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Zhao CY, Liu F, Dong JM, Du CP, Zhang CL, Wang CY, Zhang XY, Zhou Q, Liu W, Yang AJ, Zhou YN, Dang Y, Shang LN, Wang M, Li M. SDCBP Orchestrated Gastric Cancer Aggression Through Epithelial- Mesenchymal Transition and Macrophages M2 Polarization. Mol Carcinog 2025. [PMID: 40256939 DOI: 10.1002/mc.23923] [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: 12/02/2024] [Revised: 03/13/2025] [Accepted: 03/24/2025] [Indexed: 04/22/2025]
Abstract
Gastric cancer remains a significant global health burden with limited treatment options and high mortality. Syndecan-binding protein (SDCBP), a scaffolding protein involved in tumor differentiation, has attracted attention as a potential therapeutic target in cancers. However, its precise role in gastric cancer progression is not fully understood. In this study, through bioinformatics analysis and gastric cancer samples detection, we discovered that SDCBP was highly expressed in gastric cancer tissues, which was correlated with clinicopathological features such as tumor invasion depth and distant metastasis, and exhibited heterogeneity across histological or molecular subtypes. Elevated SDCBP expression promoted the proliferation, invasion and migration of gastric cancer cells, and modulated epithelial-mesenchymal transition (EMT) via the ERK signaling pathway. Xenograft experiments in mice confirmed that inhibiting SDCBP or ERK signaling could delay cancer progression. We also found that gastric cancer cells with SDCBP knockdown were able to inhibit the M2 polarization of cocultured macrophages, reduce chemotaxis and enhance phagocytosis of macrophages. Therefore, SDCBP plays a crucial role in driving gastric cancer progression. Targeting SDCBP in gastric cancer can partially reverse the malignant phenotype, and SDCBP is expected to be a promising therapeutic target for gastric cancer.
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Affiliation(s)
- Chan-Yuan Zhao
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Feng Liu
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- The Forensic Identification Unit of Lanzhou University, Lanzhou, China
| | - Jia-Ming Dong
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Cun-Pu Du
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Chen-Li Zhang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- The Forensic Identification Unit of Lanzhou University, Lanzhou, China
| | - Chen-Yu Wang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- The Forensic Identification Unit of Lanzhou University, Lanzhou, China
| | - Xiao-Yu Zhang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Quan Zhou
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Wei Liu
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- The Forensic Identification Unit of Lanzhou University, Lanzhou, China
| | - Ai-Jun Yang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- The Forensic Identification Unit of Lanzhou University, Lanzhou, China
| | - Yong-Ning Zhou
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yun Dang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- Gansu Provincial Maternity and Child-care Hospital/Gansu Provincial Central Hospital, Lanzhou, China
| | - Li-Na Shang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- Medical College of Northwest Minzu University, Lanzhou, China
| | - Min Wang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- The Forensic Identification Unit of Lanzhou University, Lanzhou, China
- Experimental Teaching Center of Basic Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Min Li
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- The Forensic Identification Unit of Lanzhou University, Lanzhou, China
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, China
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Das SK, Fisher PB. MDA-9/Syntenin as a therapeutic cancer metastasis target: current molecular and preclinical understanding. Expert Opin Ther Targets 2025; 29:75-92. [PMID: 40056146 PMCID: PMC12047740 DOI: 10.1080/14728222.2025.2472042] [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: 09/24/2024] [Revised: 02/08/2025] [Accepted: 02/21/2025] [Indexed: 03/10/2025]
Abstract
INTRODUCTION Metastasis is a principal cause of patient morbidity and death from solid cancers with current therapies being inadequate. AREAS COVERED Detailed genomic analyses document mutational differences between the initial tumor and metastatic clones, posing a challenge to current targeted therapies, which focus predominantly on the phenotype of primary tumors. Considering the diverse signaling cascades and numerous compensatory pathways in metastasis, designing broad-spectrum anti-metastatic therapies remains challenging. Although significant anti-cancer activity is evident in specific patients with advanced cancers and metastases treated with single or combination immunotherapies, there are limitations, i.e. toxicity, immune inhibitory 'cold' tumors and the tumor microenvironment (TME), and intra- and intertumoral heterogeneity. Accordingly, multidisciplinary strategies are required to attack metastases and the TME to obtain optimal therapeutic responses. EXPERT OPINION To create potent anti-metastatic agents, defining critical genes/proteins and drugs controlling discrete steps in the metastatic cascade are mandatory. Melanoma differentiation-associated gene-9 (MDA-9), Syndecan Binding Protein (SDCBP) or Syntenin (MDA-9/Syntenin) is robustly expressed and serves essential roles in cancer disease progression through protein-protein interactions with additional metastasis-associated molecules and pathways. The importance of MDA-9/Syntenin in the metastatic process is now established and first-in-class inhibitory molecules look promising with some moving toward clinical evaluation.
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Affiliation(s)
- Swadesh K. Das
- VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Paul B. Fisher
- VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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Tripathi S, Sharma Y, Kumar D. Biological Cargo: Exosomes and their Role in Cancer Progression and Metastasis. Curr Top Med Chem 2025; 25:263-285. [PMID: 38984577 DOI: 10.2174/0115680266304636240626055711] [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: 01/16/2024] [Revised: 05/23/2024] [Accepted: 05/23/2024] [Indexed: 07/11/2024]
Abstract
Cancer cells are among the many types of cells that release exosomes, which are nanovesicles. Because of their many potential applications, exosomes have recently garnered much attention from cancer researchers. The bioactive substances that exosomes release as cargo have been the subject of several investigations. The substances in question may operate as biomarkers for diagnosis or affect apoptosis, the immune system, the development and spread of cancer, and other processes. Others have begun to look at exosomes in experimental therapeutic trials because they believe they may be useful in the treatment of cancer. This review started with a short description of exosome biogenesis and key features. Next, the potential of tumor-derived exosomes and oncosomes to influence the immune system throughout the development of cancer, as well as alter tumor microenvironments (TMEs) and pre-metastatic niche creation, was investigated. Finally, there was talk of exosomes' possible use in cancer treatment. Furthermore, there is emerging consensus about the potential application of exosomes to be biological reprogrammers of cancer cells, either as carriers of naturally occurring chemicals, including anticancer medications, or as carriers of anticancer vaccines for immunotherapy as well as boron neutron capture therapy (BNCT). We briefly review the key ideas and logic behind this intriguing therapy recommendation.
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Affiliation(s)
- Siddhant Tripathi
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
| | - Yashika Sharma
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
| | - Dileep Kumar
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
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Manna D, Chidambaranathan Reghupaty S, Camarena MDC, Mendoza RG, Subler MA, Koblinski JE, Martin R, Dozmorov MG, Mukhopadhyay ND, Liu J, Qu X, Das SK, Lai Z, Windle JJ, Fisher PB, Sarkar D. Melanoma differentiation associated gene-9/syndecan binding protein promotes hepatocellular carcinoma. Hepatology 2023; 78:1727-1741. [PMID: 36120720 PMCID: PMC11261751 DOI: 10.1002/hep.32797] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS The oncogene Melanoma differentiation associated gene-9/syndecan binding protein (MDA-9/SDCBP) is overexpressed in many cancers, promoting aggressive, metastatic disease. However, the role of MDA-9 in regulating hepatocellular carcinoma (HCC) has not been well studied. APPROACH AND RESULTS To unravel the function of MDA-9 in HCC, we generated and characterized a transgenic mouse with hepatocyte-specific overexpression of MDA-9 (Alb/MDA-9). Compared with wild-type (WT) littermates, Alb/MDA-9 mice demonstrated significantly higher incidence of N-nitrosodiethylamine/phenobarbital-induced HCC, with marked activation and infiltration of macrophages. RNA sequencing (RNA-seq) in naive WT and Alb/MDA-9 hepatocytes identified activation of signaling pathways associated with invasion, angiogenesis, and inflammation, especially NF-κB and integrin-linked kinase signaling pathways. In nonparenchymal cells purified from naive livers, single-cell RNA-seq showed activation of Kupffer cells and macrophages in Alb/MDA-9 mice versus WT mice. A robust increase in the expression of Secreted phosphoprotein 1 (Spp1/osteopontin) was observed upon overexpression of MDA-9. Inhibition of NF-κB pathway blocked MDA-9-induced Spp1 induction, and knock down of Spp1 resulted in inhibition of MDA-9-induced macrophage migration, as well as angiogenesis. CONCLUSIONS Alb/MDA-9 is a mouse model with MDA-9 overexpression in any tissue type. Our findings unravel an HCC-promoting role of MDA-9 mediated by NF-κB and Spp1 and support the rationale of using MDA-9 inhibitors as a potential treatment for aggressive HCC.
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Affiliation(s)
- Debashri Manna
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
| | | | - Maria Del Carmen Camarena
- C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Rachel G. Mendoza
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Mark A. Subler
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jennifer E. Koblinski
- Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
- Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Rebecca Martin
- Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Mikhail G. Dozmorov
- Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Nitai D. Mukhopadhyay
- Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jinze Liu
- Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Xufeng Qu
- Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Swadesh K. Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
- Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
- Virginia Commonwealth University Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, Virginia, USA
| | - Zhao Lai
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA
| | - Jolene J. Windle
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
- Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
- Virginia Commonwealth University Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, Virginia, USA
| | - Paul B. Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
- Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
- Virginia Commonwealth University Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, Virginia, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
- Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
- Virginia Commonwealth University Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, Virginia, USA
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He Y, Zheng CC, Yang J, Li SJ, Xu TY, Wei X, Chen WY, Jiang ZL, Xu JJ, Zhang GG, Cheng C, Chen KS, Shi XY, Qin DJ, Liu JB, Li B. Lysine butyrylation of HSP90 regulated by KAT8 and HDAC11 confers chemoresistance. Cell Discov 2023; 9:74. [PMID: 37460462 DOI: 10.1038/s41421-023-00570-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/24/2023] [Indexed: 07/20/2023] Open
Abstract
Posttranslational modification dramatically enhances protein complexity, but the function and precise mechanism of novel lysine acylation modifications remain unknown. Chemoresistance remains a daunting challenge to successful treatment. We found that lysine butyrylation (Kbu) is specifically upregulated in chemoresistant tumor cells and tissues. By integrating butyrylome profiling and gain/loss-of-function experiments, lysine 754 in HSP90 (HSP90 K754) was identified as a substrate for Kbu. Kbu modification leads to overexpression of HSP90 in esophageal squamous cell carcinoma (ESCC) and its further increase in relapse samples. Upregulation of HSP90 contributes to 5-FU resistance and can predict poor prognosis in cancer patients. Mechanistically, HSP90 K754 is regulated by the cooperation of KAT8 and HDAC11 as the writer and eraser, respectively; SDCBP increases the Kbu level and stability of HSP90 by binding competitively to HDAC11. Furthermore, SDCBP blockade with the lead compound V020-9974 can target HSP90 K754 to overcome 5-FU resistance, constituting a potential therapeutic strategy.
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Affiliation(s)
- Yan He
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China
| | - Can-Can Zheng
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jing Yang
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China
| | - Shu-Jun Li
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China
| | - Tao-Yang Xu
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China
| | - Xian Wei
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Wen-You Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Zhi-Li Jiang
- Department of Radiation Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jiao-Jiao Xu
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China
| | - Guo-Geng Zhang
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China
| | - Chao Cheng
- Department of Thoracic Surgery, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China
| | - Kui-Sheng Chen
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Tumor Pathology, Zhengzhou, Henan, China
| | - Xing-Yuan Shi
- Department of Radiation Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Da-Jiang Qin
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jin-Bao Liu
- Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Bin Li
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
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Lee KM, Seo EC, Lee JH, Kim HJ, Hwangbo C. The Multifunctional Protein Syntenin-1: Regulator of Exosome Biogenesis, Cellular Function, and Tumor Progression. Int J Mol Sci 2023; 24:ijms24119418. [PMID: 37298370 DOI: 10.3390/ijms24119418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/20/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Syntenin acts as an adaptor and scaffold protein through its two PSD-95, Dlg, and ZO-1 (PDZ) domains, participating in multiple signaling pathways and modulating cellular physiology. It has been identified as an oncogene, promoting cancer development, metastasis, and angiogenesis in various carcinomas. Syntenin-1 is also associated with the production and release of exosomes, small extracellular vesicles that play a significant role in intercellular communication by containing bioactive molecules such as proteins, lipids, and nucleic acids. The trafficking of exosomes involves a complex interplay of various regulatory proteins, including syntenin-1, which interacts with its binding partners, syndecan and activated leukocyte cell adhesion molecule (ALIX). Exosomal transfer of microRNAs, a key cargo, can regulate the expression of various cancer-related genes, including syntenin-1. Targeting the mechanism involving the regulation of exosomes by syntenin-1 and microRNAs may provide a novel treatment strategy for cancer. This review highlights the current understanding of syntenin-1's role in regulating exosome trafficking and its associated cellular signaling pathways.
