, serglycin was detected in normal epithelium but was also expressed in higher levels in advanced grade tumors as shown by immunohistochemistry. Serglycin staining was diffuse, granular, and mainly cytoplasmic. In some cancer cells serglycin also exhibited membrane and/or nuclear immunolocalization. Interestingly, the stromal cells of the reactive tumor stroma were positive for serglycin, suggesting an enhanced biosynthesis for this proteoglycan in activated tumor microenvironment. Our study investigated for first time the distribution of serglycin in normal epithelial and cancerous lesions in most common cancer types. The elevated levels of serglycin in aggressive cancer and stromal cells may suggest a key role for serglycin in disease progression.
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Hjorth M, Norheim F, Meen AJ, Pourteymour S, Lee S, Holen T, Jensen J, Birkeland KI, Martinov VN, Langleite TM, Eckardt K, Drevon CA, Kolset SO. The effect of acute and long-term physical activity on extracellular matrix and serglycin in human skeletal muscle. Physiol Rep 2015; 3:e12473. [PMID: 26290530 PMCID: PMC4562559 DOI: 10.14814/phy2.12473] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 07/01/2015] [Accepted: 07/02/2015] [Indexed: 12/20/2022] Open
Abstract
Remodeling of extracellular matrix (ECM), including regulation of proteoglycans in skeletal muscle can be important for physiological adaptation to exercise. To investigate the effects of acute and long-term exercise on the expression of ECM-related genes and proteoglycans in particular, 26 middle-aged, sedentary men underwent a 12 weeks supervised endurance and strength training intervention and two acute, 45 min bicycle tests (70% VO2max), one at baseline and one after 12 weeks of training. Total gene expression in biopsies from m. vastus lateralis was measured with deep mRNA sequencing. After 45 min of bicycling approximately 550 gene transcripts were >50% upregulated. Of these, 28 genes (5%) were directly related to ECM. In response to long-term exercise of 12 weeks 289 genes exhibited enhanced expression (>50%) and 20% of them were ECM related. Further analyses of proteoglycan mRNA expression revealed that more than half of the proteoglycans expressed in muscle were significantly enhanced after 12 weeks intervention. The proteoglycan serglycin (SRGN) has not been studied in skeletal muscle and was one of few proteoglycans that showed increased expression after acute (2.2-fold, P < 0.001) as well as long-term exercise (1.4-fold, P < 0.001). Cultured, primary human skeletal muscle cells expressed and secreted SRGN. When the expression of SRGN was knocked down, the expression and secretion of serpin E1 (SERPINE1) increased. In conclusion, acute and especially long-term exercise promotes enhanced expression of several ECM components and proteoglycans. SRGN is a novel exercise-regulated proteoglycan in skeletal muscle with a potential role in exercise adaptation.
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Affiliation(s)
- Marit Hjorth
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Frode Norheim
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Astri J Meen
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Shirin Pourteymour
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Sindre Lee
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Torgeir Holen
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Jørgen Jensen
- Department of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway
| | - Kåre I Birkeland
- Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital and Institute of Clinical Medicine University of Oslo, Oslo, Norway
| | - Vladimir N Martinov
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Torgrim M Langleite
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital and Institute of Clinical Medicine University of Oslo, Oslo, Norway
| | - Kristin Eckardt
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Christian A Drevon
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Svein O Kolset
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
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Theocharis AD, Skandalis SS, Neill T, Multhaupt HAB, Hubo M, Frey H, Gopal S, Gomes A, Afratis N, Lim HC, Couchman JR, Filmus J, Sanderson RD, Schaefer L, Iozzo RV, Karamanos NK. Insights into the key roles of proteoglycans in breast cancer biology and translational medicine. Biochim Biophys Acta Rev Cancer 2015; 1855:276-300. [PMID: 25829250 DOI: 10.1016/j.bbcan.2015.03.006] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 02/27/2015] [Accepted: 03/24/2015] [Indexed: 12/18/2022]
Abstract
Proteoglycans control numerous normal and pathological processes, among which are morphogenesis, tissue repair, inflammation, vascularization and cancer metastasis. During tumor development and growth, proteoglycan expression is markedly modified in the tumor microenvironment. Altered expression of proteoglycans on tumor and stromal cell membranes affects cancer cell signaling, growth and survival, cell adhesion, migration and angiogenesis. Despite the high complexity and heterogeneity of breast cancer, the rapid evolution in our knowledge that proteoglycans are among the key players in the breast tumor microenvironment suggests their potential as pharmacological targets in this type of cancer. It has been recently suggested that pharmacological treatment may target proteoglycan metabolism, their utilization as targets for immunotherapy or their direct use as therapeutic agents. The diversity inherent in the proteoglycans that will be presented herein provides the potential for multiple layers of regulation of breast tumor behavior. This review summarizes recent developments concerning the biology of selected proteoglycans in breast cancer, and presents potential targeted therapeutic approaches based on their novel key roles in breast cancer.
