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Ruperti F, Dzieciatkowska M, Pankey MS, Asensio CS, Anselmetti D, Fernàndez-Busquets X, Nichols SA. Proteomic analysis of the sponge Aggregation Factor implicates an ancient toolkit for allorecognition and adhesion in animals. Proc Natl Acad Sci U S A 2024; 121:e2409125121. [PMID: 39693348 DOI: 10.1073/pnas.2409125121] [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: 05/07/2024] [Accepted: 11/12/2024] [Indexed: 12/20/2024] Open
Abstract
The discovery that sponges (Porifera) can fully regenerate from aggregates of dissociated cells launched them as one of the earliest experimental models to study the evolution of cell adhesion and allorecognition in animals. This process depends on an extracellular glycoprotein complex called the Aggregation Factor (AF), which is composed of proteins thought to be unique to sponges. We used quantitative proteomics to identify additional AF components and interacting proteins in the classical model, Clathria prolifera, and compared them to proteins involved in cell interactions in Bilateria. Our results confirm MAFp3/p4 proteins as the primary components of the AF but implicate related proteins with calx-beta and wreath domains as additional components. Using AlphaFold, we unveiled close structural similarities of AF components to protein domains in other animals, previously masked by the mutational decay of sequence similarity. The wreath domain, believed to be unique to the AF, was predicted to contain a central beta-sandwich of the same organization as the vWFD domain (also found in extracellular, gel-forming glycoproteins in other animals). Additionally, many copurified proteins share a conserved C-terminus, containing divergent immunoglobulin (Ig) and Fn3 domains predicted to serve as an AF-interaction interface. One of these proteins, MAF-associated protein 1, resembles Ig superfamily cell adhesion molecules and we hypothesize that it may function to link the AF to the surface of cells. Our results highlight the existence of an ancient toolkit of conserved protein domains regulating cell-cell and cell-extracellular matrix protein interactions in all animals, and likely reflect a common origin of cell adhesion and allorecognition.
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Affiliation(s)
- Fabian Ruperti
- Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
| | - Monika Dzieciatkowska
- Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045
| | - M Sabrina Pankey
- Department of Molecular, Cellular and Biomedical Science, University of New Hampshire, Durham, NH 03824
| | - Cedric S Asensio
- Department of Biological Sciences, University of Denver, Denver, CO 80208
| | - Dario Anselmetti
- Nanomalaria Group, Faculty of Physics, Experimental Biophysics, Bielefeld University, Bielefeld 33501, Germany
| | - Xavier Fernàndez-Busquets
- Nanomalaria Group, Barcelona Institute for Global Health, Hospital Clínic Universitat de Barcelona, Barcelona 08036, Spain
- Nanomalaria Group, Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology, Barcelona 08028, Spain
| | - Scott A Nichols
- Department of Biological Sciences, University of Denver, Denver, CO 80208
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Shi S, Ma HY, Sang YZ, Ju YB, Wang XG, Zhang ZG. CD147 expression as a clinicopathological and prognostic indicator in breast cancer: a meta-analysis and bioinformatics analysis. BMC Cancer 2024; 24:1429. [PMID: 39567919 PMCID: PMC11577919 DOI: 10.1186/s12885-024-13202-9] [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: 08/15/2024] [Accepted: 11/14/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND CD147 belongs to the immunoglobulin superfamily, also known as Basigin (BSG), and is a highly glycosylated single transmembrane glycoprotein present in various tissues. Meta and bioinformatic analyses were used to explore the correlation between CD147 expression and the clinicopathological characteristics prognosis of breast cancer. METHOD Literature related to breast cancer was retrieved through PubMed and CNKI databases, and a meta-analysis was conducted using Review Manager 5.2 software. RESULTS The meta-analysis revealed that all articles included data on 522 patients with breast cancer and 492 normal tissues. CD147 expression in breast cancer tissue was higher compared to that in normal tissue([8.92-139.52]; p < 0.00001 I2 = 80%) and negatively correlated with LM, clinical stage, histological grade, and ER positive expression. Bioinformatic analysis revealed that the expression of CD147 in breast cancer tissue was higher than that in normal tissue, and its high expression was closely related to the clinicopathological characteristics of patients, such as LM, histological grading, and clinical staging. According to the TIMER database, CD147 expression was closely related to immune cell infiltration in breast cancer. CONCLUSION These results indicated that high CD147 expression might be closely linked to the occurrence as well as the development of breast cancer, and can function as a good indicator of prognosis in the future, providing new methods and ideas for the prevention and treatment of breast cancer.
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Affiliation(s)
- Shuai Shi
- Department of Pathology, Cangzhou People's Hospital, 7 Qingchi Avenue, Cangzhou City, 061000, China
| | - Hong-Yan Ma
- Department of Pathology, Cangzhou People's Hospital, 7 Qingchi Avenue, Cangzhou City, 061000, China
| | - Yin-Zhou Sang
- Department of Pathology, Cangzhou People's Hospital, 7 Qingchi Avenue, Cangzhou City, 061000, China
| | - Ying-Bo Ju
- Department of Pathology, Cangzhou People's Hospital, 7 Qingchi Avenue, Cangzhou City, 061000, China
| | - Xing-Guang Wang
- Department of Pathology, Cangzhou People's Hospital, 7 Qingchi Avenue, Cangzhou City, 061000, China
| | - Zhi-Gang Zhang
- Department of Pathology, Cangzhou People's Hospital, 7 Qingchi Avenue, Cangzhou City, 061000, China.