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Affiliation(s)
- Kwang-Min Lee
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea
- Division of Applied Life Science (BK21 Four), Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Eun-Chan Seo
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea
- Division of Applied Life Science (BK21 Four), Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Jeong-Hyung Lee
- Department of Biochemistry (BK21 Four), College of Natural Sciences, Kangwon National University, Chuncheon 24414, Republic of Korea
| | - Hyo-Jin Kim
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea
- Division of Applied Life Science (BK21 Four), Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Cheol Hwangbo
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea
- Division of Applied Life Science (BK21 Four), Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea
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Meyer A, Sienes RE, Nijim W, Zanotti B, Umar S, Volin MV, Van Raemdonck K, Lewis M, Pitzalis C, Arami S, Al-Awqati M, Chang HJ, Jetanalin P, Schett G, Sweiss N, Shahrara S. Syntenin-1-mediated arthritogenicity is advanced by reprogramming RA metabolic macrophages and Th1 cells. Ann Rheum Dis 2023; 82:483-495. [PMID: 36593091 PMCID: PMC10314955 DOI: 10.1136/ard-2022-223284] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 12/14/2022] [Indexed: 01/03/2023]
Abstract
OBJECTIVES Syntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal synovial tissue (ST). However, the cellular origin, immunoregulation and molecular mechanism of syntenin-1 are undescribed in RA. METHODS RA patient myeloid and lymphoid cells, as well as preclinical models, were used to investigate the impact of syntenin-1/syndecan-1 on the inflammatory and metabolic landscape. RESULTS Syntenin-1 and syndecan-1 (SDC-1) co-localise on RA ST macrophages (MΦs) and endothelial cells. Intriguingly, blood syntenin-1 and ST SDC-1 transcriptome are linked to cyclic citrullinated peptide, erythrocyte sedimentation rate, ST thickness and bone erosion. Metabolic CD14+CD86+GLUT1+MΦs reprogrammed by syntenin-1 exhibit a wide range of proinflammatory interferon transcription factors, monokines and glycolytic factors, along with reduced oxidative intermediates that are downregulated by blockade of SDC-1, glucose uptake and/or mTOR signalling. Inversely, IL-5R and PDZ1 inhibition are ineffective on RA MΦs-reprogrammed by syntenin-1. In syntenin-1-induced arthritis, F4/80+iNOS+RAPTOR+MΦs represent glycolytic RA MΦs, by amplifying the inflammatory and glycolytic networks. Those networks are abrogated in SDC-1-/- animals, while joint prorepair monokines are unaffected and the oxidative metabolites are moderately replenished. In RA cells and/or preclinical model, syntenin-1-induced arthritogenicity is dependent on mTOR-activated MΦ remodelling and its ability to cross-regulate Th1 cells via IL-12 and IL-18 induction. Moreover, RA and joint myeloid cells exposed to Syntenin-1 are primed to transform into osteoclasts via SDC-1 ligation and RANK, CTSK and NFATc1 transcriptional upregulation. CONCLUSION The syntenin-1/SDC-1 pathway plays a critical role in the inflammatory and metabolic landscape of RA through glycolytic MΦ and Th1 cell cross-regulation (graphical abstract).
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Affiliation(s)
- Anja Meyer
- Jesse Brown VA Medical Center, Chicago, Illinois, USA
- Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
| | - Ryan E Sienes
- Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
| | - Wes Nijim
- Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
| | - Brian Zanotti
- Department of Microbiology and Immunology, Midwestern University, Downers Grove, Illinois, USA
| | - Sadiq Umar
- Jesse Brown VA Medical Center, Chicago, Illinois, USA
- Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
| | - Michael V Volin
- Department of Microbiology and Immunology, Midwestern University, Downers Grove, Illinois, USA
| | - Katrien Van Raemdonck
- Jesse Brown VA Medical Center, Chicago, Illinois, USA
- Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
| | - Myles Lewis
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, UK
- Centre for Translational Bioinformatics, Queen Mary University of London William Harvey Research Institute, London, UK
| | - Costantino Pitzalis
- Experimental Medicine and Rheumatology, William Harvey Research Institute, London, UK
| | - Shiva Arami
- Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
| | - Mina Al-Awqati
- Jesse Brown VA Medical Center, Chicago, Illinois, USA
- Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
| | - Huan J Chang
- Jesse Brown VA Medical Center, Chicago, Illinois, USA
- Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
| | - Pim Jetanalin
- Jesse Brown VA Medical Center, Chicago, Illinois, USA
- Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
| | - Georg Schett
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Nadera Sweiss
- Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
| | - Shiva Shahrara
- Jesse Brown VA Medical Center, Chicago, Illinois, USA
- Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
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8
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Pintor-Romero VG, Hurtado-Ortega E, Nicolás-Morales ML, Gutiérrez-Torres M, Vences-Velázquez A, Ortuño-Pineda C, Espinoza-Rojo M, Navarro-Tito N, Cortés-Sarabia K. Biological Role and Aberrant Overexpression of Syntenin-1 in Cancer: Potential Role as a Biomarker and Therapeutic Target. Biomedicines 2023; 11:biomedicines11041034. [PMID: 37189651 DOI: 10.3390/biomedicines11041034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/17/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023] Open
Abstract
Syntenin-1 is a 298 amino acid protein codified by the melanoma differentiation-associated gene-9 (MDA-9). Structurally, it is composed of four domains: N-terminal, PDZ1, PDZ2, and C-terminal. The PDZ domains of syntenin-1 are involved in the stability and interaction with other molecules such as proteins, glycoproteins, and lipids. Domains are also associated with several biological functions such as the activation of signaling pathways related to cell-to-cell adhesion, signaling translation, and the traffic of intracellular lipids, among others. The overexpression of syntenin-1 has been reported in glioblastoma, colorectal, melanoma, lung, prostate, and breast cancer, which promotes tumorigenesis by regulating cell migration, invasion, proliferation, angiogenesis, apoptosis, and immune response evasion, and metastasis. The overexpression of syntenin-1 in samples has been associated with worst prognostic and recurrence, whereas the use of inhibitors such as shRNA, siRNA, and PDZli showed a diminution of the tumor size and reduction in metastasis and invasion. Syntenin-1 has been suggested as a potential biomarker and therapeutic target in cancer for developing more effective diagnostic/prognostic tests or passive/active immunotherapies.
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Tang H, Wang L, Li S, Wei X, Lv M, Zhong F, Liu Y, Liu J, Fu B, Zhu Q, Wang D, Liu J, Ruan K, Gao J, Xu W. Inhibitors against Two PDZ Domains of MDA-9 Suppressed Migration of Breast Cancer Cells. Int J Mol Sci 2023; 24:ijms24043431. [PMID: 36834839 PMCID: PMC9964117 DOI: 10.3390/ijms24043431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/01/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
Melanoma differentiation-associated gene 9 (MDA-9) is a small adaptor protein with tandem PDZ domains that promotes tumor progression and metastasis in various human cancers. However, it is difficult to develop drug-like small molecules with high affinity due to the narrow groove of the PDZ domains of MDA-9. Herein, we identified four novel hits targeting the PDZ1 and PDZ2 domains of MDA-9, namely PI1A, PI1B, PI2A, and PI2B, using a protein-observed nuclear magnetic resonance (NMR) fragment screening method. We also solved the crystal structure of the MDA-9 PDZ1 domain in complex with PI1B and characterized the binding poses of PDZ1-PI1A and PDZ2-PI2A, guided by transferred paramagnetic relaxation enhancement. The protein-ligand interaction modes were then cross-validated by the mutagenesis of the MDA-9 PDZ domains. Competitive fluorescence polarization experiments demonstrated that PI1A and PI2A blocked the binding of natural substrates to the PDZ1 and PDZ2 domains, respectively. Furthermore, these inhibitors exhibited low cellular toxicity, but suppressed the migration of MDA-MB-231 breast carcinoma cells, which recapitulated the phenotype of MDA-9 knockdown. Our work has paved the way for the development of potent inhibitors using structure-guided fragment ligation in the future.
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Affiliation(s)
- Heng Tang
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Lei Wang
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Shuju Li
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Xiaoli Wei
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Mengqi Lv
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Fumei Zhong
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Yaqian Liu
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Jiuyang Liu
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Bangguo Fu
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Qizhi Zhu
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Dan Wang
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Jiajia Liu
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Ke Ruan
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Jia Gao
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Correspondence: (J.G.); (W.X.)
| | - Weiping Xu
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Correspondence: (J.G.); (W.X.)
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10
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Huaier Inhibits Gastric Cancer Growth and Hepatic Metastasis by Reducing Syntenin Expression and STAT3 Phosphorylation. JOURNAL OF ONCOLOGY 2022; 2022:6065516. [PMID: 35756080 PMCID: PMC9217535 DOI: 10.1155/2022/6065516] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 05/05/2022] [Indexed: 11/17/2022]
Abstract
Gastric cancer (GC) is a common malignant tumor worldwide and poses a serious threat to human health. As a traditional Chinese medicine, Huaier (Trametes robiniophila Murr.) has been used in the clinical treatment of GC. However, the mechanism underlying the anticancer effect of Huaier remains poorly understood. In this study, we used in vivo imaging technology to determine the anticancer effect of the Huaier n-butanol extract (HBE) on orthotopic and hepatic metastasis of GC mouse models. We found that HBE suppressed tumor growth and metastasis without causing apparent host toxicity. Proteomic analysis of GC cells before and after HBE intervention revealed syntenin to be one of the most significantly downregulated proteins after HBE intervention. We further demonstrated that HBE suppressed the growth and metastasis of GC by reducing the expression of syntenin and the phosphorylation of STAT3 at Y705 and reversing the epithelial-mesenchymal transition (EMT). In addition, we confirmed that syntenin was highly expressed in GC tissue and correlated with metastasis and poor prognosis. In conclusion, our results suggest that Huaier, a clinically used anticancer drug, may inhibit the growth and liver metastasis of GC by inhibiting the syntenin/STAT3 signaling pathway and reversing EMT.
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11
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Nan J, Hu X, Guo B, Xu M, Yao Y. Inhibition of endoplasmic reticulum stress alleviates triple-negative breast cancer cell viability, migration, and invasion by Syntenin/SOX4/Wnt/β-catenin pathway via regulation of heat shock protein A4. Bioengineered 2022; 13:10564-10577. [PMID: 35442158 PMCID: PMC9161907 DOI: 10.1080/21655979.2022.2062990] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Endoplasmic reticulum stress (ER stress) is a double-edged sword in the occurrence and development of malignant cancer. The aim of this study was to explore the roles of ER stress in metastasis and epithelial-mesenchymal transitionin triple-negative breast cancer (TNBC) and potential mechanisms. In this study, 4-PBA was administrated to inhibit the ER stress. Cell viability was evaluated using a cell counting kit-8 assay. Cell migration and invasion were identified by wound healing and transwell assay, respectively. Levels of MMP2 and MMP9 were measured by enzyme-linked immunosorbent assay and immunohistochemical staining. Western blot assay was used to assess the levels of ER stress-related proteins, Syndecan-1 (SDC-1)/Syntenin-1 (SDCBP-1)/SRY-related HMG-box 4 (SOX4) signaling and Wnt/β-catenin signaling. Moreover, a xenograft mice model was conducted to confirm the role of ER stress in TNBC. The data indicate that the ability of viability and metastasis of breast cancer cells were stronger than normal mammary epithelial cells. More aggressiveness was manifested in TNBC cells than that in non-TNBC cells. 4-PBA significantly suppressed the viability, migration, and invasion in BC cells and inhibited the SDC/SDCBP/SOX4 axis and Wnt/β-catenin signaling. Furthermore, heat shock protein A4 (HSPA4) overexpression stimulated ER stress and activated the SDC-1/SDCBP-1/SOX4 pathway and Wnt/β-catenin signaling. Animal experiments showed similar results that 4-PBA repressed tumor growth and inactivated the two pathways, while HSPA4 overexpression reversed the effects of 4-PBA. In summary, inhibition of ER stress inhibited TNBC viability, migration, and invasion by Syntenin/SOX4/Wnt/β-catenin pathway via regulation of HSPA4 in vivo and in vitro.
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Affiliation(s)
- Jinniang Nan
- School of Clinical Medicine, Nanchang Medical College, Jiangxi Province, Nanchang, P.R.China
| | - Xuguang Hu
- Department of Organ Transplantation, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi Province, P.R.China
| | - Binbin Guo
- School of Clinical Medicine, Nanchang Medical College, Jiangxi Province, Nanchang, P.R.China
| | - Meiyun Xu
- School of Clinical Medicine, Nanchang Medical College, Jiangxi Province, Nanchang, P.R.China
| | - Yufeng Yao
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, Nanchang, Jiangxi Province, P.R.China
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12
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Buenafe AC, Dorrell C, Reddy AP, Klimek J, Marks DL. Proteomic analysis distinguishes extracellular vesicles produced by cancerous versus healthy pancreatic organoids. Sci Rep 2022; 12:3556. [PMID: 35241737 PMCID: PMC8894448 DOI: 10.1038/s41598-022-07451-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 02/14/2022] [Indexed: 02/07/2023] Open
Abstract
Extracellular vesicles (EVs) are produced and released by both healthy and malignant cells and bear markers indicative of ongoing biological processes. In the present study we utilized high resolution flow cytometry to detect EVs in the plasma of patients with pancreatic ductal adenocarcinoma (PDAC) and in the supernatants of PDAC and healthy control (HC) pancreatic organoid cultures. Using ultrafiltration and size exclusion chromatography, PDAC and HC pancreatic organoid EVs were isolated for mass spectrometry analysis. Proteomic and functional protein network analysis showed a striking distinction in that EV proteins profiled in pancreatic cancer organoids were involved in vesicular transport and tumorigenesis while EV proteins in healthy organoids were involved in cellular homeostasis. Thus, the most abundant proteins identified in either case represented non-overlapping cellular programs. Tumor-promoting candidates LAMA5, SDCBP and TENA were consistently upregulated in PDAC EVs. Validation of specific markers for PDAC EVs versus healthy pancreatic EVs will provide the biomarkers and enhanced sensitivity necessary to monitor early disease or disease progression, with or without treatment. Moreover, disease-associated changes in EV protein profiles provide an opportunity to investigate alterations in cellular programming with disease progression.