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Affiliation(s)
- Achilleas D Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece
| | - Spyros S Skandalis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece
| | - Thomas Neill
- Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Hinke A B Multhaupt
- Department of Biomedical Sciences and Biotech Research & Innovation Center, University of Copenhagen, Denmark
| | - Mario Hubo
- University of Frankfurt, Institute of Pharmacology and Toxicology, Theodor-Stern Kai 7, Frankfurt 60590, Germany
| | - Helena Frey
- University of Frankfurt, Institute of Pharmacology and Toxicology, Theodor-Stern Kai 7, Frankfurt 60590, Germany
| | - Sandeep Gopal
- Department of Biomedical Sciences and Biotech Research & Innovation Center, University of Copenhagen, Denmark
| | - Angélica Gomes
- Department of Biomedical Sciences and Biotech Research & Innovation Center, University of Copenhagen, Denmark
| | - Nikos Afratis
- Department of Biomedical Sciences and Biotech Research & Innovation Center, University of Copenhagen, Denmark
| | - Hooi Ching Lim
- Department of Biomedical Sciences and Biotech Research & Innovation Center, University of Copenhagen, Denmark
| | - John R Couchman
- Department of Biomedical Sciences and Biotech Research & Innovation Center, University of Copenhagen, Denmark
| | - Jorge Filmus
- Department of Biological Sciences, Sunnybrook Research Institute and Department of Medical Biophysics, University of Toronto, Canada
| | - Ralph D Sanderson
- University of Alabama at Birmingham, Department of Pathology, UAB Comprehensive Cancer Center, 1720 2nd Ave. S, WTI 602B, Birmingham, AL 35294, USA
| | - Liliana Schaefer
- University of Frankfurt, Institute of Pharmacology and Toxicology, Theodor-Stern Kai 7, Frankfurt 60590, Germany
| | - Renato V Iozzo
- Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Nikos K Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece.
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Iozzo RV, Schaefer L. Proteoglycan form and function: A comprehensive nomenclature of proteoglycans. Matrix Biol 2015; 42:11-55. [PMID: 25701227 PMCID: PMC4859157 DOI: 10.1016/j.matbio.2015.02.003] [Citation(s) in RCA: 848] [Impact Index Per Article: 84.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 02/09/2015] [Indexed: 02/07/2023]
Abstract
We provide a comprehensive classification of the proteoglycan gene families and respective protein cores. This updated nomenclature is based on three criteria: Cellular and subcellular location, overall gene/protein homology, and the utilization of specific protein modules within their respective protein cores. These three signatures were utilized to design four major classes of proteoglycans with distinct forms and functions: the intracellular, cell-surface, pericellular and extracellular proteoglycans. The proposed nomenclature encompasses forty-three distinct proteoglycan-encoding genes and many alternatively-spliced variants. The biological functions of these four proteoglycan families are critically assessed in development, cancer and angiogenesis, and in various acquired and genetic diseases where their expression is aberrant.
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Affiliation(s)
- Renato V Iozzo
- Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA.
| | - Liliana Schaefer
- Pharmazentrum Frankfurt/ZAFES, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany.
