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Yang T, Liu Y, Lin Z, Chen F, Zhu L, Zhang L, Zhou B, Li F, Sun H. Altered N6-methyladenosine methylation level in spermatozoa messenger RNA of the male partners is related to unexplained recurrent pregnancy loss. Andrology 2025; 13:531-543. [PMID: 38979761 DOI: 10.1111/andr.13678] [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: 02/14/2024] [Revised: 05/17/2024] [Accepted: 05/30/2024] [Indexed: 07/10/2024]
Abstract
BACKGROUND Understanding the pathogenesis of unexplained recurrent pregnancy loss is paramount for advancing effective treatments. Various biological processes, including spermatogenesis and embryo development, are tightly regulated by N6-methyladenosine modifications. However, few studies have focused on the impact of sperm N6-methyladenosine modifications on embryonic development. Therefore, we aimed to study altered N6-methyladenosine-mediated messenger RNA methylation modifications in the spermatozoa of male partners from couples experiencing unexplained recurrent pregnancy loss, to identify potential diagnostic markers and explore their potential molecular mechanisms in pregnancy loss and embryogenesis. METHODS Methylated RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing were conducted on the spermatozoa of men from couples in the 'unexplained recurrent pregnancy loss' group (n = 6), and the fertility control group (n = 6). To identify the role of the detected key genes, zebrafish model embryos were studied, and multi-omics (transcriptomics, proteomics, and metabolomics) analyses helped to explore the molecular mechanism of abnormal embryogenesis. FINDINGS Comparing unexplained recurrent pregnancy loss with the fertility control group, 217 N6-methyladenosine peaks were significantly upregulated, and 40 were downregulated in the spermatozoa. The combined analyses of spermatozoa-methylated RNA immunoprecipitation sequencing and RNA sequencing indicated that N6-methyladenosine methylation and the expression of SEMA5A, MT-ATP6, ZNF662, and KDM4C were significantly different. In zebrafish embryos, the altered expression of the four genes increased embryonic mortality and malformations by disturbing several key signaling pathways and zygotic genome activation. INTERPRETATION This study highlights the paternal epigenome, which could be one of the reasons for faulty embryogenesis leading to pregnancy loss. The N6-methyladenosine modification, the most prevalent RNA modification, contributes to the exploration and understanding of the paternal epigenome in the maintenance of pregnancy and fetal growth and development. The four genes identified in this study may serve as potential diagnostic markers and elucidate novel molecular mechanisms of embryogenesis.
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Affiliation(s)
- Tingting Yang
- Department of Andrology/Human Sperm Bank of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yanyan Liu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- Department of Medical Genetics, Prenatal Diagnosis Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Ziyuan Lin
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- SCU-CUHK Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Feng Chen
- Department of Andrology/Human Sperm Bank of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- SCU-CUHK Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Lin Zhu
- Department of Nephrology/Hemodialysis Center, West China Hospital, Sichuan University and West China School of Nursing, Sichuan University, Chengdu, China
| | - Lin Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Bin Zhou
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Fuping Li
- Department of Andrology/Human Sperm Bank of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Huaqin Sun
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- SCU-CUHK Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
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Liu Z, Lin H, Li X, Xue H, Lu Y, Xu F, Shuai J. The network structural entropy for single-cell RNA sequencing data during skin aging. Brief Bioinform 2024; 26:bbae698. [PMID: 39757115 DOI: 10.1093/bib/bbae698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 11/29/2024] [Accepted: 12/18/2024] [Indexed: 01/07/2025] Open
Abstract
Aging is a complex and heterogeneous biological process at cellular, tissue, and individual levels. Despite extensive effort in scientific research, a comprehensive understanding of aging mechanisms remains lacking. This study analyzed aging-related gene networks, using single-cell RNA sequencing data from >15 000 cells. We constructed a gene correlation network, integrating gene expressions into the weights of network edges, and ranked gene importance using a random walk model to generate a gene importance matrix. This unsupervised method improved the clustering performance of cell types. To further quantify the complexity of gene networks during aging, we introduced network structural entropy. The findings of our study reveal that the overall network structural entropy increases in the aged cells compared to the young cells. However, network entropy changes varied greatly within different cell subtypes. Specifically, the network structural entropy among various cell types may increase, remain unchanged, or decrease. This wide range of changes may be closely related to their individual functions, highlighting the cellular heterogeneity and potential key network reconfigurations. Analyzing gene network entropy provides insights into the molecular mechanisms behind aging. This study offers new scientific evidence and theoretical support for understanding the changes in cell functions during aging.
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Affiliation(s)
- Zhilong Liu
- Department of Physics, Xiamen University, No. 422, Siming South Road, Xiamen, Fujian, 361005, China
| | - Hai Lin
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), No. 999, Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, Zhejiang, 325000, China; Wenzhou Institute, University of Chinese Academy of Sciences, No. 1, Jinlian Road, Longwan District, Wenzhou, Zhejiang, 325000, China
| | - Xiang Li
- Department of Physics, Xiamen University, No. 422, Siming South Road, Xiamen, Fujian, 361005, China
| | - Hao Xue
- Department of Computational Biology, Cornell University, 110 Biotechnology Building, Ithaca, 14853 NY, United States
| | - Yuer Lu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), No. 999, Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, Zhejiang, 325000, China; Wenzhou Institute, University of Chinese Academy of Sciences, No. 1, Jinlian Road, Longwan District, Wenzhou, Zhejiang, 325000, China
| | - Fei Xu
- Department of Physics, Anhui Normal University, No. 189 Jiuhua South Road, Wuhu, Anhui, 241002, China
| | - Jianwei Shuai
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), No. 999, Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, Zhejiang, 325000, China; Wenzhou Institute, University of Chinese Academy of Sciences, No. 1, Jinlian Road, Longwan District, Wenzhou, Zhejiang, 325000, China
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Chen X, Zhu L, Xu J, Cheng Q, Dong Y, Xie Y, Hua L, Du Y. Semaphorin 5A promotes Th17 differentiation via PI3K-Akt-mTOR in systemic lupus erythematosus. Arthritis Res Ther 2024; 26:204. [PMID: 39563449 PMCID: PMC11575155 DOI: 10.1186/s13075-024-03437-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 11/11/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Previously, we reported that serum Semaphorin 5 A (Sema5A) levels were increased in systemic lupus erythematosus (SLE) patients compared with healthy controls (HC), and elevated Sema5A correlated with disease activity and lupus nephritis in SLE patients. In this study, we aimed to further understand the role of Sema5A in promoting Th17 cells differentiation in SLE. METHODS Sema5A, interferon gamma (IFN-γ), interleukin 4 (IL-4), interleukin 17 A (IL-17 A) and interleukin 10 (IL-10) were measured by Enzyme Linked Immunosorbent Assay (ELISA). RNA and protein were isolated from peripheral blood mononuclear cells (PBMCs) in SLE patients and HC. Expression of PlexinA1 and PlexinB3 were measured by quantitative RT-PCR (qRT-PCR) and Western Blot. Th cell subsets were detected by flow cytometry. Treatment with recombinant human Sema5A (rhSema5A) and small interfering RNA (siRNA) were employed to examine the in vitro effect of Sema5A in CD4+T cell differentiation in SLE patients. RESULTS IL-17 A elevated in SLE patients and positively correlated with Sema5A. PlexinA1 was upregulated and mainly expressed in CD4+ T cells of SLE; Sema5A treatment induced the differentiation of Th17 cells, while did not affect the Th1 and Th2 skewing. These effects were associated with an upregulation of the transcription factor RORγt by Th17 cells, but not T-bet or GATA3 in Th1 and Th2 cells, respectively. Knock down PlexinA1 regulates IL-17 A production by CD4+T cells. Functional assays showed that Sema5A-PlexinA1 axis promoted Th17 cells differentiation via PI3K/Akt/mTOR signaling. CONCLUSIONS These findings demonstrated that Sema5A-PlexinA1 axis acts as a key mediator on Th17 differentiation, suggesting that Sema5A might be a novel therapeutic target in SLE.
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Affiliation(s)
- Xin Chen
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, China
- Department of Rheumatology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Lingjiang Zhu
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Jieying Xu
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Qi Cheng
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Yuanji Dong
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Yifan Xie
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Li Hua
- Department of Rheumatology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Yan Du
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, China.