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Affiliation(s)
- Abigail C Buenafe
- Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, OR, USA.
| | - Craig Dorrell
- Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, OR, USA
| | - Ashok P Reddy
- Proteomics Shared Resource, Oregon Health and Science University, Portland, OR, USA
| | - John Klimek
- Proteomics Shared Resource, Oregon Health and Science University, Portland, OR, USA
| | - Daniel L Marks
- Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
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13
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Pharmacological inhibition of MDA-9/Syntenin blocks breast cancer metastasis through suppression of IL-1β. Proc Natl Acad Sci U S A 2021; 118:2103180118. [PMID: 34016751 PMCID: PMC8166168 DOI: 10.1073/pnas.2103180118] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Melanoma differentiation associated gene-9 (MDA-9), Syntenin-1, or syndecan binding protein is a differentially regulated prometastatic gene with elevated expression in advanced stages of melanoma. MDA-9/Syntenin expression positively associates with advanced disease stage in multiple histologically distinct cancers and negatively correlates with patient survival and response to chemotherapy. MDA-9/Syntenin is a highly conserved PDZ-domain scaffold protein, robustly expressed in a spectrum of diverse cancer cell lines and clinical samples. PDZ domains interact with a number of proteins, many of which are critical regulators of signaling cascades in cancer. Knockdown of MDA-9/Syntenin decreases cancer cell metastasis, sensitizing these cells to radiation. Genetic silencing of MDA-9/Syntenin or treatment with a pharmacological inhibitor of the PDZ1 domain, PDZ1i, also activates the immune system to kill cancer cells. Additionally, suppression of MDA-9/Syntenin deregulates myeloid-derived suppressor cell differentiation via the STAT3/interleukin (IL)-1β pathway, which concomitantly promotes activation of cytotoxic T lymphocytes. Biologically, PDZ1i treatment decreases metastatic nodule formation in the lungs, resulting in significantly fewer invasive cancer cells. In summary, our observations indicate that MDA-9/Syntenin provides a direct therapeutic target for mitigating aggressive breast cancer and a small-molecule inhibitor, PDZ1i, provides a promising reagent for inhibiting advanced breast cancer pathogenesis.
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14
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Proteomics Profiling of the Urine of Patients with Hyperthyroidism after Anti-Thyroid Treatment. Molecules 2021; 26:molecules26071991. [PMID: 33915895 PMCID: PMC8036843 DOI: 10.3390/molecules26071991] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/17/2021] [Accepted: 03/24/2021] [Indexed: 12/11/2022] Open
Abstract
Hyperthyroidism, which is characterized by increased circulating thyroid hormone levels, alters the body’s metabolic and systemic hemodynamic balance and directly influences renal function. In this study, the urinary proteome of patients with hyperthyroidism was characterized using an untargeted proteomic approach with network analysis. Urine samples were collected from nine age-matched patients before and after carbimazole treatment. Differences in the abundance of urinary proteins between hyperthyroid and euthyroid states were determined using a 2D-DIGE coupled to MALDI-TOF mass spectrometry. Alterations in the abundance of urinary proteins, analyzed via Progenesis software, revealed a statistically significant difference in abundance in a total of 40 spots corresponding to 32 proteins, 25 up and 7 down (≥1.5-fold change, ANOVA, p ≤ 0.05). The proteins identified in the study are known to regulate processes associated with cellular metabolism, transport, and acute phase response. The notable upregulated urinary proteins were serotransferrin, transthyretin, serum albumin, ceruloplasmin, alpha-1B-glycoprotein, syntenin-1, and glutaminyl peptide cyclotransferase, whereas the three notable downregulated proteins were plasma kallikrein, protein glutamine gamma-glutamyl transferase, and serpin B3 (SERPINB3). Bioinformatic analysis using ingenuity pathway analysis (IPA) identified the dysregulation of pathways associated with cellular compromise, inflammatory response, cellular assembly, and organization and identified the involvement of the APP and AKT signaling pathways via their interactions with interleukins as the central nodes.
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15
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Epigenetic regulation of TGF-β-induced EMT by JMJD3/KDM6B histone H3K27 demethylase. Oncogenesis 2021; 10:17. [PMID: 33637682 PMCID: PMC7910473 DOI: 10.1038/s41389-021-00307-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 01/26/2021] [Accepted: 02/04/2021] [Indexed: 11/22/2022] Open
Abstract
Transforming growth factor-β (TGF-β) signaling pathways are well-recognized for their role in proliferation and epithelial–mesenchymal transition (EMT) of cancer cells, but much less is understood about their contribution to interactions with other signaling events. Recent studies have indicated that crosstalk between TGF-β and Ras signaling makes a contribution to TGF-β-mediated EMT. Here, we demonstrate that Jumonji domain containing-3 (JMJD3 also called KDM6B) promotes TGF-β-mediated Smad activation and EMT in Ras-activated lung cancer cells. JMJD3 in lung cancer patients was significantly increased and JMJD3 expression in lung tumor tissues was correlated with expression of K-Ras or H-Ras in particular, and its expression was regulated by Ras activity in lung cancer cells. JMJD3 promotes TGF-β-induced Smad activation and EMT in Ras-activated lung cancer cells through the induction of syntenin, a protein that regulates TGF-β receptor activation upon ligand binding. Tissue array and ChIP analysis revealed that JMJD3 epigenetically induces syntenin expression by directly regulating H3K27 methylation levels. Mechanical exploration identified a physical and functional association of JMJD3 with syntenin presiding over the TGF-β in Ras-activated lung cancer cells. Taken together, these findings provide new insight into the mechanisms by which JMJD3 promotes syntenin expression resulting in oncogenic Ras cooperation with TGF-β to promote EMT.
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16
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Nicolini A, Ferrari P, Biava PM. Exosomes and Cell Communication: From Tumour-Derived Exosomes and Their Role in Tumour Progression to the Use of Exosomal Cargo for Cancer Treatment. Cancers (Basel) 2021; 13:cancers13040822. [PMID: 33669294 PMCID: PMC7920050 DOI: 10.3390/cancers13040822] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Recently, within the research community, exosomes, transporters of bioactive molecules involved in many signalling pathways and cell-to-cell communication with the capacity to alter the tumour microenvironment, have been attracting increasing interest among oncologists. These molecules can play multiple roles, e.g., as useful biomarkers in diagnosis, modulators of the immune system, promoters of the formation of the pre-metastatic niches and cancer metastasis and carriers of substances or factors with anticancer properties. This review focuses on the use of exosomes as a novel therapeutic strategy for cancer treatment. Particularly, it highlights the potential of exosomes as carriers of stem cell differentiation stage factors (SCDSFs) for “cell reprogramming” therapy, a promising research field on which we have reported previously. Here, the main characteristics of this treatment and the advantages that can be obtained using mesenchymal stem cell-derived exosomes up-loaded with the SCDSFs as carriers of these factors are also discussed. Abstract Exosomes are nano-vesicle-shaped particles secreted by various cells, including cancer cells. Recently, the interest in exosomes among cancer researchers has grown enormously for their many potential roles, and many studies have focused on the bioactive molecules that they export as exosomal cargo. These molecules can function as biomarkers in diagnosis or play a relevant role in modulating the immune system and in promoting apoptosis, cancer development and progression. Others, considering exosomes potentially helpful for cancer treatment, have started to investigate them in experimental therapeutic trials. In this review, first, the biogenesis of exosomes and their main characteristics was briefly described. Then, the capability of tumour-derived exosomes and oncosomes in tumour microenvironments (TMEs) remodelling and pre-metastatic niche formation, as well as their interference with the immune system during cancer development, was examined. Finally, the potential role of exosomes for cancer therapy was discussed. Particularly, in addition, their use as carriers of natural substances and drugs with anticancer properties or carriers of boron neutron capture therapy (BNCT) and anticancer vaccines for immunotherapy, exosomes as biological reprogrammers of cancer cells have gained increased consensus. The principal aspects and the rationale of this intriguing therapeutic proposal are briefly considered.
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Affiliation(s)
- Andrea Nicolini
- Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, 56126 Pisa, Italy
- Correspondence:
| | - Paola Ferrari
- Unit of Oncology 1, Azienda Ospedaliera Universitaria Pisana, 56126 Pisa, Italy;
| | - Pier Mario Biava
- Scientific Institute of Research and Care Multimedica, 20099 Milan, Italy;
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17
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Pradhan AK, Maji S, Das SK, Emdad L, Sarkar D, Fisher PB. MDA-9/Syntenin/SDCBP: new insights into a unique multifunctional scaffold protein. Cancer Metastasis Rev 2021; 39:769-781. [PMID: 32410111 DOI: 10.1007/s10555-020-09886-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tumor metastasis comprises a series of coordinated events that culminate in dissemination of cancer cells to distant sites within the body representing the greatest challenge impeding effective therapy of cancer and the leading cause of cancer-associated morbidity. Cancer cells exploit multiple genes and pathways to colonize to distant organs. These pathways are integrated and regulated at different levels by cellular- and extracellular-associated factors. Defining the genes and pathways that govern metastasis can provide new targets for therapeutic intervention. Melanoma differentiation associated gene-9 (mda-9) (also known as Syntenin-1 and SDCBP (Syndecan binding protein)) was identified by subtraction hybridization as a novel gene displaying differential temporal expression during differentiation of melanoma. MDA-9/Syntenin is an established Syndecan binding protein that functions as an adaptor protein. Expression of MDA-9/Syntenin is elevated at an RNA and protein level in a wide-range of cancers including melanoma, glioblastoma, neuroblastoma, and prostate, breast and liver cancer. Expression is increased significantly in metastatic cancer cells as compared with non-metastatic cancer cells or normal cells, which make it an attractive target in treating cancer metastasis. In this review, we focus on the role and regulation of mda-9 in cancer progression and metastasis.
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Affiliation(s)
- Anjan K Pradhan
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA
| | - Santanu Maji
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA. .,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA. .,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
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18
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Leblanc R, Kashyap R, Barral K, Egea-Jimenez AL, Kovalskyy D, Feracci M, Garcia M, Derviaux C, Betzi S, Ghossoub R, Platonov M, Roche P, Morelli X, Hoffer L, Zimmermann P. Pharmacological inhibition of syntenin PDZ2 domain impairs breast cancer cell activities and exosome loading with syndecan and EpCAM cargo. J Extracell Vesicles 2020; 10:e12039. [PMID: 33343836 PMCID: PMC7737769 DOI: 10.1002/jev2.12039] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 11/02/2020] [Accepted: 11/14/2020] [Indexed: 12/17/2022] Open
Abstract
Exosomes support cell-to-cell communication in physiology and disease, including cancer. We currently lack tools, such as small chemicals, capable of modifying exosome composition and activity in a specific manner. Building on our previous understanding of how syntenin, and its PDZ partner syndecan (SDC), impact on exosome composition we optimized a small chemical compound targeting the PDZ2 domain of syntenin. In vitro , in tests on MCF-7 breast carcinoma cells, this compound is non-toxic and impairs cell proliferation, migration and primary sphere formation. It does not affect the size or the number of secreted particles, yet it decreases the amounts of exosomal syntenin, ALIX and SDC4 while leaving other exosomal markers unaffected. Interestingly, it also blocks the sorting of EpCAM, a bona fide target used for carcinoma exosome immunocapture. Our study highlights the first characterization of a small pharmacological inhibitor of the syntenin-exosomal pathway, of potential interest for exosome research and oncology.