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Chupradit K, Muneekaew S, Wattanapanitch M. Engineered CD147-CAR macrophages for enhanced phagocytosis of cancers. Cancer Immunol Immunother 2024; 73:170. [PMID: 38954079 PMCID: PMC11219683 DOI: 10.1007/s00262-024-03759-6] [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: 04/04/2024] [Accepted: 06/11/2024] [Indexed: 07/04/2024]
Abstract
Chimeric antigen receptor (CAR) T cell therapy has shown promising results in hematologic malignancies, but its effectiveness in solid cancers remains challenging. Macrophages are immune cells residing within the tumor microenvironment. They can phagocytose tumor cells. Recently, CAR macrophages (CAR-M) have been a promising candidate for treating solid cancers. One of the common cancer antigens overexpressed in various types of cancer is CD147. CAR-T and NK cells targeting CD147 antigen have shown significant efficacy against hepatocellular carcinoma. Nevertheless, CAR-M targeting the CD147 molecule has not been investigated. In this study, we generated CAR targeting the CD147 molecule using the THP-1 monocytic cell line (CD147 CAR-M). The CD147 CAR-M exhibited typical macrophage characteristics, including phagocytosis of zymosan bioparticles and polarization ability toward M1 and M2 phenotypes. Furthermore, the CD147 CAR-M demonstrated enhanced anti-tumor activity against K562 and MDA-MB-231 cells without exhibiting off-target cytotoxicity against normal cells. Our research provides valuable insights into the potential of CD147 CAR-M as a promising platform for cancer immunotherapy, with applications in both hematologic malignancies and solid cancers.
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Affiliation(s)
- Koollawat Chupradit
- Siriraj Center for Regenerative Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Saitong Muneekaew
- Siriraj Center for Regenerative Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Methichit Wattanapanitch
- Siriraj Center for Regenerative Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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Kanekura T. CD147/Basigin Is Involved in the Development of Malignant Tumors and T-Cell-Mediated Immunological Disorders via Regulation of Glycolysis. Int J Mol Sci 2023; 24:17344. [PMID: 38139173 PMCID: PMC10743398 DOI: 10.3390/ijms242417344] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/07/2023] [Accepted: 12/10/2023] [Indexed: 12/24/2023] Open
Abstract
CD147/Basigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is a multifunctional molecule with various binding partners. CD147 binds to monocarboxylate transporters (MCTs) and supports their expression on plasma membranes. MTC-1 and MCT-4 export the lactic acid that is converted from pyruvate in glycolysis to maintain the intracellular pH level and a stable metabolic state. Under physiological conditions, cellular energy production is induced by mitochondrial oxidative phosphorylation. Glycolysis usually occurs under anaerobic conditions, whereas cancer cells depend on glycolysis under aerobic conditions. T cells also require glycolysis for differentiation, proliferation, and activation. Human malignant melanoma cells expressed higher levels of MCT-1 and MCT-4, co-localized with CD147 on the plasma membrane, and showed an increased glycolysis rate compared to normal human melanocytes. CD147 silencing by siRNA abrogated MCT-1 and MCT-4 membrane expression and disrupted glycolysis, inhibiting cancer cell activity. Furthermore, CD147 is involved in psoriasis. MCT-1 was absent on CD4+ T cells in CD147-deficient mice. The naïve CD4+ T cells from CD147-deficient mice exhibited a low capacity to differentiate into Th17 cells. Imiquimod-induced skin inflammation was significantly milder in the CD147-deficient mice than in the wild-type mice. Overall, CD147/Basigin is involved in the development of malignant tumors and T-cell-mediated immunological disorders via glycolysis regulation.