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Guo AJ, Deng QY, Dong P, Zhou L, Shi L. Biomarkers associated with immune-related adverse events induced by immune checkpoint inhibitors. World J Clin Oncol 2024; 15:1002-1020. [PMID: 39193157 PMCID: PMC11346067 DOI: 10.5306/wjco.v15.i8.1002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 05/13/2024] [Accepted: 06/21/2024] [Indexed: 08/16/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) constitute a pivotal class of immunotherapeutic drugs in cancer treatment. However, their widespread clinical application has led to a notable surge in immune-related adverse events (irAEs), significantly affecting the efficacy and survival rates of patients undergoing ICI therapy. While conventional hematological and imaging tests are adept at detecting organ-specific toxicities, distinguishing adverse reactions from those induced by viruses, bacteria, or immune diseases remains a formidable challenge. Consequently, there exists an urgent imperative for reliable biomarkers capable of accurately predicting or diagnosing irAEs. Thus, a thorough review of existing studies on irAEs biomarkers is indispensable. Our review commences by providing a succinct overview of major irAEs, followed by a comprehensive summary of irAEs biomarkers across various dimensions. Furthermore, we delve into innovative methodologies such as machine learning, single-cell RNA sequencing, multiomics analysis, and gut microbiota profiling to identify novel, robust biomarkers that can facilitate precise irAEs diagnosis or prediction. Lastly, this review furnishes a concise exposition of irAEs mechanisms to augment understanding of irAEs prediction, diagnosis, and treatment strategies.
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Affiliation(s)
- An-Jie Guo
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Qing-Yuan Deng
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Pan Dong
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Lian Zhou
- Head and Neck Cancer Center, Chongqing University Cancer Hospital, Chongqing 400000, China
| | - Lei Shi
- School of Life Sciences, Chongqing University, Chongqing 400044, China
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Peng W, Chen Q, Zheng F, Xu L, Fang X, Wu Z. The emerging role of the semaphorin family in cartilage and osteoarthritis. Histochem Cell Biol 2024:10.1007/s00418-024-02303-y. [PMID: 38849589 DOI: 10.1007/s00418-024-02303-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2024] [Indexed: 06/09/2024]
Abstract
In the pathogenesis of osteoarthritis, various signaling pathways may influence the bone joint through a common terminal pathway, thereby contributing to the pathological remodeling of the joint. Semaphorins (SEMAs) are cell-surface proteins actively involved in and primarily responsible for regulating chondrocyte function in the pathophysiological process of osteoarthritis (OA). The significance of the SEMA family in OA is increasingly acknowledged as pivotal. This review aims to summarize the mechanisms through which different members of the SEMA family impact various structures within joints. The findings indicate that SEMA3A and SEMA4D are particularly relevant to OA, as they participate in cartilage injury, subchondral bone remodeling, or synovitis. Additionally, other elements such as SEMA4A and SEMA5A may also contribute to the onset and progression of OA by affecting different components of the bone and joint. The mentioned mechanisms demonstrate the indispensable role of SEMA family members in OA, although the detailed mechanisms still require further exploration.
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Affiliation(s)
- Wenjing Peng
- School of Stomatology, Clinical Research Center for Oral Diseases of Zhejiang Province, Stomatology HospitalZhejiang University School of MedicineKey Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 310016, China
- School of Stomatology, Xuzhou Medical University, Xuzhou, China
- Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou, China
| | - Qian Chen
- School of Stomatology, Clinical Research Center for Oral Diseases of Zhejiang Province, Stomatology HospitalZhejiang University School of MedicineKey Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 310016, China
| | - Fengjuan Zheng
- The Department of Orthodontics, Hangzhou Stomatology Hospital, Hangzhou, China
| | - Li Xu
- School of Stomatology, Clinical Research Center for Oral Diseases of Zhejiang Province, Stomatology HospitalZhejiang University School of MedicineKey Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 310016, China
| | - Xinyi Fang
- School of Stomatology, Clinical Research Center for Oral Diseases of Zhejiang Province, Stomatology HospitalZhejiang University School of MedicineKey Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 310016, China.
| | - Zuping Wu
- School of Stomatology, Clinical Research Center for Oral Diseases of Zhejiang Province, Stomatology HospitalZhejiang University School of MedicineKey Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 310016, China.
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6
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Rosik J, Kulpa J, Szczepanik M, Pawlik A. The Role of Semaphorins in the Pathogenesis of Rheumatoid Arthritis. Cells 2024; 13:618. [PMID: 38607057 PMCID: PMC11011349 DOI: 10.3390/cells13070618] [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: 02/06/2024] [Revised: 03/28/2024] [Accepted: 04/01/2024] [Indexed: 04/13/2024] Open
Abstract
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Inflammation of the synovial fluid propagates the pathological process of angiogenesis. Semaphorins play a crucial role in the context of endothelial cell function, and their pleiotropic nature has various effects on the further development of RA. This narrative review summarises the various roles of semaphorins in the pathology of RA and whether they could play a role in developing novel RA treatment options.
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Affiliation(s)
- Jakub Rosik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.R.); (J.K.); (M.S.)
| | | | | | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.R.); (J.K.); (M.S.)
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Gao S, Song H. Integrated comparison of the mRNAome in cartilage, synovium, and macrophages in osteoarthritis. Z Rheumatol 2024; 83:62-70. [PMID: 35178608 DOI: 10.1007/s00393-022-01171-y] [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] [Accepted: 01/21/2022] [Indexed: 11/09/2022]
Abstract
The precise molecular mechanisms associated with osteoarthritis (OA), the most common musculoskeletal disorder, are poorly understood. There are currently no effective treatments to prevent the initiation and progression of the disease. In recent years, the development of mRNAome has made it possible to identify new mechanisms and therapeutic targets. However, the differentially expressed genes screened by different microarrays are not completely the same. In order to avoid this shortcoming, we integrate the different genes from different tissues and data sets, and select the commonly expressed genes for further studies.
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Affiliation(s)
- Siming Gao
- Department of Rheumatology, Beijing Jishuitan Hospital, No. 31, Xin Jie Kou East Street, Xicheng District, 100035, Beijing, China
| | - Hui Song
- Department of Rheumatology, Beijing Jishuitan Hospital, No. 31, Xin Jie Kou East Street, Xicheng District, 100035, Beijing, China.
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Qin Y, Jin J, Zhang J, Wang H, Liu L, Zhang Y, Ling S, Hu J, Li N, Wang J, Lv C, Yang X. A fully human monoclonal antibody targeting Semaphorin 5A alleviates the progression of rheumatoid arthritis. Biomed Pharmacother 2023; 168:115666. [PMID: 37832409 DOI: 10.1016/j.biopha.2023.115666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 10/03/2023] [Accepted: 10/06/2023] [Indexed: 10/15/2023] Open
Abstract
Rheumatoid arthritis (RA) is the most common chronic autoimmune disease worldwide. Although progress has been made in RA treatment in recent decades, remission cannot be effectively achieved for a considerable proportion of RA patients. Thus, novel potential targets for therapeutic strategies are needed. Semaphorin 5A (SEMA5A) plays a pivotal role in RA progression by facilitating pannus formation, and it is a promising therapeutic target. In this study, we sought to develop an antibody treatment strategy targeting SEMA5A and evaluate its therapeutic effect using a collagen-induced arthritis (CIA) model. We generated SYD12-12, a fully human SEMA5A blocking antibody, through phage display technology. SYD12-12 intervention effectively inhibited angiogenesis and aggressive phenotypes of RA synoviocytes in vitro and dose-dependently inhibited synovial hyperplasia, pannus formation, bone destruction in CIA mice. Notably, SYD12-12 also improved the Treg/Th17 imbalance in CIA mice. We confirmed through immunofluorescence and molecular docking that SYD12-12 integrated with the unique TSP-1 domain of SEMA5A. In conclusion, we developed and characterized a fully human SEMA5A-blocking antibody for the first time. SYD12-12 effectively alleviated disease progression in CIA mice by inhibiting pannus formation and improving the Treg/Th17 imbalance, demonstrating its potential for the RA treatment.
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Affiliation(s)
- Yang Qin
- Institute of Autoimmune Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China; Department of Anesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jiayi Jin
- Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Jiani Zhang
- Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Hui Wang
- Institute of Autoimmune Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Li Liu
- Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yanwen Zhang
- Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Sunwang Ling
- Institute of Autoimmune Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Jinzhu Hu
- Institute of Autoimmune Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Nuan Li
- Department of Anesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jianguang Wang
- Institute of Autoimmune Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China; Department of Anesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Chen Lv
- Department of Orthopedics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Xinyu Yang
- Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China; Department of Anesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
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Thomas R, Yang X. Semaphorins in immune cell function, inflammatory and infectious diseases. CURRENT RESEARCH IN IMMUNOLOGY 2023; 4:100060. [PMID: 37645659 PMCID: PMC10461194 DOI: 10.1016/j.crimmu.2023.100060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 05/08/2023] [Accepted: 05/14/2023] [Indexed: 08/31/2023] Open
Abstract
The Semaphorin family is a group of proteins studied broadly for their functions in nervous systems. They consist of eight subfamilies ubiquitously expressed in vertebrates, invertebrates, and viruses and exist in membrane-bound or secreted forms. Emerging evidence indicates the relevance of semaphorins outside the nervous system, including angiogenesis, cardiogenesis, osteoclastogenesis, tumour progression, and, more recently, the immune system. This review provides a broad overview of current knowledge on the role of semaphorins in the immune system, particularly its involvement in inflammatory and infectious diseases, including chlamydial infections.