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Affiliation(s)
- R Leblanc
- Equipe labellisée Ligue 2018 Centre de Recherche en Cancérologie de Marseille (CRCM) Aix-Marseille Université, Inserm, CNRS, Institut Paoli-Calmettes Marseille France
| | - R Kashyap
- Equipe labellisée Ligue 2018 Centre de Recherche en Cancérologie de Marseille (CRCM) Aix-Marseille Université, Inserm, CNRS, Institut Paoli-Calmettes Marseille France
| | - K Barral
- Centre de Recherche en Cancérologie de Marseille Integrative Structural & Chemical Biology Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes Marseille France
| | - A L Egea-Jimenez
- Equipe labellisée Ligue 2018 Centre de Recherche en Cancérologie de Marseille (CRCM) Aix-Marseille Université, Inserm, CNRS, Institut Paoli-Calmettes Marseille France
| | - D Kovalskyy
- Enamine Ltd. Kyiv Ukraine.,Taras Shevchenko National University of Kyiv Kyiv Ukraine
| | - M Feracci
- Centre de Recherche en Cancérologie de Marseille Integrative Structural & Chemical Biology Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes Marseille France
| | - M Garcia
- Centre de Recherche en Cancérologie de Marseille Integrative Structural & Chemical Biology Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes Marseille France
| | - C Derviaux
- Centre de Recherche en Cancérologie de Marseille Integrative Structural & Chemical Biology Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes Marseille France
| | - S Betzi
- Centre de Recherche en Cancérologie de Marseille Integrative Structural & Chemical Biology Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes Marseille France
| | - R Ghossoub
- Equipe labellisée Ligue 2018 Centre de Recherche en Cancérologie de Marseille (CRCM) Aix-Marseille Université, Inserm, CNRS, Institut Paoli-Calmettes Marseille France
| | - M Platonov
- Enamine Ltd. Kyiv Ukraine.,Institute of Molecular Biology and Genetics National Academy of Sciences of Ukraine Kyiv Ukraine
| | - P Roche
- Centre de Recherche en Cancérologie de Marseille Integrative Structural & Chemical Biology Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes Marseille France
| | - X Morelli
- Centre de Recherche en Cancérologie de Marseille Integrative Structural & Chemical Biology Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes Marseille France
| | - L Hoffer
- Centre de Recherche en Cancérologie de Marseille Integrative Structural & Chemical Biology Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes Marseille France
| | - Pascale Zimmermann
- Equipe labellisée Ligue 2018 Centre de Recherche en Cancérologie de Marseille (CRCM) Aix-Marseille Université, Inserm, CNRS, Institut Paoli-Calmettes Marseille France.,Department of Human Genetics K. U. Leuven Leuven Belgium
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19
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Ferrucci V, Asadzadeh F, Collina F, Siciliano R, Boccia A, Marrone L, Spano D, Carotenuto M, Chiarolla CM, De Martino D, De Vita G, Macrì A, Dassi L, Vandenbussche J, Marino N, Cantile M, Paolella G, D'Andrea F, di Bonito M, Gevaert K, Zollo M. Prune-1 drives polarization of tumor-associated macrophages (TAMs) within the lung metastatic niche in triple-negative breast cancer. iScience 2020; 24:101938. [PMID: 33426510 PMCID: PMC7779777 DOI: 10.1016/j.isci.2020.101938] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/22/2020] [Accepted: 12/09/2020] [Indexed: 12/16/2022] Open
Abstract
M2-tumor-associated macrophages (M2-TAMs) in the tumor microenvironment represent a prognostic indicator for poor outcome in triple-negative breast cancer (TNBC). Here we show that Prune-1 overexpression in human TNBC patients has positive correlation to lung metastasis and infiltrating M2-TAMs. Thus, we demonstrate that Prune-1 promotes lung metastasis in a genetically engineered mouse model of metastatic TNBC augmenting M2-polarization of TAMs within the tumor microenvironment. Thus, this occurs through TGF-β enhancement, IL-17F secretion, and extracellular vesicle protein content modulation. We also find murine inactivating gene variants in human TNBC patient cohorts that are involved in activation of the innate immune response, cell adhesion, apoptotic pathways, and DNA repair. Altogether, we indicate that the overexpression of Prune-1, IL-10, COL4A1, ILR1, and PDGFB, together with inactivating mutations of PDE9A, CD244, Sirpb1b, SV140, Iqca1, and PIP5K1B genes, might represent a route of metastatic lung dissemination that need future prognostic validations.
Prune-1 correlates to M2-TAMs confirming lung metastatic dissemination in GEMM Cytokines and EV proteins are responsible of M2-TAMs polarization processes A small molecule with immunomodulatory properties ameliorates metastatic dissemination Identification of gene variants within immune response and cell adhesion in TNBC
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Affiliation(s)
- Veronica Ferrucci
- CEINGE, Biotecnologie Avanzate, Naples 80145, Italy.,Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), 'Federico II' University of Naples, Naples 80134, Italy.,European School of Molecular Medicine (SEMM), University of Milan, Milan, Italy
| | - Fatemeh Asadzadeh
- CEINGE, Biotecnologie Avanzate, Naples 80145, Italy.,Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), 'Federico II' University of Naples, Naples 80134, Italy
| | - Francesca Collina
- Pathology Unit, Istituto Nazionale Tumori-IRCS- Fondazione G.Pascale, Naples 80131, Italy
| | | | | | - Laura Marrone
- CEINGE, Biotecnologie Avanzate, Naples 80145, Italy.,Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), 'Federico II' University of Naples, Naples 80134, Italy
| | | | - Marianeve Carotenuto
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), 'Federico II' University of Naples, Naples 80134, Italy
| | | | - Daniela De Martino
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), 'Federico II' University of Naples, Naples 80134, Italy
| | - Gennaro De Vita
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), 'Federico II' University of Naples, Naples 80134, Italy
| | | | - Luisa Dassi
- CEINGE, Biotecnologie Avanzate, Naples 80145, Italy
| | - Jonathan Vandenbussche
- VIB-UGent Centre for Medical Biotechnology, Ghent 9052, Belgium.,Department of Biomolecular Medicine, Ghent University, B9052 Ghent, Belgium
| | - Natascia Marino
- CEINGE, Biotecnologie Avanzate, Naples 80145, Italy.,Department of Medicine, Indiana University-Purdue University Indianapolis, Indianapolis 46202, USA
| | - Monica Cantile
- Pathology Unit, Istituto Nazionale Tumori-IRCS- Fondazione G.Pascale, Naples 80131, Italy
| | | | - Francesco D'Andrea
- Dipartimento di Sanità pubblica - AOU, Università; degli Studi di Napoli Federico II, Naples 80131, Italy
| | - Maurizio di Bonito
- Pathology Unit, Istituto Nazionale Tumori-IRCS- Fondazione G.Pascale, Naples 80131, Italy
| | - Kris Gevaert
- VIB-UGent Centre for Medical Biotechnology, Ghent 9052, Belgium.,Department of Biomolecular Medicine, Ghent University, B9052 Ghent, Belgium
| | - Massimo Zollo
- CEINGE, Biotecnologie Avanzate, Naples 80145, Italy.,Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), 'Federico II' University of Naples, Naples 80134, Italy.,European School of Molecular Medicine (SEMM), University of Milan, Milan, Italy.,DAI Medicina di Laboratorio e Trasfusionale, AOU Federico II, Naples 80131, Italy
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20
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Nasiri G, Azarpira N, Alizadeh A, Goshtasbi S, Tayebi L. Shedding light on the role of keratinocyte-derived extracellular vesicles on skin-homing cells. Stem Cell Res Ther 2020; 11:421. [PMID: 32993791 PMCID: PMC7523352 DOI: 10.1186/s13287-020-01929-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/08/2020] [Indexed: 01/03/2023] Open
Abstract
Extracellular vesicles (EVs) are secretory lipid membranes with the ability to regulate cellular functions by exchanging biological components between different cells. Resident skin cells such as keratinocytes, fibroblasts, melanocytes, and inflammatory cells can secrete different types of EVs depending on their biological state. These vesicles can influence the physiological properties and pathological processes of skin, such as pigmentation, cutaneous immunity, and wound healing. Since keratinocytes constitute the majority of skin cells, secreted EVs from these cells may alter the pathophysiological behavior of other skin cells. This paper reviews the contents of keratinocyte-derived EVs and their impact on fibroblasts, melanocytes, and immune cells to provide an insight for better understanding of the pathophysiological mechanisms of skin disorders and their use in related therapeutic approaches.
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Affiliation(s)
- Golara Nasiri
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Khalili Street, Shiraz, 7193711351 Iran
| | - Aliakbar Alizadeh
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sanaz Goshtasbi
- Transplant Research Center, Shiraz University of Medical Sciences, Khalili Street, Shiraz, 7193711351 Iran
| | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, WI 53233 USA
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21
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SDCBP/MDA-9/syntenin phosphorylation by AURKA promotes esophageal squamous cell carcinoma progression through the EGFR-PI3K-Akt signaling pathway. Oncogene 2020; 39:5405-5419. [PMID: 32572158 DOI: 10.1038/s41388-020-1369-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 05/19/2020] [Accepted: 06/11/2020] [Indexed: 01/02/2023]
Abstract
SDCBP is an adapter protein containing two tandem PDZ domains mediating cell adhesion. The role and underlying molecular mechanism of SDCBP in ESCC remain obscure. Here, we report that SDCBP is frequently overexpressed in ESCC tissues and cells compared to normal controls and that its overexpression is correlated with late clinical stage and predicts poor prognosis in ESCC patients. Functionally, high expression of SDCBP is positively related to ESCC progression both in vitro and in vivo. Furthermore, mechanistic studies show that SDCBP activates the EGFR-PI3K-Akt signaling pathway by binding to EGFR and preventing EGFR internalization. Moreover, we provide evidence that AURKA binds to SDCBP and phosphorylates it at the Ser131 and Thr200 sites to inhibit ubiquitination-mediated SDCBP degradation. More importantly, the sites at which AURKA phosphorylates SDCBP are crucial for the EGFR signaling-mediated oncogenic function of SDCBP. Taken together, we propose that SDCBP phosphorylation by AURKA prevents SDCBP degradation and promotes ESCC tumor growth through the EGFR-PI3K-Akt signaling pathway. Our findings unveil a new AURKA-SDCBP-EGFR axis that is involved in ESCC progression and provide a promising therapeutic target for ESCC treatment in the clinic.
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22
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Das SK, Maji S, Wechman SL, Bhoopathi P, Pradhan AK, Talukdar S, Sarkar D, Landry J, Guo C, Wang XY, Cavenee WK, Emdad L, Fisher PB. MDA-9/Syntenin (SDCBP): Novel gene and therapeutic target for cancer metastasis. Pharmacol Res 2020; 155:104695. [PMID: 32061839 PMCID: PMC7551653 DOI: 10.1016/j.phrs.2020.104695] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/12/2020] [Accepted: 02/12/2020] [Indexed: 02/06/2023]
Abstract
The primary cause of cancer-related death from solid tumors is metastasis. While unraveling the mechanisms of this complicated process continues, our ability to effectively target and treat it to decrease patient morbidity and mortality remains disappointing. Early detection of metastatic lesions and approaches to treat metastases (both pharmacological and genetic) are of prime importance to obstruct this process clinically. Metastasis is complex involving both genetic and epigenetic changes in the constantly evolving tumor cell. Moreover, many discrete steps have been identified in metastatic spread, including invasion, intravasation, angiogenesis, attachment at a distant site (secondary seeding), extravasation and micrometastasis and tumor dormancy development. Here, we provide an overview of the metastatic process and highlight a unique pro-metastatic gene, melanoma differentiation associated gene-9/Syntenin (MDA-9/Syntenin) also called syndecan binding protein (SDCBP), which is a major contributor to the majority of independent metastatic events. MDA-9 expression is elevated in a wide range of carcinomas and other cancers, including melanoma, glioblastoma multiforme and neuroblastoma, suggesting that it may provide an appropriate target to intervene in metastasis. Pre-clinical studies confirm that inhibiting MDA-9 either genetically or pharmacologically profoundly suppresses metastasis. An additional benefit to blocking MDA-9 in metastatic cells is sensitization of these cells to a second therapeutic agent, which converts anti-invasion effects to tumor cytocidal effects. Continued mechanistic and therapeutic insights hold promise to advance development of truly effective therapies for metastasis in the future.
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Affiliation(s)
- Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
| | - Santanu Maji
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Stephen L Wechman
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Praveen Bhoopathi
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Anjan K Pradhan
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Sarmistha Talukdar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Joseph Landry
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Chunqing Guo
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Xiang-Yang Wang
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Webster K Cavenee
- Ludwig Institute for Cancer Research, University of California, San Diego, CA, USA
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
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23
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Saber SH, Ali HEA, Gaballa R, Gaballah M, Ali HI, Zerfaoui M, Abd Elmageed ZY. Exosomes are the Driving Force in Preparing the Soil for the Metastatic Seeds: Lessons from the Prostate Cancer. Cells 2020; 9:E564. [PMID: 32121073 PMCID: PMC7140426 DOI: 10.3390/cells9030564] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 02/17/2020] [Accepted: 02/20/2020] [Indexed: 12/13/2022] Open
Abstract
Exosomes are nano-membrane vesicles that various cell types secrete during physiological and pathophysiological conditions. By shuttling bioactive molecules such as nucleic acids, proteins, and lipids to target cells, exosomes serve as key regulators for multiple cellular processes, including cancer metastasis. Recently, microvesicles have emerged as a challenge in the treatment of prostate cancer (PCa), encountered either when the number of vesicles increases or when the vesicles move into circulation, potentially with an ability to induce drug resistance, angiogenesis, and metastasis. Notably, the exosomal cargo can induce the desmoplastic response of PCa-associated cells in a tumor microenvironment (TME) to promote PCa metastasis. However, the crosstalk between PCa-derived exosomes and the TME remains only partially understood. In this review, we provide new insights into the metabolic and molecular signatures of PCa-associated exosomes in reprogramming the TME, and the subsequent promotion of aggressive phenotypes of PCa cells. Elucidating the molecular mechanisms of TME reprogramming by exosomes draws more practical and universal conclusions for the development of new therapeutic interventions when considering TME in the treatment of PCa patients.
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Affiliation(s)
- Saber H. Saber
- Laboratory of Molecular Cell Biology, Department of Zoology, Faculty of Science, Assiut University, Assiut 71515, Egypt;
| | - Hamdy E. A. Ali
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX 77843, USA; (H.E.A.A.); (R.G.); (M.G.); (H.I.A.)
| | - Rofaida Gaballa
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX 77843, USA; (H.E.A.A.); (R.G.); (M.G.); (H.I.A.)
| | - Mohamed Gaballah
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX 77843, USA; (H.E.A.A.); (R.G.); (M.G.); (H.I.A.)
| | - Hamed I. Ali
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX 77843, USA; (H.E.A.A.); (R.G.); (M.G.); (H.I.A.)
| | - Mourad Zerfaoui
- Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA;
| | - Zakaria Y. Abd Elmageed
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX 77843, USA; (H.E.A.A.); (R.G.); (M.G.); (H.I.A.)