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Kolseth IBM, Reine TM, Vuong TT, Meen AJ, Fan Q, Jenssen TG, Grønning-Wang LM, Kolset SO. Serglycin is part of the secretory repertoire of LPS-activated monocytes. IMMUNITY INFLAMMATION AND DISEASE 2015; 3:23-31. [PMID: 25866637 PMCID: PMC4386912 DOI: 10.1002/iid3.47] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 11/13/2014] [Accepted: 12/18/2014] [Indexed: 12/15/2022]
Abstract
Monocytes play multiple roles in the immune system, and are active in both acute and chronic diseases. Patients exposed to bacterial infections depend on monocytes in defense reactions, but excessive immune reactions may also cause morbidity through systemic inflammatory responses. Few studies have addressed the importance of proteoglycans, and in particular, the hematopoietic serglycin, in such monocyte immune reactions. Adherent primary monocytes were cultured in absence and presence of LPS. Media were analyzed by ELISA for detection of serglycin. Lysed cell fractions were used to determine the mRNA level of serglycin. Monocytes were also cultured on chamber slides to investigate if serglycin could be detected intracellularly by immunocytochemistry. Monocytes secreted serglycin, and LPS-stimulation increased the secretion. Secretion of inflammatory cytokines increased to a larger extent than serglycin. mRNA levels of serglycin were also increased, suggesting both increased expression and secretion. Immunocytochemistry revealed the presence of serglycin in intracellular vesicles, many destined for secretion. Serglycin containing vesicles increased in number and size when the cells were exposed to LPS. Intracellular vesicle localization and secretion of the proteoglycan serglycin is shown for the first time in primary human monocytes. Monocyte activation by LPS increased the expression and secretion of serglycin, suggesting roles for serglycin in inflammatory processes.
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Affiliation(s)
| | - Trine Marita Reine
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo Oslo, Norway
| | - Tram Thu Vuong
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo Oslo, Norway
| | - Astri Jeanette Meen
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo Oslo, Norway
| | - Qiong Fan
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo Oslo, Norway
| | - Trond Geir Jenssen
- Department of Transplant Medicine, Section of Nephrology, Oslo University Hospital Rikshospitalet, Oslo, Norway ; Metabolic and Renal Research Group, UiT The Arctic University of Norway Tromsø, Norway
| | | | - Svein Olav Kolset
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo Oslo, Norway
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Theocharis AD, Gialeli C, Bouris P, Giannopoulou E, Skandalis SS, Aletras AJ, Iozzo RV, Karamanos NK. Cell-matrix interactions: focus on proteoglycan-proteinase interplay and pharmacological targeting in cancer. FEBS J 2014; 281:5023-42. [PMID: 25333340 PMCID: PMC5036392 DOI: 10.1111/febs.12927] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 07/04/2014] [Accepted: 07/09/2014] [Indexed: 01/10/2023]
Abstract
Proteoglycans are major constituents of extracellular matrices, as well as cell surfaces and basement membranes. They play key roles in supporting the dynamic extracellular matrix by generating complex structural networks with other macromolecules and by regulating cellular phenotypes and signaling. It is becoming evident, however, that proteolytic enzymes are required partners for matrix remodeling and for modulating cell signaling via matrix constituents. Proteinases contribute to all stages of diseases, particularly cancer development and progression, and contextually participate in either the removal of damaged products or in the processing of matrix molecules and signaling receptors. The dynamic interplay between proteoglycans and proteolytic enzymes is a crucial biological step that contributes to the pathophysiology of cancer and inflammation. Moreover, proteoglycans are implicated in the expression and secretion of proteolytic enzymes and often modulate their activities. In this review, we describe the emerging biological roles of proteoglycans and proteinases, with a special emphasis on their complex interplay. We critically evaluate this important proteoglycan-proteinase interactome and discuss future challenges with respect to targeting this axis in the treatment of cancer.