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Affiliation(s)
- Rony Thomas
- Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Xi Yang
- Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
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Šamadan L, Papić N, Mijić M, Knežević Štromar I, Gašparov S, Vince A. Do Semaphorins Play a Role in Development of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease? Biomedicines 2022; 10:3014. [PMID: 36551769 PMCID: PMC9775767 DOI: 10.3390/biomedicines10123014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 11/24/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is associated with systemic changes in immune response linked with chronic low-grade inflammation and disease progression. Semaphorins, a large family of biological response modifiers, were recently recognized as one of the key regulators of immune responses, possibly also associated with chronic liver diseases. The aim of this study was to identify semaphorins associated with NAFLD and their relationship with steatosis and fibrosis stages. In this prospective, case-control study, serum semaphorin concentrations (SEMA3A, -3C, -4A, -4D, -5A and -7A) were measured in 95 NAFLD patients and 35 healthy controls. Significantly higher concentrations of SEMA3A, -3C and -4D and lower concentrations of SEAMA5A and -7A were found in NAFLD. While there was no difference according to steatosis grades, SEMA3C and SEMA4D significantly increased and SEMA3A significantly decreased with fibrosis stages and had better accuracy in predicting fibrosis compared to the FIB-4 score. Immunohistochemistry confirmed higher expression of SEMA4D in hepatocytes, endothelial cells and lymphocytes in NAFLD livers. The SEMA5A rs1319222 TT genotype was more frequent in the NAFLD group and was associated with higher liver stiffness measurements. In conclusion, we provide the first evidence of the association of semaphorins with fibrosis in patients with NAFLD.
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Affiliation(s)
- Lara Šamadan
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Neven Papić
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Department for Viral Hepatitis, University Hospital for Infectious Diseases Zagreb, 10000 Zagreb, Croatia
| | - Maja Mijić
- Department of Internal Medicine, Division of Gastroenterology, University Hospital Merkur, 10000 Zagreb, Croatia
| | - Ivana Knežević Štromar
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University Hospital Center Zagreb, 10000 Zagreb, Croatia
| | - Slavko Gašparov
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Department of Pathology, University Hospital Merkur, 10000 Zagreb, Croatia
| | - Adriana Vince
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Department for Viral Hepatitis, University Hospital for Infectious Diseases Zagreb, 10000 Zagreb, Croatia
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Cheng Q, Chen M, Liu M, Chen X, Zhu L, Xu J, Xue J, Wu H, Du Y. Semaphorin 5A suppresses ferroptosis through activation of PI3K-AKT-mTOR signaling in rheumatoid arthritis. Cell Death Dis 2022; 13:608. [PMID: 35835748 PMCID: PMC9283415 DOI: 10.1038/s41419-022-05065-4] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 07/03/2022] [Accepted: 07/04/2022] [Indexed: 01/21/2023]
Abstract
Abnormal activation of synovial fibroblasts (SFs) plays an important role in rheumatoid arthritis (RA), the mechanism of which remains unknown. The purpose of our study is to comprehensively and systematically explore the mechanism for Semaphorin 5A-mediated abnormal SF activation in RA. Here, we found that Semaphorin 5A levels were significantly higher in synovial fluid and synovial tissue from RA patients compared with osteoarthritis patients. We further found that the mRNA level and protein abundance of Plexin-A1 was elevated in RA SFs compared with OA SFs, while Plexin-B3 expression showed no significant difference. The increased Semaphorin 5A in RA synovial fluid was mainly derived from CD68+ synovial macrophages, and the elevation led to increased binding between Semaphorin 5A and its receptors, thereby promoting cytokine secretion, proliferation, and migration, and decreasing apoptosis. Moreover, the effect of Semaphorin 5A on enhancing activation (cytokine secretion, cell proliferation and migration) and reducing apoptosis of SFs was significantly abolished after knockdown of Plexin-A1 and Plexin-B3 by small interfering RNA. Transcriptome sequencing and protein array detection revealed that Semaphorin 5A activated the PI3K/AKT/mTOR signaling pathway and inhibited ferroptosis. Morphologically, transmission electron microscopy results showed that Semaphorin 5A could significantly eliminate the mitochondrial diminution, membrane density increased and crest ruptured of SFs induced by ferroptosis inducer RSL3. Mechanistically, Semaphorin 5A enhanced GPX4 expression and SREBP1/SCD-1 signaling by activating the PI3K/AKT/mTOR signaling pathway, thus suppressing ferroptosis of RA SFs. In conclusion, our study provided the first evidence that elevated Semaphorin 5A in RA synovial fluid promotes SF activation by suppressing ferroptosis through the PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Qi Cheng
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China.,Department of Clinic Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China
| | - Mo Chen
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China
| | - Mengdan Liu
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China
| | - Xin Chen
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China.,Department of Clinic Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China
| | - Lingjiang Zhu
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China
| | - Jieying Xu
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China.,Department of Neurology, Linping District Hospital of Integrated Traditional Chinese and Western Medicine, 311199, Hangzhou, Zhejiang, China
| | - Jing Xue
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China
| | - Huaxiang Wu
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China.
| | - Yan Du
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China.
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Xiao C, Lv C, Sun S, Zhao H, Ling H, Li M, Qin Y, Zhang J, Wang J, Yang X. TSP1 is the essential domain of SEMA5A involved in pannus formation in rheumatoid arthritis. Rheumatology (Oxford) 2021; 60:5833-5842. [PMID: 33616619 DOI: 10.1093/rheumatology/keab133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 11/12/2020] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE In this study, we explored the effect of semaphorin5A (SEMA5A) on RA pathogenesis and its specific TSP1 domain on pannus formation. METHODS The expression of SEMA5A was detected in the synovium, the fibroblast-like synoviocytes (FLSs) and the SF of RA patients and healthy controls (HCs) by real-time quantitative PCR (q-PCR), immunohistochemistry staining, western blot and ELISA. SEMA5A-mAb intervention was performed to appraise the severity of joints in the CIA model. Transcriptome sequencing and bioinformatics analysis in SEMA5A-transfected FLSs from HCs were performed to screen differentially expressed genes after SEMA5A overexpression. An MTT assay in RA-FLSs, a chicken embryo allantoic membrane experiment and a tube formation experiment were used to clarify the influence of SEMA5A on cell proliferation and angiogenesis. Furthermore, a rescue experiment verified the function of the TSP1 domain of SEMA5A in the progress of RA with Sema5a-/- CIA mice. RESULTS The expression of SEMA5A increased in RA compared with that in HCs. Simultaneously, SEMA5A-mAbs significantly attenuated joint injury and the inflammatory response in CIA models. In addition, transcriptome sequencing and angiogenesis-related experiments verified the ability of SEMA5A to promote FLS proliferation and angiogenesis. Moreover, TSP1 was proved to be an essential domain in SEMA5A-induced angiogenesis in vitro. Additionally, rescue of TSP1-deleted SEMA5A failed to reduce the severity of arthritis in a CIA model constructed with Sema5a -/- mice. CONCLUSION In summary, upregulation of SEMA5A was first confirmed in pathological lesions of RA patients. Furthermore, treatment with SEMA5A-mAbs attenuated the progress of RA in the CIA model. Moreover, TSP1 was indicated as the key domain of SEMA5A in the promotion of pannus formation in RA.
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Affiliation(s)
- Chipeng Xiao
- Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University
| | - Chen Lv
- Department of Orthopedics, Wenzhou Medical University First Affiliated Hospital
| | - Siyuan Sun
- Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University
| | - Heping Zhao
- Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University
| | - Hanzhi Ling
- Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University
| | - Man Li
- Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University
| | - Yang Qin
- Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University
| | - Jinhao Zhang
- Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University
| | - Jianguang Wang
- Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University
| | - Xinyu Yang
- Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
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13
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Immune Checkpoint Blockade and Skin Toxicity Pathogenesis. J Invest Dermatol 2021; 142:951-959. [PMID: 34844731 DOI: 10.1016/j.jid.2021.06.040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/18/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022]
Abstract
Immune checkpoint blockade has revolutionized the treatment of multiple tumor types, including melanoma and nonmelanoma skin cancers. The use of immune checkpoint blockade is curtailed by tissue toxicities termed immune-related adverse events (irAEs), which occur most quickly and most often in the skin. We review the rationale for immune checkpoint blockade use, current agents, use in skin cancers, autoimmune manifestations in the skin, and considerations for predictive biomarkers and treatment options on the basis of skin pathogenesis. We also highlight major gaps in the field and the lack of preclinical modeling in the skin. A deeper understanding of irAE pathophysiology may help to uncouple toxicity and efficacy but mandates an interdisciplinary approach, including foundational skin immunology and autoimmune pathogenesis.