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24
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Syntenin: PDZ Protein Regulating Signaling Pathways and Cellular Functions. Int J Mol Sci 2019; 20:ijms20174171. [PMID: 31454940 PMCID: PMC6747541 DOI: 10.3390/ijms20174171] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/22/2019] [Accepted: 08/22/2019] [Indexed: 12/29/2022] Open
Abstract
Syntenin is an adaptor-like molecule that has two adjacent tandem postsynaptic density protein 95/Discs large protein/Zonula occludens 1 (PDZ) domains. The PDZ domains of syntenin recognize multiple peptide motifs with low to moderate affinity. Many reports have indicated interactions between syntenin and a plethora of proteins. Through interactions with various proteins, syntenin regulates the architecture of the cell membrane. As a result, increases in syntenin levels induce the metastasis of tumor cells, protrusion along the neurite in neuronal cells, and exosome biogenesis in various cell types. Here, we review the updated data that support various roles for syntenin in the regulation of neuronal synapses, tumor cell invasion, and exosome control.
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25
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Identification of a Rat Mammary Tumor Risk Locus That Is Syntenic with the Commonly Amplified 8q12.1 and 8q22.1 Regions in Human Breast Cancer Patients. G3-GENES GENOMES GENETICS 2019; 9:1739-1743. [PMID: 30914425 PMCID: PMC6505137 DOI: 10.1534/g3.118.200873] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Breast cancer risk is 31% heritable, yet the majority of the underlying risk factors remain poorly defined. Here, we used F2-linkage analysis in a rat mammary tumor model to identify a novel 11.2 Mb modifier locus of tumor incidence and burden on rat chromosome 5 (chr5: 15.4 – 26.6 Mb). Genomic and RNA sequencing analysis identified four differentially expressed candidates: TMEM68, IMPAD1, SDCBP, and RBM12B. Analysis of the human syntenic candidate region revealed that SDCBP is in close proximity to a previously reported genetic risk locus for human breast cancer. Moreover, analysis of the candidate genes in The Cancer Genome Atlas (TCGA) revealed that they fall within the commonly amplified 8q12.1 and 8q22.1 regions in human breast cancer patients and are correlated with worse overall survival. Collectively, this study presents novel evidence suggesting that TMEM68, IMPAD1, SDCBP, and RBM12B are potential modifiers of human breast cancer risk and outcome.
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26
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Das SK, Sarkar D, Emdad L, Fisher PB. MDA-9/Syntenin: An emerging global molecular target regulating cancer invasion and metastasis. Adv Cancer Res 2019; 144:137-191. [PMID: 31349898 DOI: 10.1016/bs.acr.2019.03.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
With few exceptions, metastasis is the terminal stage of cancer with limited therapeutic options. Metastasis consists of numerous phenotypic and genotypic alterations of cells that are directly and indirectly induced by multiple intrinsic (cellular) and extrinsic (micro-environmental) factors. To metastasize, a cancer cell often transitions from an epithelial to mesenchymal morphology (EMT), modifies the extracellular matrix, forms emboli and survives in the circulation, escapes immune surveillance, adheres to sites distant from the initial tumor and finally develops a blood supply (angiogenesis) and colonizes in a secondary niche (a micrometastasis). Scientific advances have greatly enhanced our understanding of the precise molecular and genetic changes, operating independently or collectively, that lead to metastasis. This review focuses on a unique gene, melanoma differentiation associated gene-9 (also known as Syntenin-1; Syndecan Binding Protein (sdcbp); mda-9/syntenin), initially cloned and characterized from metastatic human melanoma and shown to be a pro-metastatic gene. In the last two decades, our comprehension of the diversity of actions of MDA-9/Syntenin on cellular phenotype has emerged. MDA-9/Sytenin plays pivotal regulatory roles in multiple signaling cascades and orchestrates both metastatic and non-metastatic events. Considering the relevance of this gene in controlling cancer invasion and metastasis, approaches have been developed to uniquely and selectively target this gene. We also provide recent updates on strategies that have been successfully employed in targeting MDA-9/Syntenin resulting in profound pre-clinical anti-cancer activity.
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Affiliation(s)
- Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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27
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Yu Y, Li S, Wang K, Wan X. A PDZ Protein MDA-9/Syntenin: As a Target for Cancer Therapy. Comput Struct Biotechnol J 2019; 17:136-141. [PMID: 30766662 PMCID: PMC6360254 DOI: 10.1016/j.csbj.2019.01.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 12/27/2018] [Accepted: 01/02/2019] [Indexed: 12/17/2022] Open
Abstract
Melanoma differentiation-associated gene 9 (MDA-9)/Syntenin is a multidomain PDZ protein and identified as a key oncogene in melanoma initially. This protein contains a unique tandem PDZ domain architecture (PDZ1 and PDZ2 spaced by a 4-amino acid linker), an N-terminal domain (NTD) that is structurally uncharacterized and a short C-terminal domain (CTD). The PDZ1 domain is regarded as the PDZ signaling domain while PDZ2 served as the PDZ superfamily domain. It has various cellular roles by regulating many of major signaling pathways in numerous cancertypes. Through the use of novel drug design methods, such as dimerization and unnatural amino acid substitution of inhibitors in our group, the protein may provide a valuable therapeutic target. The objective of this review is to provide a current perspective on the cancer-specific role of MDA-9/Syntenin in order to explore its potential for cancer drug discovery and cancer therapy.
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Affiliation(s)
- Yongsheng Yu
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Shuangdi Li
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Kai Wang
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Xiaoping Wan
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China
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28
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Lu S, Xu Q. MicroRNA-23a inhibits melanoma cell proliferation, migration, and invasion in mice through a negative feedback regulation of sdcbp and the MAPK/ERK signaling pathway. IUBMB Life 2018; 71:587-600. [PMID: 30589231 DOI: 10.1002/iub.1979] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 10/23/2018] [Accepted: 11/10/2018] [Indexed: 12/15/2022]
Abstract
Melanoma is the main cause of death associated with skin cancer. Surgical resection and adjuvant therapy are currently effective treatments, but the recurrence rate is very high. The understanding of microRNA (miR) dynamics after surgical resection of melanoma is essential to accurately explain the changes in the recurrence of melanoma. In this study, we hypothesized that microRNA-23a (miR-23a) affects the cell proliferation, migration, and invasion of melanoma with a mechanism related to SDCBP and the MAPK/ERK signaling pathway. To validate this, we performed a series of experiments in cells of melanoma modeled. Initially, positive expression of SDCBP and morphology of normal and melanoma tissues and cells were observed. Expression of miR-23a, SDCBP, and MAPK/ERK signaling pathway-related genes was identified in melanoma tissues. Melanoma cells transfected with mimic or inhibitor of miR-23a or si-SDCBP were detected to validate effect of miR-23a on SDCBP and the MAPK/ERK signaling pathway. MTT assay, scratch test, transwell assay, and flow cytometry were performed to evaluate cell viability, invasion, metastasis, and apoptosis in vitro, respectively. Tumorigenicity assay in nude mice was conducted to test the tumorigenesis of the transfected cells in vivo. High positive expression of SDCBP and abnormal morphology were observed in melanoma tissues and cells. Reduced expression of miR-23a and increased expression of SDCBP and MAPK/ERK signaling pathway-related genes were identified in the melanoma tissues of melanoma mice. Overexpressed miR-23a dampened SDCBP and the MAPK/ERK signaling pathway. The melanoma cells with overexpressed miR-23a presented ascended cell apoptosis and descended cell proliferation, migration, invasion as well as tumor size. Taken together, our study demonstrated that miR-23a could inhibit the development of melanoma in mice through a negative feedback regulation of SDCBP and the MAPK/ERK signaling pathway. © 2018 IUBMB Life, 71(5):587-600, 2019.
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Affiliation(s)
- Shelian Lu
- Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, Beijing, China
| | - Qunyuan Xu
- Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, Beijing, China
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29
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Ternette N, Olde Nordkamp MJM, Müller J, Anderson AP, Nicastri A, Hill AVS, Kessler BM, Li D. Immunopeptidomic Profiling of HLA-A2-Positive Triple Negative Breast Cancer Identifies Potential Immunotherapy Target Antigens. Proteomics 2018; 18:e1700465. [PMID: 29786170 PMCID: PMC6032843 DOI: 10.1002/pmic.201700465] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 04/26/2018] [Indexed: 11/06/2022]
Abstract
The recent development in immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cells in the treatment of cancer has not only demonstrated the potency of utilizing T-cell reactivity for cancer therapy, but has also highlighted the need for developing new approaches to discover targets suitable for such novel therapeutics. Here we analyzed the immunopeptidomes of six HLA-A2-positive triple negative breast cancer (TNBC) samples by nano-ultra performance liquid chromatography tandem mass spectrometry (nUPLC-MS2 ). Immunopeptidomic profiling identified a total of 19 675 peptides from tumor and adjacent normal tissue and 130 of the peptides were found to have higher abundance in tumor than in normal tissues. To determine potential therapeutic target proteins, we calculated the average tumor-associated cohort coverage (aTaCC) that represents the percentage coverage of each protein in this cohort by peptides that had higher tumoral abundance. Cofilin-1 (CFL-1), interleukin-32 (IL-32), proliferating cell nuclear antigen (PCNA), syntenin-1 (SDCBP), and ribophorin-2 (RPN-2) were found to have the highest aTaCC scores. We propose that these antigens could be evaluated further for their potential as targets in breast cancer immunotherapy and the small cohort immunopeptidomics analysis technique could be used in a wide spectrum of target discovery. Data are available via ProteomeXchange with identifier PXD009738.
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Affiliation(s)
- Nicola Ternette
- The Jenner InstituteUniversity of OxfordOxfordOX3 7FZUK
- Target Discovery InstituteNuffield Department of MedicineOxfordOX3 7FZUK
| | - Marloes J. M. Olde Nordkamp
- Nuffield Division of Clinical Laboratory SciencesRadcliffe Department of MedicineUniversity of OxfordOxfordOX3 9DUUK
| | - Julius Müller
- The Jenner InstituteUniversity of OxfordOxfordOX3 7FZUK
| | - Amanda P. Anderson
- Nuffield Division of Clinical Laboratory SciencesRadcliffe Department of MedicineUniversity of OxfordOxfordOX3 9DUUK
| | - Annalisa Nicastri
- Target Discovery InstituteNuffield Department of MedicineOxfordOX3 7FZUK
| | | | | | - Demin Li
- Nuffield Division of Clinical Laboratory SciencesRadcliffe Department of MedicineUniversity of OxfordOxfordOX3 9DUUK
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30
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Tae N, Lee S, Kim O, Park J, Na S, Lee JH. Syntenin promotes VEGF-induced VEGFR2 endocytosis and angiogenesis by increasing ephrin-B2 function in endothelial cells. Oncotarget 2018; 8:38886-38901. [PMID: 28418925 PMCID: PMC5503580 DOI: 10.18632/oncotarget.16452] [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: 07/04/2016] [Accepted: 02/27/2017] [Indexed: 12/21/2022] Open
Abstract
Syntenin, a tandem PDZ-domain-containing scaffold protein, is involved in the regulation of diverse biological functions, including protein trafficking, exosome biogenesis, and cancer metastasis. Here, we present the first study to explore the significance of syntenin in endothelial cells. Syntenin knockdown in human umbilical vein endothelial cells (HUVECs) impaired vascular endothelial growth factor (VEGF)-mediated proliferation, migration, invasion, vascular permeability, and nitric oxide (NO) production. Syntenin knockdown also suppressed expression of the VEGFR2 target genes VEGF, MMP2, and Nurr77 as well as VEGF-induced angiogenesis in vitro and in vivo. And it decreased cell-surface levels of ephrin-B2. Biochemical analyses revealed that syntenin exists in complex with VEGFR2 and ephrin-B2. Syntenin knockdown abolished the association between VEGFR2 and ephrin-B2, suggesting syntenin functions as a scaffold protein facilitating their association in HUVECs. Consistent with these observations, knocking down syntenin or ephrin-B2 abolished VEGF-induced endocytosis and VEGFR2 phosphorylation and activation of its downstream signaling molecules. Treatment with MG132, a proteasome inhibitor, rescued the downregulation of ephrin-B2 and VEGFR2 signaling induced by syntenin knockdown. These findings demonstrate that syntenin promotes VEGF signaling and, through its PDZ-dependent interaction with ephrin-B2, enhances VEGF-mediated VEGFR2 endocytosis and subsequent downstream signaling and angiogenesis in endothelial cells.