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Affiliation(s)
- Achilleas D. Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
| | - Chrisostomi Gialeli
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
| | - Panagiotis Bouris
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
| | - Efstathia Giannopoulou
- Clinical Oncology Laboratory, Division of Oncology, University Hospital of Patras, Patras Medical School, Patras 26110, Greece
| | - Spyros S. Skandalis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
| | - Alexios J. Aletras
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
| | - Renato V. Iozzo
- Department of Pathology, Anatomy and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
| | - Nikos K. Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
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Korpetinou A, Skandalis SS, Labropoulou VT, Smirlaki G, Noulas A, Karamanos NK, Theocharis AD. Serglycin: at the crossroad of inflammation and malignancy. Front Oncol 2014; 3:327. [PMID: 24455486 PMCID: PMC3888995 DOI: 10.3389/fonc.2013.00327] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 12/20/2013] [Indexed: 12/14/2022] Open
Abstract
Serglycin has been initially characterized as an intracellular proteoglycan expressed by hematopoietic cells. All inflammatory cells highly synthesize serglycin and store it in granules, where it interacts with numerous inflammatory mediators, such as proteases, chemokines, cytokines, and growth factors. Serglycin is implicated in their storage into the granules and their protection since they are secreted as complexes and delivered to their targets after secretion. During the last decade, numerous studies have demonstrated that serglycin is also synthesized by various non-hematopoietic cell types. It has been shown that serglycin is highly expressed by tumor cells and promotes their aggressive phenotype and confers resistance against drugs and complement system attack. Apart from its direct beneficial role to tumor cells, serglycin may promote the inflammatory process in the tumor cell microenvironment thus enhancing tumor development. In the present review, we discuss the role of serglycin in inflammation and tumor progression.
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Affiliation(s)
- Angeliki Korpetinou
- Laboratory of Biochemistry, Department of Chemistry, University of Patras , Patras , Greece
| | - Spyros S Skandalis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras , Patras , Greece
| | | | - Gianna Smirlaki
- Laboratory of Biochemistry, Department of Chemistry, University of Patras , Patras , Greece
| | | | - Nikos K Karamanos
- Laboratory of Biochemistry, Department of Chemistry, University of Patras , Patras , Greece
| | - Achilleas D Theocharis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras , Patras , Greece
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Korpetinou A, Skandalis SS, Moustakas A, Happonen KE, Tveit H, Prydz K, Labropoulou VT, Giannopoulou E, Kalofonos HP, Blom AM, Karamanos NK, Theocharis AD. Serglycin is implicated in the promotion of aggressive phenotype of breast cancer cells. PLoS One 2013; 8:e78157. [PMID: 24205138 PMCID: PMC3815026 DOI: 10.1371/journal.pone.0078157] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 09/17/2013] [Indexed: 12/13/2022] Open
Abstract
Serglycin is a proteoglycan expressed by some malignant cells. It promotes metastasis and protects some tumor cells from complement system attack. In the present study, we show for the first time the in situ expression of serglycin by breast cancer cells by immunohistochemistry in patients' material. Moreover, we demonstrate high expression and constitutive secretion of serglycin in the aggressive MDA-MB-231 breast cancer cell line. Serglycin exhibited a strong cytoplasmic staining in these cells, observable at the cell periphery in a thread of filaments near the cell membrane, but also in filopodia-like structures. Serglycin was purified from conditioned medium of MDA-MB-231 cells, and represented the major proteoglycan secreted by these cells, having a molecular size of ~ 250 kDa and carrying chondroitin sulfate side chains, mainly composed of 4-sulfated (~ 87%), 6-sulfated (~ 10%) and non-sulfated (~ 3%) disaccharides. Purified serglycin inhibited early steps of both the classical and the lectin pathways of complement by binding to C1q and mannose-binding lectin. Stable expression of serglycin in less aggressive MCF-7 breast cancer cells induced their proliferation, anchorage-independent growth, migration and invasion. Interestingly, over-expression of serglycin lacking the glycosaminoglycan attachment sites failed to promote these cellular functions, suggesting that glycanation of serglycin is a pre-requisite for its oncogenic properties. Our findings suggest that serglycin promotes a more aggressive cancer cell phenotype and may protect breast cancer cells from complement attack supporting their survival and expansion.