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Karatas KS, Bahceci I, Telatar TG, Bahceci B, Hocaoglu C. Relationship between disease and disease severity and semaphorin 5A and hemogram level in obsessive-compulsive disorder. Nord J Psychiatry 2021; 75:509-515. [PMID: 33771090 DOI: 10.1080/08039488.2021.1896779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVE Semaphorin 5A (SEMA 5A) is a neuroprotein that regulates the formation of excitatory synapses between neurons, important in autoimmunity, inflammatory processes and behaviors. This study aimed to investigate the SEMA 5A levels in patients with obsessive-compulsive disorder (OCD) diagnosed for the first time and evaluate the relationship of disease and disease severity with the blood SEMA 5A level and hemogram. METHODS More than 41,465 patients who applied to the psychiatry clinic from January 2018 to December 2020 were evaluated according to the DSM-5 criteria; 57 patients diagnosed with OCD for the first time, who met the inclusion criteria, were included in the study. Disease severity was investigated administering the Yale Brown Obsessive Compulsion Scale. The peripheral blood SEMA 5A level and hemogram were measured and evaluated in relation to platelet (PLT) activity, neutrophil-lymphocyte ratio (NLR), PLT-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), C-reactive protein (CRP), and compared with control group of 26 people. RESULTS The comparison of the groups revealed a significant difference in SEMA 5A and CRP level, neutrophil count and percentage, lymphocyte count, PLT activity. A significant correlation was found between disease and SEMA 5A level, NLR, PLR, and PLT parameters in diagnosis of OCD. As the severity of OCD increased, the SEMA 5A level and PLT count decreased, while the PDW and MLR values increased. CONCLUSION In patients with OCD, a relationship was found between plasma SEMA 5A, PLT activity, NLR, PLR, and MLR activity levels with disease and the disease severity.
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Affiliation(s)
- Kader Semra Karatas
- Psychiatry Department, Recep Tayyip Erdoğan University Medical School, Rize, Turkey
| | - Ilkay Bahceci
- Medical Microbiology and Clinical Microbiology Department, Recep Tayyip Erdoğan University Medical School, Rize, Turkey
| | - Tahsin Gokhan Telatar
- Public Health Department, Recep Tayyip Erdoğan University Medical School, Rize, Turkey
| | - Bulent Bahceci
- Psychiatry Department, Recep Tayyip Erdoğan University Medical School, Rize, Turkey
| | - Cicek Hocaoglu
- Psychiatry Department, Recep Tayyip Erdoğan University Medical School, Rize, Turkey
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15
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Abdel-Wahab N, Diab A, Yu RK, Futreal A, Criswell LA, Tayar JH, Dadu R, Shannon V, Shete SS, Suarez-Almazor ME. Genetic determinants of immune-related adverse events in patients with melanoma receiving immune checkpoint inhibitors. Cancer Immunol Immunother 2021; 70:1939-1949. [PMID: 33409738 PMCID: PMC10992432 DOI: 10.1007/s00262-020-02797-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 11/08/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) can cause profound immune-related adverse events (irAEs). The host genetic background is likely to play a role in irAE susceptibility because the presentation of toxicity varies among patients and many do not develop irAEs despite continued ICI use. We sought to identify potential genetic markers conferring risk for irAEs. METHODS We conducted a pilot exploratory study in 89 melanoma patients who received ICIs (44 with irAEs, and 45 without irAEs after at least 1 year from starting treatment). Genotyping was performed using the Infinium Multi-Ethnic Global-8 v1.0 Bead Chip. The genotype data were extracted using PLINK (v1.90b3.34) and processed for quality control. Population structure-based clustering was carried out using IBS matrix, pairwise population concordance test (p < 1 × 10-3), and phenotype distribution for all study participants, resulting in seven population structure-based clusters. In the analytical stage, 599,931 variants in autosomal chromosomes were included for the association study. The association test was performed using an additive genetic model with exact logistic regression, adjusted for age, sex, and population cluster. RESULTS A total of 30 variants or single-nucleotide polymorphisms with p < 1 × 10-4 were identified; 12 were associated with an increased risk of irAEs, and the remaining 18 were associated with a decreased risk. Overall, nine of the identified single-nucleotide polymorphisms mapped to eight unique genes that have been associated with autoimmunity or inflammatory diseases. CONCLUSION Several genetic variants associated with irAEs were identified. Additional larger studies are needed to validate these findings and establish their potential functional relevance.
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Affiliation(s)
- Noha Abdel-Wahab
- Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, Assiut University Hospitals, Assiut, Egypt
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Adi Diab
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Robert K Yu
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lindsey A Criswell
- Russell/Engleman Rheumatology Research Center, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Jean H Tayar
- Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ramona Dadu
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vickie Shannon
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sanjay S Shete
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Maria E Suarez-Almazor
- Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Kanth SM, Gairhe S, Torabi-Parizi P. The Role of Semaphorins and Their Receptors in Innate Immune Responses and Clinical Diseases of Acute Inflammation. Front Immunol 2021; 12:672441. [PMID: 34012455 PMCID: PMC8126651 DOI: 10.3389/fimmu.2021.672441] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/20/2021] [Indexed: 12/16/2022] Open
Abstract
Semaphorins are a group of proteins that have been studied extensively for their critical function in neuronal development. They have been shown to regulate airway development, tumorigenesis, autoimmune diseases, and the adaptive immune response. Notably, emerging literature describes the role of immunoregulatory semaphorins and their receptors, plexins and neuropilins, as modulators of innate immunity and diseases defined by acute injury to the kidneys, abdomen, heart and lungs. In this review we discuss the pathogenic functions of semaphorins in clinical conditions of acute inflammation, including sepsis and acute lung injury, with a focus on regulation of the innate immune response as well as potential future therapeutic targeting.
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Affiliation(s)
- Shreya M Kanth
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Salina Gairhe
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Parizad Torabi-Parizi
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, United States
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The Expression of IL-17, in Chronic Spontaneous Urticaria Is Linked to Semaphorin5A. Biomolecules 2021; 11:biom11030373. [PMID: 33801296 PMCID: PMC7998863 DOI: 10.3390/biom11030373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/24/2021] [Accepted: 02/25/2021] [Indexed: 01/07/2023] Open
Abstract
Background: Patients with chronic spontaneous urticaria (CSU), an autoimmune disorder, show increased skin expression of IL-17A and can benefit from treatment with the anti-IL-17A biologic secukinumab. The mechanisms that drive IL-17A expression in CSU are currently unknown, but may involve Semaphorin5A (Sema5A). Objective: To explore the expression, role, and effects of Sema5A in CSU and its link to IL-17A. Material and Methods: We investigated patients with CSU and healthy controls for skin expression of expressing peripheral T cells. Results: Sema5A was highly expressed in the skin of CSU patients as compared to healthy control skin. Both CD4+ T cells and mast cells in CSU skin expressed Sema5A, and many of them expressed both Sema5A and IL-17A. Patients with CSU had significantly higher rates of IL-17A-expressing CD4+ T cells as compared to healthy controls. Incubation with Sema5A increased the rates of IL-17A-expressing CD4+ T cells in healthy controls to CSU levels. Conclusion: Sema5A may drive the expression and effects of IL-17A in CSU. Further studies in larger cohorts are needed to confirm the role of Sema5A in the pathogenesis of CSU and to explore its potential as a therapeutic target.