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Affiliation(s)
- Nara Tae
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 243-41, Republic of Korea
| | - Suhyun Lee
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 243-41, Republic of Korea
| | - Okwha Kim
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 243-41, Republic of Korea
| | - Juhee Park
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 243-41, Republic of Korea
| | - Sunghun Na
- Department of Obstetrics and Gynecology, Kangwon National University Hospital, school of Medicine, Kangwon National University, Chuncheon, Gangwon-Do 243-41, Republic of Korea
| | - Jeong-Hyung Lee
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 243-41, Republic of Korea
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Das SK, Pradhan AK, Bhoopathi P, Talukdar S, Shen XN, Sarkar D, Emdad L, Fisher PB. The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer Invasion. Cancer Res 2018; 78:2852-2863. [PMID: 29572229 DOI: 10.1158/0008-5472.can-17-2992] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 02/26/2018] [Accepted: 03/19/2018] [Indexed: 11/16/2022]
Abstract
Although prostate cancer is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation-associated gene-9 [syntenin, or syndecan binding protein (SDCBP)] in prostate cancer progression. Using tissue samples from various Gleason stage prostate cancer patients with adjacent normal tissue, a series of normal prostate and prostate cancer cell lines (with differing tumorigenic/metastatic properties), mda-9/syntenin-manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/Syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/syntenin in prostate cancer invasion. MDA-9/Syntenin physically interacted with insulin-like growth factor-1 receptor following treatment with insulin-like growth factor binding protein-2 (IGFBP2), regulating downstream signaling processes that enabled STAT3 phosphorylation. This activation enhanced expression of MMP2 and MMP9, two established enzymes that positively regulate invasion. In addition, MDA-9/syntenin-mediated upregulation of proangiogenic factors including IGFBP2, IL6, IL8, and VEGFA also facilitated migration of prostate cancer cells. Collectively, our results draw attention to MDA-9/Syntenin as a positive regulator of prostate cancer metastasis, and the potential application of targeting this molecule to inhibit invasion and metastasis in prostate cancer and potentially other cancers.Significance: This study provides new mechanistic insight into the proinvasive role of MDA-9/Syntenin in prostate cancer and has potential for therapeutic application to prevent prostate cancer metastasis. Cancer Res; 78(11); 2852-63. ©2018 AACR.
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Affiliation(s)
- Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. .,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Anjan K Pradhan
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Praveen Bhoopathi
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Sarmistha Talukdar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Xue-Ning Shen
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. .,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
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32
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Bebelman MP, Smit MJ, Pegtel DM, Baglio SR. Biogenesis and function of extracellular vesicles in cancer. Pharmacol Ther 2018; 188:1-11. [PMID: 29476772 DOI: 10.1016/j.pharmthera.2018.02.013] [Citation(s) in RCA: 581] [Impact Index Per Article: 83.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Extracellular vesicles (EVs) are heterogeneous multi-signal messengers that support cancer growth and dissemination by mediating the tumor-stroma crosstalk. Exosomes are a subtype of EVs that originate from the limiting membrane of late endosomes, and as such contain information linked to both the intrinsic cell "state" and the extracellular signals cells received from their environment. Resolving the signals affecting exosome biogenesis, cargo sorting and release will increase our understanding of tumorigenesis. In this review we highlight key cell biological processes that couple exosome biogenesis to cargo sorting in cancer cells. Moreover, we discuss how the bidirectional communication between tumor and non-malignant cells affect cancer growth and metastatic behavior.
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Affiliation(s)
- Maarten P Bebelman
- Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, VU University, Amsterdam, The Netherlands
| | - Martine J Smit
- Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, VU University, Amsterdam, The Netherlands
| | - D Michiel Pegtel
- Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
| | - S Rubina Baglio
- Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
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MDA-9/Syntenin (SDCBP) modulates small GTPases RhoA and Cdc42 via transforming growth factor β1 to enhance epithelial-mesenchymal transition in breast cancer. Oncotarget 2018; 7:80175-80189. [PMID: 27863394 PMCID: PMC5348312 DOI: 10.18632/oncotarget.13373] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 11/01/2016] [Indexed: 12/31/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is one of the decisive steps regulating cancer invasion and metastasis. However, the molecular mechanisms underlying this transition require further clarification. MDA-9/syntenin (SDCBP) expression is elevated in breast cancer patient samples as well as cultured breast cancer cells. Silencing expression of MDA-9 in mesenchymal metastatic breast cancer cells triggered a change in cell morphology in both 2D- and 3D-cultures to a more epithelial-like phenotype, along with changes in EMT markers, cytoskeletal rearrangement and decreased invasion. Conversely, over expressing MDA-9 in epithelial non-metastatic breast cancer cells instigated a change in morphology to a more mesenchymal phenotype with corresponding changes in EMT markers, cytoskeletal rearrangement and an increase in invasion. We also found that MDA-9 upregulated active levels of known modulators of EMT, the small GTPases RhoA and Cdc42, via TGFβ1. Reintroducing TGFβ1 in MDA-9 silenced cells restored active RhoA and cdc42 levels, modulated cytoskeletal rearrangement and increased invasion. We further determined that MDA-9 interacts with TGFβ1 via its PDZ1 domain. Finally, in vivo studies demonstrated that silencing the expression of MDA-9 resulted in decreased lung metastasis and TGFβ1 re-expression partially restored lung metastases. Our findings provide evidence for the relevance of MDA-9 in mediating EMT in breast cancer and support the potential of MDA-9 as a therapeutic target against metastatic disease.
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Zhang J, Qian X, Liu F, Guo X, Gu F, Fu L. Silencing of syndecan-binding protein enhances the inhibitory effect of tamoxifen and increases cellular sensitivity to estrogen. Cancer Biol Med 2018; 15:29-38. [PMID: 29545966 PMCID: PMC5842332 DOI: 10.20892/j.issn.2095-3941.2017.0122] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 12/17/2017] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Tamoxifen is used as a complementary treatment for estrogen receptor (ER)-positive breast cancer (BCa), but many patients developed resistance. The aim of this study was to examine the role of syndecan-binding protein (SDCBP) silencing in ER-positive BCa cells. METHODS In MCF-7/T47D cells, the effects of SDCBP silence/overexpression on cell proliferation and estrogenic response were examined. Cell proliferation was examined using the MTT assay and cell cycle regulators were examined by Western blot. Estrogen response was examined from a luciferase activity and evaluation of transcript levels of pS2 and progesterone receptor (PR) upon estrogen administration. Samples of ER-positive BCa were stained with ERα, PR, and SDCBP antibodies, and their expression correlations were analyzed. RESULTS We found that SDCBP silencing inhibited the proliferation of ER-positive BCa cells and arrested a greater number of cells in the G1 phase of the cell cycle compared to tamoxifen alone, while SDCBP overexpression limited the anti-cancer effects of tamoxifen. SDCBP silencing and overexpression also enhanced and attenuated the estrogenic response, respectively. Expression of SDCBP was negatively correlated with PR, ERα, and the PR/ERα ratio in ER-positive BCa tissue samples. CONCLUSIONS SDCBP may be involved in tamoxifen resistance in ER-positive BCa. Tamoxifen treatment combined with SDCBP silencing may provide a novel treatment for endocrine therapy-resistant BCa.
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Affiliation(s)
- Jun Zhang
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin 300060, China
| | - Xiaolong Qian
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin 300060, China
| | - Fangfang Liu
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin 300060, China
| | - Xiaojing Guo
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin 300060, China
| | - Feng Gu
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin 300060, China
| | - Li Fu
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin 300060, China
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Abstract
Viral-like nanovesicles of endosomal origin, or “exosomes,” are newly recognized vehicles of signals that cells use to communicate, in various systemic diseases, including cancer. Yet the molecular mechanisms that regulate the biogenesis and activity of exosomes remain obscure. Here, we establish that the oncogenic protein SRC stimulates the secretion of exosomes loaded with syntenin and syndecans, known co-receptors for a plethora of signaling and adhesion molecules. SRC phosphorylates conserved tyrosine residues in the syndecans and syntenin and stimulates their endosomal budding. Moreover, SRC-dependent exosomes have a promigratory activity that strictly depends on syntenin expression. This work sheds light on a function of SRC in cell-to-cell communication and mechanisms of exosome biogenesis and activity, with potential broad impact for physiopathology. The cytoplasmic tyrosine kinase SRC controls cell growth, proliferation, adhesion, and motility. The current view is that SRC acts primarily downstream of cell-surface receptors to control intracellular signaling cascades. Here we reveal that SRC functions in cell-to-cell communication by controlling the biogenesis and the activity of exosomes. Exosomes are viral-like particles from endosomal origin that can reprogram recipient cells. By gain- and loss-of-function studies, we establish that SRC stimulates the secretion of exosomes having promigratory activity on endothelial cells and that syntenin is mandatory for SRC exosomal function. Mechanistically, SRC impacts on syndecan endocytosis and on syntenin–syndecan endosomal budding, upstream of ARF6 small GTPase and its effector phospholipase D2, directly phosphorylating the conserved juxtamembrane DEGSY motif of the syndecan cytosolic domain and syntenin tyrosine 46. Our study uncovers a function of SRC in cell–cell communication, supported by syntenin exosomes, which is likely to contribute to tumor–host interactions.
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36
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Wang Y, Chen Y, Zhang Y, Wei W, Li Y, Zhang T, He F, Gao Y, Xu P. Multi-Protease Strategy Identifies Three PE2 Missing Proteins in Human Testis Tissue. J Proteome Res 2017; 16:4352-4363. [PMID: 28959888 DOI: 10.1021/acs.jproteome.7b00340] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Although 5 years of the missing proteins (MPs) study have been completed, searching for MPs remains one of the core missions of the Chromosome-Centric Human Proteome Project (C-HPP). Following the next-50-MPs challenge of the C-HPP, we have focused on the testis-enriched MPs by various strategies since 2015. On the basis of the theoretical analysis of MPs (2017-01, neXtProt) using multiprotease digestion, we found that nonconventional proteases (e.g. LysargiNase, GluC) could improve the peptide diversity and sequence coverage compared with Trypsin. Therefore, a multiprotease strategy was used for searching more MPs in the same human testis tissues separated by 10% SDS-PAGE, followed by high resolution LC-MS/MS system (Q Exactive HF). A total of 7838 proteins were identified. Among them, three PE2 MPs in neXtProt 2017-01 have been identified: beta-defensin 123 ( Q8N688 , chr 20q), cancer/testis antigen family 45 member A10 ( P0DMU9 , chr Xq), and Histone H2A-Bbd type 2/3 ( P0C5Z0 , chr Xq). However, because only one unique peptide of ≥9 AA was identified in beta-defensin 123 and Histone H2A-Bbd type 2/3, respectively, further analysis indicates that each falls under the exceptions clause of the HPP Guidelines v2.1. After a spectrum quality check, isobaric PTM and single amino acid variant (SAAV) filtering, and verification with a synthesized peptide, and based on overlapping peptides from different proteases, these three MPs should be considered as exemplary examples of MPs found by exceptional criteria. Other MPs were considered as candidates but need further validation. All MS data sets have been deposited to the ProteomeXchange with identifier PXD006465.
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Affiliation(s)
- Yihao Wang
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.,Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine , Beijing 100850, China
| | - Yang Chen
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China
| | - Yao Zhang
- State Key Laboratory of Biocontrol and Guangdong Provincial Key Laboratory of Plant Resources, College of Ecology and Evolution, Sun Yat-Sen University , Guangzhou 510275, China
| | - Wei Wei
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China
| | - Yanchang Li
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China
| | - Tao Zhang
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China
| | - Fuchu He
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China
| | - Yue Gao
- Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine , Beijing 100850, China
| | - Ping Xu
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.,Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, Wuhan University , Wuhan 430072, China.,Graduate School, Anhui Medical University , Hefei 230032, China.,Tianjin Baodi Hospital , Tianjin 301800, China
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Darwish S, Parang K, Marshall J, Goebel DJ, Tiwari R. Efficient synthesis of CN2097 using in situ activation of sulfhydryl group. Tetrahedron Lett 2017; 58:3053-3056. [PMID: 28824209 PMCID: PMC5557301 DOI: 10.1016/j.tetlet.2017.06.066] [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] [Indexed: 10/19/2022]
Abstract
CN2097 (R7Cs-sCYK[KTE(β-Ala)]V) is a rationally designed peptidomimetic that shows effectiveness in preclinical models for the treatment of neurological disorders, such as Angelman syndrome, traumatic brain injury (TBI) and stroke. Because of its therapeutic activity for the treatment of human CNS disorders, there was an urgent need to develop an efficient strategy for large-scale synthesis of CN2097. The synthesis of CN2097 was accomplished using Fmoc/tBu solid phase chemistry in multiple steps. Two different peptide fragments (activated polyarginine peptide Npys-sCR7 and CYK[KTE(β-Ala)]V) were synthesized, followed by solution phase coupling in water. Activation of the polyarginine (CR7) was achieved in situ during cleavage of protected peptide (C(Trt)R(Pbf)7) from the Rink amide resin using 5 equiv. of 2,2-dithopyridine in TFA:TIS:H2O (95:2.5:2.5, v/v/v) for 4 h. The disulfide coupling was efficient which provided a 60% yield.
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Affiliation(s)
- Shaban Darwish
- Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, California 92618, USA
- Organometallic and Organometalloid Chemistry Department, National Research Centre, El Bohouth st., Dokki, Giza, Egypt
| | - Keykavous Parang
- Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, California 92618, USA
| | - John Marshall
- Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, USA
| | - Dennis J Goebel
- Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, USA
| | - Rakesh Tiwari
- Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, California 92618, USA
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38
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Li Q, Tofaris GK, Davis JJ. Concentration-Normalized Electroanalytical Assaying of Exosomal Markers. Anal Chem 2017; 89:3184-3190. [PMID: 28192902 DOI: 10.1021/acs.analchem.6b05037] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Exosomes are both active in mediating intracellular communication and potentially present a potent cargo of disease biomarkers to an assay. The robust evaluation of exosomal markers could lead to a paradigm shift in clinical analysis and associated care. To date, much of this has been hindered by issues of sample preparation and assay signal-to-noise. We introduce here the use of ultrasensitive electrochemical impedance spectroscopy to quantify both external (tetraspanin) and internal (syntenin) exosome-specific markers. Associated exosome detection limits are 1.9 × 105 particles mL-1 (equivalent to 320 aM or 9500 exosomes in 50 μL) for intact exosomes and 3-5 picomolar for internal exosomal syntenin levels with almost 5 decades of linear dynamic range. Sample preparation can be carried out by simple fine filtering of cell-conditioned medium prior to a non-NTA-determined (i.e., nanoparticle tracking analysis) exosome concentration analysis, lysing, and subsequent internal syntenin quantification. Such concentration-normalized dual-marker analysis can be used to define "analytical zones" in a manner which is then independent of absolute exosome concentration and sample preparation.
