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      Genistein inhibits angiogenesis developed during rheumatoid arthritis through the IL-6/JAK2/STAT3/VEGF signalling pathway

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          Abstract

          Background

          Angiogenesis plays an important role in the development of rheumatoid arthritis (RA), which increases the supply of nutrients, cytokines, and inflammatory cells to the synovial membrane. Genistein (GEN), a soy-derived isoflavone, has been validated that can effectively inhibit the angiogenesis of several tumours. We thus carried out a study in vitro to investigate the effect of GEN in vascular endothelial growth factor (VEGF) expression and angiogenesis induced by the inflammatory environment of RA.

          Methods

          MH7A cells were used to verify whether GEN can inhibit the expression of VEGF in MH7A cells under inflammatory conditions and demonstrate the mechanism. EA.hy926 ​cells were used to verify whether GEN can inhibit the migration and tube formation of vascular endothelial cells in inflammatory environment.

          Results

          GEN dose-dependently inhibited the expression and secretion of interleukin (IL)-6 and VEGF, as well as the nucleus translocation of Signal transducer and activator of transcription 3 (STAT3) in MH7A. Furthermore, GEN inhibited IL-6–induced vascular endothelial cell migration and tube formation in vitro.

          Conclusion

          GEN inhibits IL-6–induced VEGF expression and angiogenesis partially through the Janus kinase 2 (JAK2)/STAT3 pathway in RA, which has provided a novel insight into the antiangiogenic activity of GEN in RA.

          The translational potential of this article

          Our study provides scientific guidance for the clinical translational research of GEN in the RA treatment.

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          Most cited references31

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          Genistein and cancer: current status, challenges, and future directions.

          Carmela Spagnuolo, Gian Russo, Ilkay Orhan … (2015)
          Primary prevention through lifestyle interventions is a cost-effective alternative for preventing a large burden of chronic and degenerative diseases, including cancer, which is one of the leading causes of morbidity and mortality worldwide. In the past decade, epidemiologic and preclinical evidence suggested that polyphenolic phytochemicals present in many plant foods possess chemopreventive properties against several cancer forms. Thus, there has been increasing interest in the potential cancer chemopreventive agents obtained from natural sources, such as polyphenols, that may represent a new, affordable approach to curb the increasing burden of cancer throughout the world. Several epidemiologic studies showed a relation between a soy-rich diet and cancer prevention, which was attributed to the presence of a phenolic compound, genistein, present in soy-based foods. Genistein acts as a chemotherapeutic agent against different types of cancer, mainly by altering apoptosis, the cell cycle, and angiogenesis and inhibiting metastasis. Targeting caspases, B cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, kinesin-like protein 20A (KIF20A), extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear transcription factor κB (NF-κB), mitogen-activated protein kinase (MAPK), inhibitor of NF-κB (IκB), Wingless and integration 1 β-catenin (Wnt/β-catenin), and phosphoinositide 3 kinase/Akt (PI3K/Akt) signaling pathways may act as the molecular mechanisms of the anticancer, therapeutic effects of genistein. Genistein also shows synergistic behavior with well-known anticancer drugs, such as adriamycin, docetaxel, and tamoxifen, suggesting a potential role in combination therapy. This review critically analyzes the available literature on the therapeutic role of genistein on different types of cancer, focusing on its chemical features, plant food sources, bioavailability, and safety.
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            Signaling through the JAK/STAT pathway, recent advances and future challenges.

            Marc Braunstein, T Kisseleva, S. Bhattacharya … (2002)
            Investigation into the mechanism of cytokine signaling led to the discovery of the JAK/STAT pathway. Following the binding of cytokines to their cognate receptor, signal transducers and activators of transcription (STATs) are activated by members of the janus activated kinase (JAK) family of tyrosine kinases. Once activated, they dimerize and translocate to the nucleus and modulate the expression of target genes. During the past several years significant progress has been made in the characterization of the JAK/STAT signaling cascade, including the identification of multiple STATs and regulatory proteins. Seven STATs have been identified in mammals. The vital role these STATs play in the biological response to cytokines has been demonstrated through the generation of murine 'knockout' models. These mice will be invaluable in carefully elucidating the role STATs play in regulating the host response to various stresses. Similarly, the solution of the crystal structure of two STATs has and will continue to facilitate our understanding of how STATs function. This review will highlight these exciting developments in JAK/STAT signaling.
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              Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.