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Adjei AA, Lopez CL, Schaid DJ, Sloan JA, Le-Rademacher JG, Loprinzi CL, Norman AD, Olson JE, Couch FJ, Beutler AS, Vachon CM, Ruddy KJ. Genetic Variations and Health-Related Quality of Life (HRQOL): A Genome-Wide Study Approach. Cancers (Basel) 2021; 13:cancers13040716. [PMID: 33578652 PMCID: PMC7916362 DOI: 10.3390/cancers13040716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/01/2021] [Accepted: 02/04/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary Health-related quality of life (HRQOL) is associated with cancer prognosis as well as with age, sex, race, and lifestyle factors, including diet and physical activity. To investigate the hypothesis that HRQOL has genetic underpinnings in patients with cancer, we performed a genome-wide association study to evaluate genetic variants (single nucleotide polymorphisms, SNPs) associated with mental and physical QOL as measured by the PROMIS assessment tool in breast cancer survivors participating in a longitudinal cohort study, the Mayo Clinic Breast Disease Registry (MCBDR). Age and financial concerns were associated with worse physical and mental health, and previous receipt of chemotherapy was associated with worse mental health. SNPs in SCN10A, LMX1B, SGCD, PARP12, and SEMA5A were associated with physical and mental QOL, but none at the genome-wide significance thresholds of p < 5 × 10−8. Abstract Health-related quality of life (HRQOL) is an important prognostic patient-reported outcome in oncology. Because prior studies suggest that HRQOL is, in part, heritable, we performed a GWAS to elucidate genetic factors associated with HRQOL in breast cancer survivors. Physical and mental HRQOL were measured via paper surveys that included the PROMIS-10 physical and mental health domain scales in 1442 breast cancer survivors participating in the Mayo Clinic Breast Disease Registry (MCBDR). In multivariable regression analyses, age and financial concerns were significantly associated with global physical health (age: p = 1.6 × 10−23; financial concerns: p = 4.8 × 10−40) and mental health (age: p = 3.5 × 10−7; financial concerns: p = 2.0 × 10−69). Chemotherapy was associated with worse global mental health (p = 0.01). In the GWAS, none of the SNPs reached the genome-wide association significance threshold of 5 × 10−8 for associations with either global physical or global mental health, however, a cluster of SNPs in SCN10A, particularly rs112718371, appeared to be linked to worse global physical health (p = 5.21 × 10−8). Additionally, SNPs in LMX1B, SGCD, PARP12 and SEMA5A were also moderately associated with worse physical and mental health (p < 10−6). These biologically plausible candidate SNPs warrant further study as possible predictors of HRQOL.
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Affiliation(s)
- Araba A. Adjei
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (A.A.A.); (C.L.L.); (A.S.B.)
| | - Camden L. Lopez
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; (C.L.L.); (D.J.S.); (J.A.S.); (J.G.L.-R.); (A.D.N.); (J.E.O.); (C.M.V.)
| | - Daniel J. Schaid
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; (C.L.L.); (D.J.S.); (J.A.S.); (J.G.L.-R.); (A.D.N.); (J.E.O.); (C.M.V.)
| | - Jeff A. Sloan
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; (C.L.L.); (D.J.S.); (J.A.S.); (J.G.L.-R.); (A.D.N.); (J.E.O.); (C.M.V.)
| | - Jennifer G. Le-Rademacher
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; (C.L.L.); (D.J.S.); (J.A.S.); (J.G.L.-R.); (A.D.N.); (J.E.O.); (C.M.V.)
| | - Charles L. Loprinzi
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (A.A.A.); (C.L.L.); (A.S.B.)
| | - Aaron D. Norman
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; (C.L.L.); (D.J.S.); (J.A.S.); (J.G.L.-R.); (A.D.N.); (J.E.O.); (C.M.V.)
| | - Janet E. Olson
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; (C.L.L.); (D.J.S.); (J.A.S.); (J.G.L.-R.); (A.D.N.); (J.E.O.); (C.M.V.)
| | - Fergus J. Couch
- Department of Laboratory Medicine and Pathology, Rochester, MN 55905, USA;
| | - Andreas S. Beutler
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (A.A.A.); (C.L.L.); (A.S.B.)
| | - Celine M. Vachon
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; (C.L.L.); (D.J.S.); (J.A.S.); (J.G.L.-R.); (A.D.N.); (J.E.O.); (C.M.V.)
| | - Kathryn J. Ruddy
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (A.A.A.); (C.L.L.); (A.S.B.)
- Correspondence:
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Fard D, Tamagnone L. Semaphorins in health and disease. Cytokine Growth Factor Rev 2020; 57:55-63. [PMID: 32900601 DOI: 10.1016/j.cytogfr.2020.05.006] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 05/12/2020] [Indexed: 11/18/2022]
Abstract
Cell-cell communication is pivotal to guide embryo development, as well as to maintain adult tissues homeostasis and control immune response. Among extracellular factors responsible for this function, are the Semaphorins, a broad family of around 20 different molecular cues conserved in evolution and widely expressed in all tissues. The signaling cascades initiated by semaphorins depend on a family of conserved receptors, called Plexins, and on several additional molecules found in the receptor complexes. Moreover, multiple intracellular pathways have been described to act downstream of semaphorins, highlighting significant diversity in the signaling cascades controlled by this family. Notably, semaphorin expression is altered in many human diseases, such as immunopathologies, neurodegenerative diseases and cancer. This underscores the importance of semaphorins as regulatory factors in the tissue microenvironment and has prompted growing interest for assessing their potential relevance in medicine. This review article surveys the main contexts in which semaphorins have been found to regulate developing and healthy adult tissues, and the signaling cascades implicated in these functions. Vis a vis, we will highlight the main pathological processes in which semaphorins are thought to have a role thereof.
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Affiliation(s)
- Damon Fard
- University of Torino School of Medicine, Torino, Italy
| | - Luca Tamagnone
- Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome, Italy.
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Immune semaphorins: Crucial regulatory signals and novel therapeutic targets in asthma and allergic diseases. Eur J Pharmacol 2020; 881:173209. [PMID: 32454117 DOI: 10.1016/j.ejphar.2020.173209] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 05/14/2020] [Accepted: 05/18/2020] [Indexed: 11/20/2022]
Abstract
Asthma and allergic diseases are a group of chronic inflammatory disorders that arise as a result of excessive responses of the immune system against intrinsically harmless environmental substances. It is well known that substantial joint characteristics exist between the immune and nervous systems. The semaphorins (Semas) were initially characterized as axon-guidance molecules that play a crucial role during the development of the nervous system. However, increasing evidence indicates that a subset of Semas, termed "immune Semas", acting through their cognate receptors, namely, plexins (Plxns), and neuropilins (Nrps), also contributes to both physiological and pathological responses of the immune system. Notably, immune Semas exert critical roles in regulating a broad spectrum of biological processes, including immune cell-cell interactions, activation, differentiation, cell migration and mobility, angiogenesis, tumor progression, as well as inflammatory responses. Accumulating evidence indicates that the modification in the signaling of immune Semas could lead to various immune-mediated inflammatory diseases, ranging from cancer to autoimmunity and allergies. This review summarizes the recent evidence regarding the role of immune Semas in the pathogenesis of asthma and allergic diseases and discusses their therapeutic potential for treating these diseases.
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Dziobek K, Opławski M, Grabarek BO, Zmarzły N, Kieszkowski P, Januszyk P, Kiełbasiński K, Kiełbasiński R, Boroń D. Assessment of the Usefulness of the SEMA5A Concentration Profile Changes as a Molecular Marker in Endometrial Cancer. Curr Pharm Biotechnol 2020; 21:45-51. [PMID: 31544715 DOI: 10.2174/1389201020666190911113611] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 02/12/2019] [Accepted: 08/18/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Semaphorin 5A (SEMA5A) functions not only in the nervous system but also in cancer transformation where its role has not yet been sufficiently studied and described. OBJECTIVE The aim of the study was to determine the changes in SEMA5A expression in endometrial cancer at various degrees of its differentiation (G1-G3) compared to control. MATERIALS AND METHODS The study group consisted of 45 patients with endometrial cancer at various grades: G1, 17; G2, 15; G3, 13. The control consisted of 15 women without neoplastic changes in the routine gynecological examination. The statistical analysis of immunohistochemical assessment of SEMA5A level was carried out using the Statistica 12 program based on the Kruskal-Wallis test and Dunn's post-hoc test (p<0.05). RESULTS The expression of SEMA5A (optical density) was observed in the control group (Me = 103.43) and in the study group (G1, Me = 140.72; G2, Me = 150.88; G3, Me = 173.77). Differences in expression between each grade and control and between individual grades turned out to be statistically significant (p<0.01). The protein level of SEMA5A expression increased with the decreasing degree of endometrial cancer differentiation. CONCLUSION In our research, we indicated the overexpression of SEMA5A protein in endometrial cancer. It is a valuable starting point for further consideration of the role of SEMA5A as a new supplementary molecular marker in endometrial cancer.