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Affiliation(s)
- Qian Li
- Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford , South Parks Road, Oxford OX1 3QZ, United Kingdom
| | - George K Tofaris
- Nuffield Department of Clinical Neurosciences, University of Oxford , John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
| | - Jason J Davis
- Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford , South Parks Road, Oxford OX1 3QZ, United Kingdom
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39
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Choi Y, Yun JH, Yoo J, Lee I, Kim H, Son HN, Kim IS, Yoon HS, Zimmermann P, Couchman JR, Cho HS, Oh ES, Lee W. New structural insight of C-terminal region of Syntenin-1, enhancing the molecular dimerization and inhibitory function related on Syndecan-4 signaling. Sci Rep 2016; 6:36818. [PMID: 27830760 PMCID: PMC5103296 DOI: 10.1038/srep36818] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 10/17/2016] [Indexed: 12/15/2022] Open
Abstract
The PDZ domain-containing scaffold protein, syntenin-1, binds to the transmembrane proteoglycan, syndecan-4, but the molecular mechanism/function of this interaction are unknown. Crystal structure analysis of syntenin-1/syndecan-4 cytoplasmic domains revealed that syntenin-1 forms a symmetrical pair of dimers anchored by a syndecan-4 dimer. The syndecan-4 cytoplasmic domain is a compact intertwined dimer with a symmetrical clamp shape and two antiparallel strands forming a cavity within the dimeric twist. The PDZ2 domain of syntenin-1 forms a direct antiparallel interaction with the syndecan-4 cytoplasmic domain, inhibiting the functions of syndecan-4 such as focal adhesion formation. Moreover, C-terminal region of syntenin-1 reveals an essential role for enhancing the molecular homodimerization. Mutation of key syntenin-1 residues involved in the syndecan-4 interaction or homodimer formation abolishes the inhibitory function of syntenin-1, as does deletion of the homodimerization-related syntenin-1 C-terminal domain. Syntenin-1, but not dimer-formation-incompetent mutants, rescued the syndecan-4-mediated inhibition of migration and pulmonary metastasis by B16F10 cells. Therefore, we conclude that syntenin-1 negatively regulates syndecan-4 function via oligomerization and/or syndecan-4 interaction, impacting cytoskeletal organization and cell migration.
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Affiliation(s)
- Youngsil Choi
- Department of Life Sciences, Division of Life and Pharmaceutical Sciences and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea
| | - Ji-Hye Yun
- Department of Biochemistry, College of Life Science &Biotechnology, Yonsei University, Seoul 120-749, Korea
| | - Jiho Yoo
- Department of Biology, College of Life Science &Biotechnology, Yonsei University, Seoul 136-791, Republic of Korea
| | - Inhwan Lee
- Department of Biochemistry, College of Life Science &Biotechnology, Yonsei University, Seoul 120-749, Korea
| | - Heeyoun Kim
- Department of Biochemistry, College of Life Science &Biotechnology, Yonsei University, Seoul 120-749, Korea
| | - Hye-Nam Son
- Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea
| | - In-San Kim
- Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea
| | - Ho Sup Yoon
- Division of Structural and Computational Biology, School of Biological Sciences, Nanyang Technological University, Singapore.,Department of Genetic Engineering, College of Life Sciences, Kyung Hee University,Yongin-si Gyeonggi-do, 446-701, Republic of Korea
| | - Pascale Zimmermann
- Laboratory for Glycobiology, University of Leuven &Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium
| | - John R Couchman
- Department of Biomedical Sciences, University of Copenhagen, Biocenter, 2200 Copenhagen, Denmark
| | - Hyun-Soo Cho
- Department of Biology, College of Life Science &Biotechnology, Yonsei University, Seoul 136-791, Republic of Korea
| | - Eok-Soo Oh
- Department of Life Sciences, Division of Life and Pharmaceutical Sciences and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea
| | - Weontae Lee
- Department of Biochemistry, College of Life Science &Biotechnology, Yonsei University, Seoul 120-749, Korea
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40
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Wang LK, Pan SH, Chang YL, Hung PF, Kao SH, Wang WL, Lin CW, Yang SC, Liang CH, Wu CT, Hsiao TH, Hong TM, Yang PC. MDA-9/Syntenin-Slug transcriptional complex promote epithelial-mesenchymal transition and invasion/metastasis in lung adenocarcinoma. Oncotarget 2016; 7:386-401. [PMID: 26561205 PMCID: PMC4808006 DOI: 10.18632/oncotarget.6299] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 10/20/2015] [Indexed: 12/20/2022] Open
Abstract
Melanoma differentiation-associated gene-9 (MDA-9)/Syntenin is a novel therapeutic target because it plays critical roles in cancer progression and exosome biogenesis. Here we show that Slug, a key epithelial-mesenchymal-transition (EMT) regulator, is a MDA-9/Syntenin downstream target. Mitogen EGF stimulation increases Slug expression and MDA-9/Syntenin nuclear translocation. MDA-9/Syntenin uses its PDZ1 domain to bind with Slug, and this interaction further leads to HDAC1 recruitment, up-regulation of Slug transcriptional repressor activity, enhanced Slug-mediated EMT, and promotion of cancer invasion and metastasis. The PDZ domains and nuclear localization of MDA-9/Syntenin are both required for promoting Slug-mediated cancer invasion. Clinically, patients with high MDA-9/Syntenin and high Slug expressions were associated with poor overall survival compared to those with low expression in lung adenocarcinomas. Our findings provide evidence that MDA-9/Syntenin acts as a pivotal adaptor of Slug and it transcriptionally enhances Slug-mediated EMT to promote cancer invasion and metastasis.
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Affiliation(s)
- Lu-Kai Wang
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Szu-Hua Pan
- Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan.,Doctoral Degree Program of Translational Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yih-Leong Chang
- Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Pei-Fang Hung
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shih-Han Kao
- Research Center for Tumor Medical Science, China Medical University, Taichung, Taiwan
| | - Wen-Lung Wang
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ching-Wen Lin
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Shuenn-Chen Yang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chen-Hsien Liang
- Division of Isotope application, Institute of Nuclear Energy Research, Taoyuan, Taiwan
| | - Chen-Tu Wu
- Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tzu-Hung Hsiao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Tse-Ming Hong
- Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.,Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pan-Chyr Yang
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,NTU Center of Genomic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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Jana S, Sengupta S, Biswas S, Chatterjee A, Roy H, Bhattacharyya A. miR-216b suppresses breast cancer growth and metastasis by targeting SDCBP. Biochem Biophys Res Commun 2016; 482:126-133. [PMID: 27720715 DOI: 10.1016/j.bbrc.2016.10.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 10/02/2016] [Indexed: 12/26/2022]
Abstract
Breast cancer is the most deadly cancer among women and the second leading cause of cancer death worldwide. Treatment effectiveness is complicated with tumor invasiveness/drug resistance. To tailor treatments more effectively to individual patients, it is important to define tumor growth and metastasis at molecular levels. SDCBP is highly overexpressed and associated with a strikingly poor prognosis in breast cancer. However the post transcriptional regulation of SDCBP overexpression remains to be an unexplored area. Our study reveals that miR-216b directly regulates SDCBP expression by binding to its 3'UTR region. miR-216b is a tumor suppressive miRNA and it is underexpressed during metastatic breast cancer. Consequently, overexpression of miR-216b resulted in decreased proliferation, migration and invasion in BC cell lines by modulating the expression of SDCBP. Inhibition of miR-216b divergent the tumor suppressive role by inducing the growth proliferation, migration and invasion in vitro. There is therefore a negative correlation between the expression of miR-216b and its target gene SDCBP in the BC tissue samples as well as cell lines. Simultaneous expression of miR-216b and SDCBP rescued the growth, migration and invasion effect suggesting that tumor suppressive action of miR-216b may be directly mediated by SDCBP. In summary, the study identifies miR-216b as a regulator of SDCBP expression in breast cancer which can potentially be targeted for developing newer therapies for the effective treatment of this killer disease.
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Affiliation(s)
- Samir Jana
- Immunology Laboratory, Department of Zoology, University of Calcutta, 35. B.C.Road, Kolkata, 700019, India
| | - Suman Sengupta
- Immunology Laboratory, Department of Zoology, University of Calcutta, 35. B.C.Road, Kolkata, 700019, India
| | - Subir Biswas
- Immunology Laboratory, Department of Zoology, University of Calcutta, 35. B.C.Road, Kolkata, 700019, India
| | - Annesha Chatterjee
- Immunology Laboratory, Department of Zoology, University of Calcutta, 35. B.C.Road, Kolkata, 700019, India
| | - Himansu Roy
- Department of Surgery, Medical College, Kolkata, India
| | - Arindam Bhattacharyya
- Immunology Laboratory, Department of Zoology, University of Calcutta, 35. B.C.Road, Kolkata, 700019, India.
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High dimensional extension of the growth curve model and its application in genetics. STAT METHOD APPL-GER 2016. [DOI: 10.1007/s10260-016-0369-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Zhong D, Ran J, Zhang X, Tan Y, Chen G, Tang W, Li X, Wang B. Syntenin is expressed in human gliomas and may correlate with tumor migration. Arch Med Sci 2015; 11:1303-7. [PMID: 26788094 PMCID: PMC4697043 DOI: 10.5114/aoms.2015.49212] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Accepted: 03/18/2013] [Indexed: 11/28/2022] Open
Abstract
INTRODUCTION Invasion is usually recognized as the main reason for the high recurrence and death rates of gliomas. Therefore, properly understanding the molecular mechanisms of migration and invasion of human gliomas has become a focus and will be helpful for the treatment of gliomas. Syntenin has been demonstrated to be implicated in the migration, invasion and metastasis of many types of malignant tumors. Therefore, we investigated the expression of syntenin in human gliomas and its relationship with glioma migration. MATERIAL AND METHODS Immunohistochemistry, Western blot and real time-polymerase chain reaction (RT-PCR) were performed to detect the expression of syntenin in human gliomas. Phosphorylated FAK in human gliomas was examined by western blot. RESULTS Scattered syntenin positive glioma cells were detected by immunohistochemistry in normal tissue. Syntenin expression in grade II, III and IV gliomas increased with the degree of tumor malignancy, and no syntenin expression was detected in grade I gliomas. The level of phosphorylated FAK at the tyrosine 397 site also elevated with the degree of tumor malignancy. There was a positive correlation between the syntenin level and the pathological grade of gliomas (r s = 0.896, p < 0.05). Phosphorylated FAK was also upregulated along with the stage of glioma progression and the increase of syntenin expression. CONCLUSIONS Our results indicate that the enhanced expression of syntenin and phosphorylated FAK may correlate with the increase of the malignancy of human gliomas. Syntenin may promote human glioma migration through interaction with FAK.
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Affiliation(s)
- Dong Zhong
- Department of Neurosurgery, the 1 Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jianhua Ran
- Neuroscience Research Center, Chongqing Medical University, Chongqing, China
| | - Xiaodong Zhang
- Department of Neurosurgery, the 1 Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yun Tan
- Department of Neurosurgery, the 1 Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Guijie Chen
- Department of Neurosurgery, the 1 Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Wenyuan Tang
- Department of Neurosurgery, the 1 Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xiaosong Li
- Neuroscience Research Center, Chongqing Medical University, Chongqing, China
| | - Bing Wang
- Department of Neurosurgery, the 1 Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Kashyap R, Roucourt B, Lembo F, Fares J, Carcavilla AM, Restouin A, Zimmermann P, Ghossoub R. Syntenin controls migration, growth, proliferation, and cell cycle progression in cancer cells. Front Pharmacol 2015; 6:241. [PMID: 26539120 PMCID: PMC4612656 DOI: 10.3389/fphar.2015.00241] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Accepted: 10/07/2015] [Indexed: 11/25/2022] Open
Abstract
The scaffold protein syntenin abounds during fetal life where it is important for developmental movements. In human adulthood, syntenin gain-of-function is increasingly associated with various cancers and poor prognosis. Depending on the cancer model analyzed, syntenin affects various signaling pathways. We previously have shown that syntenin allows syndecan heparan sulfate proteoglycans to escape degradation. This indicates that syntenin has the potential to support sustained signaling of a plethora of growth factors and adhesion molecules. Here, we aim to clarify the impact of syntenin loss-of-function on cancer cell migration, growth, and proliferation, using cells from various cancer types and syntenin shRNA and siRNA silencing approaches. We observed decreased migration, growth, and proliferation of the mouse melanoma cell line B16F10, the human colon cancer cell line HT29 and the human breast cancer cell line MCF7. We further documented that syntenin controls the presence of active β1 integrin at the cell membrane and G1/S cell cycle transition as well as the expression levels of CDK4, Cyclin D2, and Retinoblastoma proteins. These data confirm that syntenin supports the migration and growth of tumor cells, independently of their origin, and further highlight the attractiveness of syntenin as potential therapeutic target.