              Daoyan Wei, Xiangdong Le, Leizhen Zheng … (2003)
              Expression of vascular endothelial growth factor (VEGF), a key angiogenic protein, has been linked with pancreatic cancer progression. However, the molecular basis for VEGF overexpression remains unclear. Immunohistochemical studies have indicated that VEGF overexpression coincides with elevated Stat3 activation in human pancreatic cancer specimens. In our study, more than 80% of the human pancreatic cancer cell lines used exhibited constitutively activated Stat3, with Stat3 activation correlated with the VEGF expression level. Blockade of activated Stat3 via ectopic expression of dominant-negative Stat3 significantly suppressed VEGF expression, angiogenesis, tumor growth, and metastasis in vivo. Furthermore, constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. A putative Stat3-responsive element on the VEGF promoter was identified using a protein-DNA binding assay and confirmed using a promoter mutagenesis assay. These results indicate that Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer, suggesting that Stat3 signaling may be targeted for treatment of pancreatic cancer.
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                Author and article information

                Contributors
                Fei Yang
                Peng Zhang
                Journal
                Journal ID (nlm-ta): J Orthop Translat
                Journal ID (iso-abbrev): J Orthop Translat
                Title: Journal of Orthopaedic Translation
                Publisher: Chinese Speaking Orthopaedic Society
                ISSN (Print): 2214-031X
                ISSN (Electronic): 2214-0328
                Publication date PMC-release: 23 August 2019
                Publication date Collection: May 2020
                Publication date (Electronic): 23 August 2019
                Volume: 22
                Pages: 92-100
                Affiliations
                [a ]Center for Translational Medicine Research and Development, Shen Zhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen, Guangdong, 518055, China
                [b ]University of Chinese Academy of Sciences, Beijing, 10049, China
                [c ]University of Chinese Academy of Sciences, Shenzhen Hospital, Shenzhen, 518000, China
                [d ]State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China
                [e ]Department of Orthopedic, University of Chinese Academy of Sciences Shenzhen Hospital, 518000, Shenzhen, China
                [f ]Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
                [g ]Shenzhen Pingle Orthopaedic Hospital, Guangdong, 518000, China
                [h ]Department of Rheumatology, People's Hospital of Bao'an District, Shenzhen, Guangdong, 518128, China
                [i ]Department of Orthopaedic, The First Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Ji'nan, Shandong, 250000, China
                [j ]School of Dentistry, Cardiff University, Cardiff, Heath Park, CF23 6AL, UK
                [k ]Shenzhen Middle School, Shenzhen, Guangdong, 518001, China
                [l ]Huizhou Second Maternal and Child Health Care Hospital, Huizhou, Guangdong, 516001, China
                [m ]Shenzhen Engineering Research Center for Medical Bioactive Materials, Shenzhen, Guangdong, 518055, China
                Author notes
                [∗ ]Corresponding author. Center for Translational Medicine Research and Development, Shen Zhen Institute of Advanced Technology, Chinese Academy of Science, 1068 Xueyuan Avenue, Shenzhen, Guangdong, 518055,China. peng.zhang@ 123456siat.ac.cn
                [∗∗ ]Corresponding author. Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China. feiyangyn@ 123456163.com
                [☆]

                These authors contributed equally to this work and should be considered co-first authors

                Article
                Publisher ID: S2214-031X(19)30190-1
                DOI: 10.1016/j.jot.2019.07.007
                PMC ID: 7231959
                SO-VID: ce6646f9-b075-4d31-87ab-e465ec02838a
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 21 February 2019
                Date revision received : 22 July 2019
                Date accepted : 28 July 2019
                Categories
                Subject: Original Article

                Keywords: angiogenesis,genistein,rheumatoid arthritis
                Data availability:
                Keywords: angiogenesis, genistein, rheumatoid arthritis

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