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Affiliation(s)
- Konrad Dziobek
- Center of Oncology, M. Sklodowska-Curie Memorial Institute, Cracow Branch, Cracow, Poland
| | - Marcin Opławski
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Kraków, Krakow, Poland
| | - Beniamin O Grabarek
- Center of Oncology, M. Sklodowska-Curie Memorial Institute, Cracow Branch, Cracow, Poland.,Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland.,Department of Molecular Biology, School of Pharmaceutical in Sosnowiec, Medical University of Silesia in Katowice, Katowice, Poland
| | - Nikola Zmarzły
- Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland.,Department of Molecular Biology, School of Pharmaceutical in Sosnowiec, Medical University of Silesia in Katowice, Katowice, Poland
| | | | - Piotr Januszyk
- Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland.,Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
| | | | - Robert Kiełbasiński
- Department of Obstetrics & Gynaecology ward, Health Center in Mikołów, Mikołów, Poland
| | - Dariusz Boroń
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Kraków, Krakow, Poland.,Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland.,Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
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22
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Iragavarapu-Charyulu V, Wojcikiewicz E, Urdaneta A. Semaphorins in Angiogenesis and Autoimmune Diseases: Therapeutic Targets? Front Immunol 2020; 11:346. [PMID: 32210960 PMCID: PMC7066498 DOI: 10.3389/fimmu.2020.00346] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 02/12/2020] [Indexed: 01/17/2023] Open
Abstract
The axonal guidance molecules, semaphorins, have been described to function both physiologically and pathologically outside of the nervous system. In this review, we focus on the vertebrate semaphorins found in classes 3 through 7 and their roles in vascular development and autoimmune diseases. Recent studies indicate that while some of these vertebrate semaphorins promote angiogenesis, others have an angiostatic function. Since some semaphorins are also expressed by different immune cells and are known to modulate immune responses, they have been implicated in autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. We conclude this review by addressing strategies targeting semaphorins as potential therapeutic agents for angiogenesis and autoimmune diseases.
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Affiliation(s)
| | - Ewa Wojcikiewicz
- Department of Biomedical Sciences, Florida Atlantic University, Boca Raton, FL, United States
| | - Alexandra Urdaneta
- Department of Biomedical Sciences, Florida Atlantic University, Boca Raton, FL, United States
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23
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Ko PH, Lenka G, Chen YA, Chuang EY, Tsai MH, Sher YP, Lai LC. Semaphorin 5A suppresses the proliferation and migration of lung adenocarcinoma cells. Int J Oncol 2019; 56:165-177. [PMID: 31789397 PMCID: PMC6910195 DOI: 10.3892/ijo.2019.4932] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 11/13/2019] [Indexed: 12/26/2022] Open
Abstract
Semaphorin 5A (SEMA5A), a member of the semaphorin family, plays an important role in axonal guidance. Previously, the authors identified another possible role of SEMA5A as a prognostic biomarker for non-smoking women with lung adenocarcinoma in Taiwan, and this phenomenon has been validated in other ethnic groups. However, the functional significance of SEMA5A in lung adenocarcinoma remains unclear. Therefore, we assessed the function of SEMA5A in three lung adenocarcinoma cell lines in this study. Kaplan-Meier Plotter for lung cancer was conducted for survival analyses. Reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis were performed to investigate the expression and post-translational regulation of SEMA5A in lung adenocar-cinoma cell lines. A pre-designed PyroMark CpG assay and 5-aza-2′-deoxycytidine treatment were used to measure the methylation levels of SEMA5A. The biological functions of lung adenocarcinoma cells overexpressing SEMA5A were investigated by microarrays, and validated both in vitro (proliferation, colony formation and migration assays) and in vivo (tumor xenografts) experiments. The results revealed that the hypermethylation of SEMA5A and the cleavage of the extracellular domain of SEMA5A were responsible for the downregulation of the SEMA5A levels in lung adenocarcinoma cells (A549 and H1299) as compared to the normal controls. Functional analysis of SEMA5A-regulated genes revealed that they were involved in cellular growth and proliferation. The overexpression of SEMA5A in A549 and H1299 cells significantly decreased the proliferation (P<0.01), colony formation (P<0.001) and migratory ability (P<0.01) of the cells. The suppressive effects of SEMA5A on the proliferative and migratory ability of the cells were also observed in both in vitro and in vivo experiments using brain metastatic Bm7 lung adenocarcinoma cells. On the whole, the findings of this study suggest a suppressive role for SEMA5A in lung adenocarcinoma involving the inhibition of the proliferation and migration of lung transformed cells.
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Affiliation(s)
- Pin-Hao Ko
- Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan, R.O.C
| | - Govinda Lenka
- Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan, R.O.C
| | - Yu-An Chen
- Bioinformatics and Biostatistics Core, Center of Genomic and Precision Medicine, National Taiwan University, Taipei 10055, Taiwan, R.O.C
| | - Eric Y Chuang
- Bioinformatics and Biostatistics Core, Center of Genomic and Precision Medicine, National Taiwan University, Taipei 10055, Taiwan, R.O.C
| | - Mong-Hsun Tsai
- Bioinformatics and Biostatistics Core, Center of Genomic and Precision Medicine, National Taiwan University, Taipei 10055, Taiwan, R.O.C
| | - Yuh-Pyng Sher
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung 40402, Taiwan, R.O.C
| | - Liang-Chuan Lai
- Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan, R.O.C
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24
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St Clair RM, Dumas CM, Williams KS, Goldstein MT, Stant EA, Ebert AM, Ballif BA. PKC induces release of a functional ectodomain of the guidance cue semaphorin6A. FEBS Lett 2019; 593:3015-3028. [PMID: 31378926 DOI: 10.1002/1873-3468.13561] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 07/16/2019] [Accepted: 07/25/2019] [Indexed: 01/06/2023]
Abstract
Semaphorins (Semas) are a family of secreted and transmembrane proteins that play critical roles in development. Interestingly, several vertebrate transmembrane Sema classes are capable of producing functional soluble ectodomains. However, little is known of soluble Sema6 ectodomains in the nervous system. Herein, we show that the soluble Sema6A ectodomain, sSema6A, exhibits natural and protein kinase C (PKC)-induced release. We show that PKC mediates Sema6A phosphorylation at specific sites and while this phosphorylation is not the primary mechanism regulating sSema6A production, we found that the intracellular domain confers resistance to ectodomain release. Finally, sSema6A is functional as it promotes the cohesion of zebrafish early eye field explants. This suggests that in addition to its canonical contact-mediated functions, Sema6A may have regulated, long-range, forward-signaling capacity.
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Affiliation(s)
- Riley M St Clair
- Department of Biology, University of Vermont, Burlington, VT, USA
| | - Caroline M Dumas
- Department of Biology, University of Vermont, Burlington, VT, USA
| | - Kori S Williams
- Department of Biology, University of Vermont, Burlington, VT, USA
| | | | | | - Alicia M Ebert
- Department of Biology, University of Vermont, Burlington, VT, USA
| | - Bryan A Ballif
- Department of Biology, University of Vermont, Burlington, VT, USA
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25
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The extracellular SEMA domain attenuates intracellular apoptotic signaling of semaphorin 6A in lung cancer cells. Oncogenesis 2018; 7:95. [PMID: 30518871 PMCID: PMC6281666 DOI: 10.1038/s41389-018-0105-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 10/01/2018] [Accepted: 11/14/2018] [Indexed: 12/27/2022] Open
Abstract
Semaphorin 6A (SEMA6A), a membrane-bound protein, is downregulated in lung cancer tissue compared to its adjacent normal tissue. However, the functions of SEMA6A in lung cancer cells are still unclear. In the present study, full length SEMA6A and various truncations were transfected into lung cancer cells to investigate the role of the different domains of SEMA6A in cell proliferation and survival, apoptosis, and in vivo tumor growth. SEMA6A-induced cell signaling was explored using gene silencing, co-immunoprecipitation, and co-culture assays. Our results showed that overexpression of SEMA6A reduced the growth of lung cancer cells in vitro and in vivo, and silencing SEMA6A increased the proliferation of normal lung fibroblasts. Truncated SEMA6A lacking the SEMA domain or the extracellular region induced more apoptosis than full length SEMA6A, and reintroducing the SEMA domain attenuated the apoptosis. Fas-associated protein with death domain (FADD) bound to the cytosolic region of truncated SEMA6A and was involved in SEMA6A-associated cytosol-induced apoptosis. This study suggests a novel function of SEMA6A in inducing apoptosis via FADD binding in lung cancer cells.
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26
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Semaphorin 5A drives melanoma progression: role of Bcl-2, miR-204 and c-Myb. J Exp Clin Cancer Res 2018; 37:278. [PMID: 30454024 PMCID: PMC6245779 DOI: 10.1186/s13046-018-0933-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 10/18/2018] [Indexed: 11/17/2022] Open
Abstract
Background Melanoma, the most aggressive form of skin cancer, is characterized by high rates of metastasis, drug resistance and mortality. Here we investigated the role of Semaphorin 5A (Sema5A) on the properties associated with melanoma progression and the factors involved in Sema5A regulation. Methods Western blotting, qRT-PCR, Chromatin immunoprecipitation (ChIP) assay, immunohistochemistry of melanoma patient specimens and xenograft tissues, in vitro Transwell assay for cell migration and invasion evaluation, in vitro capillary-like structure formation analysis. Results A significant correlation of Sema5A mRNA expression and melanoma progression was observed by analyzing GEO profile dataset. Endogenous Sema5A protein was detected in 95% of human melanoma cell lines tested, in 70% of metastatic specimens from patients affected by melanoma, and 16% of in situ melanoma specimens showed a focal positivity. We demonstrated that Sema5A regulates in vitro cell migration and invasion and the formation of vasculogenic structures. We also found an increase of Sema5A at both mRNA and protein level after forced expression of Bcl-2. By use of transcriptional and proteasome inhibitors, we showed that Bcl-2 increases the stability of Sema5A mRNA and protein. Moreover, by ChIP we demonstrated that Sema5A expression is under the control of the transcription factor c-Myb and that c-Myb recruitment on Sema5A promoter is increased after Bcl-2 overexpression. Finally, a concomitant decrease in the expression of Sema5A, Bcl-2 and c-Myb proteins was observed in melanoma cells after miR-204 overexpression. Conclusion Overall our data provide evidences supporting the role of Sema5A in melanoma progression and the involvement of Bcl-2, miR-204 and c-Myb in regulating its expression. Electronic supplementary material The online version of this article (10.1186/s13046-018-0933-x) contains supplementary material, which is available to authorized users.