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Affiliation(s)
- Rudra Kashyap
- Laboratory for Signal Integration in Cell Fate Decision, Department of Human Genetics, KU Leuven Leuven, Belgium ; Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université Marseille, France ; Inserm U1068, Institut Paoli-Calmettes Marseille, France ; Centre National de la Recherche Scientifique, UMR7258 Marseille, France
| | - Bart Roucourt
- Laboratory for Signal Integration in Cell Fate Decision, Department of Human Genetics, KU Leuven Leuven, Belgium
| | - Frederique Lembo
- Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université Marseille, France ; Inserm U1068, Institut Paoli-Calmettes Marseille, France ; Centre National de la Recherche Scientifique, UMR7258 Marseille, France
| | - Joanna Fares
- Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université Marseille, France ; Inserm U1068, Institut Paoli-Calmettes Marseille, France ; Centre National de la Recherche Scientifique, UMR7258 Marseille, France
| | - Ane Marcos Carcavilla
- Laboratory for Signal Integration in Cell Fate Decision, Department of Human Genetics, KU Leuven Leuven, Belgium
| | - Audrey Restouin
- Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université Marseille, France ; Inserm U1068, Institut Paoli-Calmettes Marseille, France ; Centre National de la Recherche Scientifique, UMR7258 Marseille, France
| | - Pascale Zimmermann
- Laboratory for Signal Integration in Cell Fate Decision, Department of Human Genetics, KU Leuven Leuven, Belgium ; Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université Marseille, France ; Inserm U1068, Institut Paoli-Calmettes Marseille, France ; Centre National de la Recherche Scientifique, UMR7258 Marseille, France
| | - Rania Ghossoub
- Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université Marseille, France ; Inserm U1068, Institut Paoli-Calmettes Marseille, France ; Centre National de la Recherche Scientifique, UMR7258 Marseille, France
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Philley JV, Kannan A, Dasgupta S. MDA-9/Syntenin Control. J Cell Physiol 2015; 231:545-50. [PMID: 26291527 DOI: 10.1002/jcp.25136] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 08/18/2015] [Indexed: 01/25/2023]
Abstract
MDA-9/Syntenin is a small PDZ domain containing scaffolding protein with diverse array of functions regulating membrane trafficking, cell adhesion, neural, and synaptic development, ubiquitination, and exosome biogenesis. An appreciable number of studies also established a pivotal role of MDA-9/Syntenin in cancer development and progression. In this review, we will discuss the dynamic role of MDA-9/Syntenin in regulating normal and abnormal fate of various cellular processes.
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Affiliation(s)
- Julie V Philley
- Department of Medicine, The University of Texas Health Science Center at Tyler, Tyler, Texas
| | - Anbarasu Kannan
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas
| | - Santanu Dasgupta
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas
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Bacolod MD, Das SK, Sokhi UK, Bradley S, Fenstermacher DA, Pellecchia M, Emdad L, Sarkar D, Fisher PB. Examination of Epigenetic and other Molecular Factors Associated with mda-9/Syntenin Dysregulation in Cancer Through Integrated Analyses of Public Genomic Datasets. Adv Cancer Res 2015; 127:49-121. [PMID: 26093898 DOI: 10.1016/bs.acr.2015.04.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
mda-9/Syntenin (melanoma differentiation-associated gene 9) is a PDZ domain containing, cancer invasion-related protein. In this study, we employed multiple integrated bioinformatic approaches to identify the probable epigenetic factors, molecular pathways, and functionalities associated with mda-9 dysregulation during cancer progression. Analyses of publicly available genomic data (e.g., expression, copy number, methylation) from TCGA, GEO, ENCODE, and Human Protein Atlas projects led to the following observations: (a) mda-9 expression correlates with both copy number and methylation level of an intronic CpG site (cg1719774) located downstream of the CpG island, (b) cg1719774 methylation is a likely prognostic marker in glioma, (c) among 22 cancer types, melanoma exhibits the highest mda-9 level, and lowest level of methylation at cg1719774, (d) cg1719774 hypomethylation is also associated with histone modifications (at the mda-9 locus) indicative of more active transcription, (e) using Gene Set Enrichment Analysis (GSEA), and the Virtual Gene Overexpression or Repression (VIGOR) analytical scheme, we were able to predict mda-9's association with extracellular matrix organization (e.g., MMPs, collagen, integrins), IGFBP2 and NF-κB signaling pathways, phospholipid metabolism, cytokines (e.g., interleukins), CTLA-4, and components of complement cascade pathways. Indeed, previous publications have shown that many of the aforementioned genes and pathways are associated with mda-9's functionality.
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Affiliation(s)
- Manny D Bacolod
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Upneet K Sokhi
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Steven Bradley
- VCU Bioinformatics Program, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - David A Fenstermacher
- VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; Department of Biostatistics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | | | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
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Hwangbo C, Tae N, Lee S, Kim O, Park OK, Kim J, Kwon SH, Lee JH. Syntenin regulates TGF-β1-induced Smad activation and the epithelial-to-mesenchymal transition by inhibiting caveolin-mediated TGF-β type I receptor internalization. Oncogene 2015; 35:389-401. [PMID: 25893292 DOI: 10.1038/onc.2015.100] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Revised: 01/12/2015] [Accepted: 02/16/2015] [Indexed: 01/14/2023]
Abstract
Syntenin, a tandem PDZ domain containing scaffold protein, functions as a positive regulator of cancer cell progression in several human cancers. We report here that syntenin positively regulates transforming growth factor (TGF)-β1-mediated Smad activation and the epithelial-to-mesenchymal transition (EMT) by preventing caveolin-1-mediated internalization of TGF-β type I receptor (TβRI). Knockdown of syntenin suppressed TGF-β1-mediated cell migration, transcriptional responses and Smad2/3 activation in various types of cells; however, overexpression of syntenin facilitated TGF-β1-mediated responses. In particular, syntenin knockdown abolished both the basal and TGF-β1-mediated repression of E-cadherin expression, as well as induction of vimentin expression along with Snail and Slug upregulation; thus, blocking the TGF-β1-induced EMT in A549 cells. In contrast, overexpression of syntenin exhibited the opposite effect. Knockdown of syntenin-induced ubiquitination and degradation of TβRI, but not TGF-β type II receptor, leading to decreased TβRI expression at the plasma membrane. Syntenin associated with TβRI at its C-terminal domain and a syntenin mutant lacking C-terminal domain failed to increase TGF-β1-induced responses. Biochemical analyzes revealed that syntenin inhibited the interaction between caveolin-1 and TβRI and knockdown of syntenin induced a massive internalization of TβRI and caveolin-1 from lipid rafts, indicating that syntenin may increase TGF-β signaling by inhibiting caveolin-1-dependent internalization of TβRI. Moreover, a positive correlation between syntenin expression and phospho-Smad2 levels is observed in human lung tumors. Taken together, these findings demonstrate that syntenin may act as an important positive regulator of TGF-β signaling by regulating caveolin-1-mediated internalization of TβRI; thus, providing a novel function for syntenin that is linked to cancer progression.
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Affiliation(s)
- C Hwangbo
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea
| | - N Tae
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea
| | - S Lee
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea
| | - O Kim
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea
| | - O K Park
- Division of Bio-imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon, Gangwon-Do, Republic of Korea
| | - J Kim
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea
| | - S-H Kwon
- Division of Bio-imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon, Gangwon-Do, Republic of Korea
| | - J-H Lee
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea
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Liu X, Zhang X, Lv Y, Xiang J, Shi J. Overexpression of syntenin enhances hepatoma cell proliferation and invasion: potential roles in human hepatoma. Oncol Rep 2014; 32:2810-2816. [PMID: 25242117 DOI: 10.3892/or.2014.3498] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 08/12/2014] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) ranks as the third leading cause of tumor-related mortality worldwide. Recently, syntenin was found to be upregulated in several tumors and to exert pivotal roles in the development of cancer. However, its function and the underlying mechanism in HCC remain to be defined. In the present study, the elevated expression levels of syntenin mRNA and protein were detected in four HCC cell lines. Overexpression of syntenin in hepatoma HCCLM3 cells enhanced cell proliferation. Furthermore, syntenin upregulation increased epidermal growth factor receptor (EGFR) expression, which accounted for syntenin‑induced cell proliferation as precondition with EGFR siRNA clearly attenuated cell proliferation in syntenin-transfected cells. At the same time, syntenin overexpression promoted cell invasion by MMP-2, as pretreatment with anti-MMP-2 antibody blocked syntenin-induced invading cell numbers. Additionally, syntenin upregulation induced the phosphorylation of p38 MAPK contributing to the increase in MMP-2 expression, as treatment with the specific inhibitor for p38 MAPK (SB203580) clearly abrogated MMP-2 expression induced by syntenin. Collectively, our results suggest that syntenin overexpression plays a critical role in promoting the proliferation and invasion of hepatoma cells. Therefore, the present study provides new insight into how syntenin accelerates the development and progression of hepatoma, and suggests that syntenin may be a promising therapeutic agent against hepatoma.
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Affiliation(s)
- Xuemin Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Xufeng Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Yi Lv
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Junxi Xiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Jianhua Shi
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
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Kegelman TP, Das SK, Emdad L, Hu B, Menezes ME, Bhoopathi P, Wang XY, Pellecchia M, Sarkar D, Fisher PB. Targeting tumor invasion: the roles of MDA-9/Syntenin. Expert Opin Ther Targets 2014; 19:97-112. [PMID: 25219541 DOI: 10.1517/14728222.2014.959495] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Melanoma differentiation-associated gene - 9 (MDA-9)/Syntenin has become an increasingly popular focus for investigation in numerous cancertypes. Originally implicated in melanoma metastasis, it has diverse cellular roles and is consistently identified as a regulator of tumor invasion and angiogenesis. As a potential target for inhibiting some of the most lethal aspects of cancer progression, further insight into the function of MDA-9/Syntenin is mandatory. AREAS COVERED Recent literature and seminal articles were reviewed to summarize the latest collective understanding of MDA-9/Syntenin's role in normal and cancerous settings. Insights into its participation in developmental processes are included, as is the functional significance of the N- and C-terminals and PDZ domains of MDA-9/Syntenin. Current reports highlight the clinical significance of MDA-9/Syntenin expression level in a variety of cancers, often correlating directly with reduced patient survival. Also presented are assessments of roles of MDA-9/Syntenin in cancer progression as well as its functions as an intracellular adapter molecule. EXPERT OPINION Multiple studies demonstrate the importance of MDA-9/Syntenin in tumor invasion and progression. Through the use of novel drug design approaches, this protein may provide a worthwhile therapeutic target. As many conventional therapies do not address, or even enhance, tumor invasion, an anti-invasive approach would be a worthwhile addition in cancer therapy.
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Affiliation(s)
- Timothy P Kegelman
- Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics , Richmond, VA , USA
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Kim WY, Jang JY, Jeon YK, Chung DH, Kim YG, Kim CW. Syntenin increases the invasiveness of small cell lung cancer cells by activating p38, AKT, focal adhesion kinase and SP1. Exp Mol Med 2014; 46:e90. [PMID: 24722482 PMCID: PMC3972791 DOI: 10.1038/emm.2014.1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Revised: 11/02/2013] [Accepted: 12/16/2013] [Indexed: 11/15/2022] Open
Abstract
Syntenin is a PDZ domain-containing adaptor protein that has been recently shown to regulate migration and invasion in several tumors. Small cell lung cancer (SCLC) is notorious for its invasiveness and strong potential for metastasis. We therefore studied the influence of syntenin on the invasiveness of SCLC. Immunohistochemistry in tumor tissues showed that syntenin was more frequently expressed in small cell carcinomas than other neuroendocrine tumors, such as carcinoids and neuroblastomas, suggesting that syntenin expression may be related to more aggressive forms of neuroendocrine tumors. In SCLC patients, syntenin overexpression in tumor cells was significantly associated with more extensive and advanced disease at the time of diagnosis (P=0.029). Overexpression of syntenin in SCLC cells that were intrinsically syntenin-low increased the invasiveness of cells and led to the induction of extracellular matrix (ECM)-degrading membrane type 1-matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase 2 (MMP2). In contrast, suppression of syntenin in syntenin-high cells was associated with the downregulation of MT1-MMP. Contrary to the results of previous studies using malignant melanomas and breast carcinomas, signaling cascades were shown to be further transduced through p38 MAPK and PI3K/AKT, with activation of SP1 rather than NF-κB, under circumstances not involving ECM interaction. In addition, the upstream molecule focal adhesion kinase was induced by syntenin activation, in spite of the absence of ECM interaction. These results suggest that syntenin might contribute to the invasiveness of SCLC and could be utilized as a new therapeutic target for controlling invasion and metastasis in SCLC.
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Affiliation(s)
- Wook Youn Kim
- 1] Department of Pathology, Seoul National University College of Medicine, Seoul, Korea [2] The Tumor Immunity Medical Research Center, Cancer Research Center, Seoul National University College of Medicine, Seoul, Korea [3] Department of Pathology, Konkuk University School of Medicine, Seoul, Korea
| | - Ji-young Jang
- The Tumor Immunity Medical Research Center, Cancer Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Yoon Kyung Jeon
- 1] Department of Pathology, Seoul National University College of Medicine, Seoul, Korea [2] The Tumor Immunity Medical Research Center, Cancer Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Doo Hyun Chung
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Young Goo Kim
- The Tumor Immunity Medical Research Center, Cancer Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Chul-Woo Kim
- 1] Department of Pathology, Seoul National University College of Medicine, Seoul, Korea [2] The Tumor Immunity Medical Research Center, Cancer Research Center, Seoul National University College of Medicine, Seoul, Korea
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