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Affiliation(s)
- Angeliki Korpetinou
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
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Skandalis SS, Afratis N, Smirlaki G, Nikitovic D, Theocharis AD, Tzanakakis GN, Karamanos NK. Cross-talk between estradiol receptor and EGFR/IGF-IR signaling pathways in estrogen-responsive breast cancers: focus on the role and impact of proteoglycans. Matrix Biol 2013; 35:182-93. [PMID: 24063949 DOI: 10.1016/j.matbio.2013.09.002] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 09/13/2013] [Accepted: 09/13/2013] [Indexed: 02/07/2023]
Abstract
In hormone-dependent breast cancer, estrogen receptors are the principal signaling molecules that regulate several cell functions either by the genomic pathway acting directly as transcription factors in the nucleus or by the non-genomic pathway interacting with other receptors and their adjacent pathways like EGFR/IGFR. It is well established in literature that EGFR and IGFR signaling pathways promote cell proliferation and differentiation. Moreover, recent data indicate the cross-talk between ERs and EGFR/IGFR signaling pathways causing a transformation of cell functions as well as deregulation on normal expression pattern of matrix molecules. Specifically, proteoglycans, a major category of extracellular matrix (ECM) and cell surface macromolecules, are modified during malignancy and cause alterations in cancer cell signaling, affecting eventually functional cell properties such as proliferation, adhesion and migration. The on-going strategies to block only one of the above signaling effectors result cancer cells to overcome such inactivation using alternative signaling pathways. In this article, we therefore review the underlying mechanisms in respect to the role of ERs and the involvement of cross-talk between ERs, IGFR and EGFR in breast cancer cell properties and expression of extracellular secreted and cell bound proteoglycans involved in cancer progression. Understanding such signaling pathways may help to establish new potential pharmacological targets in terms of using ECM molecules to design novel anticancer therapies.
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Affiliation(s)
- Spyros S Skandalis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Nikolaos Afratis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Gianna Smirlaki
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Dragana Nikitovic
- Department of Anatomy-Histology-Embryology, Medical School, University of Crete, Heraklion 71003, Greece
| | - Achilleas D Theocharis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - George N Tzanakakis
- Department of Anatomy-Histology-Embryology, Medical School, University of Crete, Heraklion 71003, Greece
| | - Nikos K Karamanos
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
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Serglycin (SRGN) overexpression predicts poor prognosis in hepatocellular carcinoma patients. Med Oncol 2013; 30:707. [PMID: 23996242 DOI: 10.1007/s12032-013-0707-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Accepted: 08/20/2013] [Indexed: 12/21/2022]
Abstract
Hepatocellular carcinoma (HCC) is known for its high rate of recurrence and poor prognosis, which makes it necessary to identify new predictive markers for HCC and to explore the underlying mechanism(s). Emerging evidence suggests that the proteoglycan serglycin (SRGN) might play a crucial role in tumor metastasis. However, currently, the function of SRGN in HCC remains unknown. Here, we evaluated the expression pattern of SRGN in 127 HCC specimens and their adjacent, non-tumorous tissues using immunohistochemical assays. We observed that SRGN was significantly upregulated in HCC tissues. Elevated expression levels of SRGN were detectable in 72/127 (56.7%) of the HCC specimens and in 4/127 (3.1%) of adjacent non-tumorous tissues (p < 0.001). Further correlation analysis demonstrated that the increased expression of SRGN was positively associated with HBV infection, GGT level, vascular invasion, advanced BCLC stage and early recurrence (p < 0.05). Increased SRGN expression correlated with unfavorable prognosis in HCC patients. In multivariate analyses, SRGN expression levels were found to represent an independent predictor for overall survival (p = 0.002) and time to recurrence (p = 0.010) of HCC patients. Furthermore, the elevated expression of SRGN in the HCC tissues was accompanied by elevated levels of vimentin and the absence of E-cadherin. Similarly, the reduced expression of SRGN was accompanied by elevated levels of E-cadherin and the absence of vimentin. E-cadherin and vimentin are well-accepted biomarkers of the epithelial-mesenchymal transition (EMT), and the expression of SRGN might correlate with EMT. Our results demonstrate that the elevated expression of SRGN represents a crucial event in HCC patients that is indicative of poor clinical outcome.
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Malla N, Berg E, Theocharis AD, Svineng G, Uhlin-Hansen L, Winberg JO. In vitroreconstitution of complexes between pro-matrix metalloproteinase-9 and the proteoglycans serglycin and versican. FEBS J 2013; 280:2870-87. [DOI: 10.1111/febs.12291] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 04/08/2013] [Accepted: 04/16/2013] [Indexed: 12/20/2022]
Affiliation(s)
- Nabin Malla
- Department of Medical Biology; University of Tromsø; Norway
| | - Eli Berg
- Department of Medical Biology; University of Tromsø; Norway
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