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27
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Nishide M, Kumanogoh A. The role of semaphorins in immune responses and autoimmune rheumatic diseases. Nat Rev Rheumatol 2017; 14:19-31. [DOI: 10.1038/nrrheum.2017.201] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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28
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Liu Y, Wang S, Guo Q, Li Y, Qin J, Zhao N, Li Y, Shan Z, Teng W. Elevated semaphorin 5A in patients with Hashimoto's thyroiditis: a case-control study. Endocr Connect 2017; 6:659-666. [PMID: 28912336 PMCID: PMC5655683 DOI: 10.1530/ec-17-0132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 09/14/2017] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Hashimoto's thyroiditis (HT) is characterized by elevated specific auto-antibodies, including TgAb and TPOAb. Increasing evidence has demonstrated the essential role of Th17 cells in HT. However, the underlying mechanism is still unclear. Semaphorin 5A (Sema 5A) is involved in several autoimmune diseases through the regulation of immune cells. The aim of the present study was to explore the role of Sema 5A in HT. METHODS We measured serum Sema 5A levels in HT (n = 92) and healthy controls (n = 111) by enzyme-linked immunosorbent assay (ELISA). RNA levels of Sema 5A and their receptors (plexin-A1 and plexin-B3), as well as several cytokines (IFN-γ, IL-4 and IL-17), were detected by real-time polymerase chain reaction in peripheral blood mononuclear cells from 23 patients with HT and 31 controls. In addition, we investigated the relationship between serum Sema 5A and HT. RESULTS Serum Sema 5A in HT increased significantly compared with healthy controls (P < 0.001). Moreover, serum Sema 5A levels were positively correlated with TgAb (r = 0.511, P < 0.001), TPOAb (r = 0.423, P < 0.001), TSH (r = 0.349, P < 0.001) and IL-17 mRNA expression (r = 0.442, P < 0.001). Increased Sema 5A RNA expression was observed (P = 0.041) in HT compared with controls. In receiver-operating characteristic (ROC) analysis, serum Sema 5A predicted HT with a sensitivity of 79.35% and specificity of 96.40%, and the area under the curve of the ROC curve was 0.836 (95% CI: 0.778-0.884, P < 0.001). CONCLUSIONS These data demonstrated elevated serum Sema 5A in HT patients for the first time. Serum Sema 5A levels were correlated with thyroid auto-antibodies and IL-17 mRNA expression. Sema 5A may be involved in immune response of HT patients.
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Affiliation(s)
- Yongping Liu
- Department of Endocrinology and MetabolismInstitute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, People's Republic of China
| | - Shuo Wang
- Department of Endocrinology and MetabolismInstitute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, People's Republic of China
| | - Qingling Guo
- Department of Endocrinology and MetabolismInstitute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, People's Republic of China
| | - Yongze Li
- Department of Endocrinology and MetabolismInstitute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, People's Republic of China
| | - Jing Qin
- Department of Endocrinology and MetabolismInstitute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, People's Republic of China
| | - Na Zhao
- Department of Endocrinology and MetabolismInstitute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, People's Republic of China
| | - Yushu Li
- Department of Endocrinology and MetabolismInstitute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, People's Republic of China
| | - Zhongyan Shan
- Department of Endocrinology and MetabolismInstitute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, People's Republic of China
| | - Weiping Teng
- Department of Endocrinology and MetabolismInstitute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, People's Republic of China
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Du Y, Wu X, Chen M, Wang W, Xv W, Ye L, Wu D, Xue J, Sun W, Luo J, Wu H. Elevated semaphorin5A in systemic lupus erythematosus is in association with disease activity and lupus nephritis. Clin Exp Immunol 2017; 188:234-242. [PMID: 28063160 DOI: 10.1111/cei.12924] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2016] [Indexed: 01/07/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by extensive immune response, including over-activation of T and B cell development of pathogenic autoantibodies, organ damage induced by the formation and deposition of immune complex and the abnormal elevation of type I interferon. Semaphorin5A (Sema5A) is involved essentially in immune cell regulation and is also implicated in the pathogenesis of autoimmune disorders. We aimed to evaluate the role of Sema5A in patients with SLE. Serum levels of Sema5A were tested by enzyme-linked immunosorbent assay (ELISA) in 152 SLE patients and 48 healthy controls. The message ribonucleic acid (mRNA) expression levels of Sema5A and ADAM metallopeptidase domain 17 (ADAM17) in the peripheral blood mononuclear cells (PBMC) from 43 patients with SLE and 19 healthy controls were detected by the real-time-quantitative polymerase chain reaction (qPCR). Serum Sema5A levels were increased significantly in SLE patients compared with healthy controls (P < 0·001). Elevated levels of Sema5A were correlated positively with 24-h proteinuria excretion (r = 0·558, P < 0·0001), SLE disease activity index (SLEDAI) (r = 0·278, P = 0·0006) and C-reactive protein (CRP) (r = 0·266, P = 0·002), but negatively with planet (PLT) (r = -0·294, P = 0·0003) and complement 3 (C3) (r = -0·287, P = 0·0004) in SLE patients. Patients with elevated Sema5A levels showed higher incidence of rash, serositis and nephritis (P < 0·05 or P < 0·001). Patients with decreased PLT, C3 or positive for proteinuria also showed elevated Sema5A (P < 0·001 or P < 0·05). The mRNA ADAM17 was increased in SLE patients and correlated positively with serum Sema5A levels. Our data demonstrated that elevated serum Sema5A in SLE patients correlated with disease activity and are involved in kidney and blood system damage; ADAM17 might be involved in the release of secreted Sema5A.
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Affiliation(s)
- Y Du
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Department of Clinic Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - X Wu
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - M Chen
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - W Wang
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - W Xv
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - L Ye
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - D Wu
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - J Xue
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - W Sun
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - J Luo
- Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, China
| | - H Wu
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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Nomura S. Chronic immune thrombocytopenia and semaphorin 5A. Thromb Res 2015; 136:843-4. [PMID: 26381436 DOI: 10.1016/j.thromres.2015.08.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 08/29/2015] [Indexed: 10/23/2022]
Affiliation(s)
- Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, 2-3-1 Shin-machi, Hirakata, Osaka 573-1191, Japan.
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Wang L, Song G, Zheng Y, Tan W, Pan J, Zhao Y, Chang X. Expression of Semaphorin 4A and its potential role in rheumatoid arthritis. Arthritis Res Ther 2015; 17:227. [PMID: 26303122 PMCID: PMC4549119 DOI: 10.1186/s13075-015-0734-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 07/31/2015] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Semaphorin 4A (Sema4A) plays critical roles in many physiological and pathological processes including neuronal development, angiogenesis, immune response regulation, autoimmunity, and infectious diseases. The present study aimed to investigate its expression and biological activity in rheumatoid arthritis (RA). METHODS RNA and protein were isolated from synovial tissues in RA and osteoarthritis (OA) patients. Treatment with recombinant human Sema4A (rhSema4A) or small interfering RNA (siRNA) was applied to examine its effect on the biological activity of synovial fibroblasts of RA (RASFs). Expression of Sema4A and NF-κB were measured by quantitative RT-PCR (qRT-PCR) and Western blot after lipopolysaccharide (LPS) stimulation. Chromatin immunoprecipitation (ChIP) and siRNA targeting p50 and p60 were applied to detect the regulation of Nuclear factor kappa (NF-κB) on Sema4A. Sema4A, interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) secretion were measured by ELISA-based assays. RESULTS Increased levels of Sema4A were detected in the synovial tissue and fluid of patients with RA compared with those with OA. Furthermore, synovial fluid level of Sema4A correlated with Disease Activity Score (DAS) in RA. Treatment with rhSema4A promoted invasion of RASFs by upregulating the expression of Matrix metallopeptidase3 (MMP3), MMP9, alpha-smooth muscle actin(α-SMA), and Vimentin, and exacerbated inflammation by promoting the production of IL-6 in RASFs, as well as IL-1β and TNF-α in THP-1 cells. The induction of IL-6 and TNF-α by Sema4A was confirmed at the protein level in fluid samples from patients with RA. Knock-down experiments showed the participation of Plexin B1 towards rhSema4A in the induction of cytokines. In addition, LPS stimulation induced Sema4A expression in RASFs in an NF-κB-dependent manner, and rhSema4A treatment could also activate NF-κB signaling. CONCLUSIONS These findings suggest an NF-κB-dependent modulation of Sema4A in the immune response. Further, increased expression of Sema4A is required to promote inflammation of RA.
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Affiliation(s)
- Lin Wang
- Research Center for Medicinal Biotechnology, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Shandong Academy of Medicinal Sciences, Jinan, China.
| | - Guanhua Song
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China.
| | - Yabing Zheng
- Medical Research Center of Shandong Provincial Qianfoshan Hospital, Shandong University, Jingshi Road 16766, Jinan, Shandong, 250014, People's Republic of China.
| | - Weiwei Tan
- Department of Pathology, Shandong University Medical School, Jinan, China.
| | - Jihong Pan
- Research Center for Medicinal Biotechnology, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Shandong Academy of Medicinal Sciences, Jinan, China.
| | - Yu Zhao
- Research Center for Medicinal Biotechnology, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Shandong Academy of Medicinal Sciences, Jinan, China.
| | - Xiaotian Chang
- Medical Research Center of Shandong Provincial Qianfoshan Hospital, Shandong University, Jingshi Road 16766, Jinan, Shandong, 250014, People's Republic of China.
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Yoshida Y, Ogata A, Kang S, Ebina K, Shi K, Nojima S, Kimura T, Ito D, Morimoto K, Nishide M, Hosokawa T, Hirano T, Shima Y, Narazaki M, Tsuboi H, Saeki Y, Tomita T, Tanaka T, Kumanogoh A. Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications. Arthritis Rheumatol 2015; 67:1481-90. [PMID: 25707877 PMCID: PMC5032998 DOI: 10.1002/art.39086] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 02/19/2015] [Indexed: 01/16/2023]
Abstract
Objective Semaphorin 4D (Sema4D)/CD100 has pleiotropic roles in immune activation, angiogenesis, bone metabolism, and neural development. We undertook this study to investigate the role of Sema4D in rheumatoid arthritis (RA). Methods Soluble Sema4D (sSema4D) levels in serum and synovial fluid were analyzed by enzyme‐linked immunosorbent assay. Cell surface expression and transcripts of Sema4D were analyzed in peripheral blood cells from RA patients, and immunohistochemical staining of Sema4D was performed in RA synovium. Generation of sSema4D was evaluated in an ADAMTS‐4–treated monocytic cell line (THP‐1 cells). The efficacy of anti‐Sema4D antibody was evaluated in mice with collagen‐induced arthritis (CIA). Results Levels of sSema4D were elevated in both serum and synovial fluid from RA patients, and disease activity markers were correlated with serum sSema4D levels. Sema4D‐expressing cells also accumulated in RA synovium. Cell surface levels of Sema4D on CD3+ and CD14+ cells from RA patients were reduced, although levels of Sema4D transcripts were unchanged. In addition, ADAMTS‐4 cleaved cell surface Sema4D to generate sSema4D in THP‐1 cells. Soluble Sema4D induced tumor necrosis factor α (TNFα) and interleukin‐6 (IL‐6) production from CD14+ monocytes. IL‐6 and TNFα induced ADAMTS‐4 expression in synovial cells. Treatment with an anti‐Sema4D antibody suppressed arthritis and reduced proinflammatory cytokine production in CIA. Conclusion A positive feedback loop involving sSema4D/IL‐6 and TNFα/ADAMTS‐4 may contribute to the pathogenesis of RA. The inhibition of arthritis by anti‐Sema4D antibody suggests that Sema4D represents a potential therapeutic target for RA.
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Affiliation(s)
- Yuji Yoshida
- Osaka University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Ogata
- Osaka University Graduate School of Medicine, Osaka, Japan
| | - Sujin Kang
- Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kousuke Ebina
- Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kenrin Shi
- Osaka University Graduate School of Medicine and Osaka University Hospital, Osaka, Japan
| | - Satoshi Nojima
- Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tetsuya Kimura
- Osaka University Graduate School of Medicine, Osaka, Japan
| | - Daisuke Ito
- Osaka University Graduate School of Medicine, Osaka, Japan
| | - Keiko Morimoto
- Osaka University Graduate School of Medicine, Osaka, Japan
| | | | | | - Toru Hirano
- Osaka University Graduate School of Medicine, Osaka, Japan
| | | | | | - Hideki Tsuboi
- National Hospital Organization Osaka Minami Medical Center, Osaka, Japan
| | - Yukihiko Saeki
- National Hospital Organization Osaka Minami Medical Center, Osaka, Japan
| | - Tetsuya Tomita
- Osaka University Graduate School of Medicine, Osaka, Japan
| | - Toshio Tanaka
- Osaka University Graduate School of Medicine, Osaka, Japan
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Copy number variations in a population-based study of Charcot-Marie-Tooth disease. BIOMED RESEARCH INTERNATIONAL 2015; 2015:960404. [PMID: 25648254 PMCID: PMC4306395 DOI: 10.1155/2015/960404] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 12/13/2014] [Indexed: 12/14/2022]
Abstract
Copy number variations (CNVs) are important in relation to diversity and evolution but can sometimes cause disease. The most common genetic cause of the inherited peripheral neuropathy Charcot-Marie-Tooth disease is the PMP22 duplication; otherwise, CNVs have been considered rare. We investigated CNVs in a population-based sample of Charcot-Marie-Tooth (CMT) families. The 81 CMT families had previously been screened for the PMP22 duplication and point mutations in 51 peripheral neuropathy genes, and a genetic cause was identified in 37 CMT families (46%). Index patients from the 44 CMT families with an unknown genetic diagnosis were analysed by whole-genome array comparative genomic hybridization to investigate the entire genome for larger CNVs and multiplex ligation-dependent probe amplification to detect smaller intragenomic CNVs in MFN2 and MPZ. One patient had the pathogenic PMP22 duplication not detected by previous methods. Three patients had potentially pathogenic CNVs in the CNTNAP2, LAMA2, or SEMA5A, that is, genes related to neuromuscular or neurodevelopmental disease. Genotype and phenotype correlation indicated likely pathogenicity for the LAMA2 CNV, whereas the CNTNAP2 and SEMA5A CNVs remained potentially pathogenic. Except the PMP22 duplication, disease causing CNVs are rare but may cause CMT in about 1% (95% CI 0–7%) of the Norwegian CMT families.
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Purohit A, Sadanandam A, Myneni P, Singh RK. Semaphorin 5A mediated cellular navigation: connecting nervous system and cancer. BIOCHIMICA ET BIOPHYSICA ACTA 2014; 1846:485-93. [PMID: 25263940 PMCID: PMC4261006 DOI: 10.1016/j.bbcan.2014.09.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 09/19/2014] [Accepted: 09/21/2014] [Indexed: 12/30/2022]
Abstract
The ultraprecise wiring of neurons banks on the instructions provided by guidance cue proteins that steer them to their appropriate target tissue during neuronal development. Semaphorins are one such family of proteins. Semaphorins are known to play major physiological roles during the development of various organs including the nervous, cardiovascular, and immune systems. Their role in different pathologies including cancer remains an intense area of investigation. This review focuses on a novel member of this family of proteins, semaphorin 5A, which is much less explored in comparison to its other affiliates. Recent reports suggest that semaphorins play important roles in the pathology of cancer by affecting angiogenesis, tumor growth and metastasis. We will firstly give a general overview of the semaphorin family and its receptors. Next, we discuss their roles in cellular movements and how that makes them a connecting link between the nervous system and cancer. Finally, we focus our discussion on semaphorin 5A to summarize the prevailing knowledge for this molecule in developmental biology and carcinogenesis.
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Affiliation(s)
- Abhilasha Purohit
- Department of Pathology Microbiology, 985950, Nebraska Medical Center, Omaha, NE 68198-5900, USA
| | - Anguraj Sadanandam
- The Institute of Cancer Research, Division of Molecular Pathology, London, UK
| | - Pavan Myneni
- Department of Pathology Microbiology, 985950, Nebraska Medical Center, Omaha, NE 68198-5900, USA
| | - Rakesh K Singh
- Department of Pathology Microbiology, 985950, Nebraska Medical Center, Omaha, NE 68198-5900, USA.
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