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Affiliation(s)
- Takuro Kanekura
- Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
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Nyalali AMK, Leonard AU, Xu Y, Li H, Zhou J, Zhang X, Rugambwa TK, Shi X, Li F. CD147: an integral and potential molecule to abrogate hallmarks of cancer. Front Oncol 2023; 13:1238051. [PMID: 38023152 PMCID: PMC10662318 DOI: 10.3389/fonc.2023.1238051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
CD147 also known as EMMPRIN, basigin, and HAb18G, is a single-chain type I transmembrane protein shown to be overexpressed in aggressive human cancers of CNS, head and neck, breasts, lungs, gastrointestinal, genitourinary, skin, hematological, and musculoskeletal. In these malignancies, the molecule is integral to the diverse but complimentary hallmarks of cancer: it is pivotal in cancerous proliferative signaling, growth propagation, cellular survival, replicative immortality, angiogenesis, metabolic reprogramming, immune evasion, invasion, and metastasis. CD147 also has regulatory functions in cancer-enabling characteristics such as DNA damage response (DDR) and immune evasion. These neoplastic functions of CD147 are executed through numerous and sometimes overlapping molecular pathways: it transduces signals from upstream molecules or ligands such as cyclophilin A (CyPA), CD98, and S100A9; activates a repertoire of downstream molecules and pathways including matrix metalloproteinases (MMPs)-2,3,9, hypoxia-inducible factors (HIF)-1/2α, PI3K/Akt/mTOR/HIF-1α, and ATM/ATR/p53; and also functions as an indispensable chaperone or regulator to monocarboxylate, fatty acid, and amino acid transporters. Interestingly, induced loss of functions to CD147 prevents and reverses the acquired hallmarks of cancer in neoplastic diseases. Silencing of Cd147 also alleviates known resistance to chemoradiotherapy exhibited by malignant tumors like carcinomas of the breast, lung, pancreas, liver, gastric, colon, ovary, cervix, prostate, urinary bladder, glioblastoma, and melanoma. Targeting CD147 antigen in chimeric and induced-chimeric antigen T cell or antibody therapies is also shown to be safer and more effective. Moreover, incorporating anti-CD147 monoclonal antibodies in chemoradiotherapy, oncolytic viral therapy, and oncolytic virus-based-gene therapies increases effectiveness and reduces on and off-target toxicity. This study advocates the expedition and expansion by further exploiting the evidence acquired from the experimental studies that modulate CD147 functions in hallmarks of cancer and cancer-enabling features and strive to translate them into clinical practice to alleviate the emergency and propagation of cancer, as well as the associated clinical and social consequences.
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Affiliation(s)
- Alphonce M. K. Nyalali
- Department of Neurosurgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Surgery, Songwe Regional Referral Hospital, Mbeya, Tanzania
- Department of Orthopedics and Neurosurgery, Mbeya Zonal Referral Hospital and Mbeya College of Health and Allied Sciences, University of Dar Es Salaam, Mbeya, Tanzania
| | - Angela U. Leonard
- Department of Pediatrics and Child Health, Mbeya Zonal Referral Hospital and Mbeya College of Health and Allied Sciences, University of Dar Es Salaam, Mbeya, Tanzania
- Department of Public Health, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
| | - Yongxiang Xu
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Huayu Li
- School of Nursing and Rehabilitation, Shandong University, Jinan, China
| | - Junlin Zhou
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xinrui Zhang
- School of Nursing and Rehabilitation, Shandong University, Jinan, China
| | - Tibera K. Rugambwa
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Internal Medicine, Mbeya Zonal Referral Hospital and Mbeya College of Health and Allied Sciences, University of Dar Es Salaam, Mbeya, Tanzania
| | - Xiaohan Shi
- School of Nursing and Rehabilitation, Shandong University, Jinan, China
| | - Feng Li
- Department of Neurosurgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
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Xu YJ, He HJ, Wu P, Li WB. Expression patterns of cluster of differentiation 147 impact the prognosis of hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:1412-1423. [PMID: 37663949 PMCID: PMC10473926 DOI: 10.4251/wjgo.v15.i8.1412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/30/2023] [Accepted: 06/27/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) has very low overall survival. According to global cancer statistics, approximately 905677 new cases were reported in 2020, with at least 830180 of them being fatal. Cluster of differentiation 147 (CD147) is a novel, transmembrane glycoprotein that is expressed in a wide variety of tumor cells and plays an important role in various stages of tumor development. Based on the reports described previously, we theorize that CD147 may be used as a novel biological indicator to predict the prognosis of HCC. To study this possibility, expression profiles of CD147 and corresponding clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed, and a hazard ratio (HR) was established. AIM To explore the pattern of CD147 expression and its applicability in the prognosis of HCC. To establish HRs and probability points for predicting the prognosis of HCC by correlating CD147 expression with clinical characteristics. To determine if CD147 can be a reliable biomarker in HCC prognosis. METHODS The CD147 expression profile in HCC and corresponding clinical data were obtained from TCGA database. The expression patterns of CD147 were then validated by analyzing data from the GEO database. In addition, CD147 immunohistochemistry in HCC was obtained from the Human Protein Atlas. CD147 expression patterns and clinical characteristics in the prognosis of HCC were analyzed by accessing the UALCAN web resource. Accuracy, sensitivity, and specificity of the CD147 expression profile in predictive prognosis were determined by the time-dependent receiver operating characteristic (ROC) curves. Kaplan-Meier curves were plotted to estimate the HR of survival in HCC. Univariate and multivariate Cox regression proportional hazards analyses of CD147 expression levels and clinical characteristics as prognostic factors of HCC were performed. Nomograms were used to establish probability points and predict prognosis. RESULTS Data from TCGA and GEO databases revealed that CD147 was significantly overexpressed in HCC (P = 1.624 × 10-12 and P = 1.2 × 10-5, respectively). The expression of CD147 and prognosis of HCC were significantly correlated with the clinical characteristics of HCC as per the data from the UALCAN web resource (P < 0.05). Kaplan-Meier analysis of CD147 expression in HCC revealed that the high expression groups showed poor prognosis and an HR of survival > 1 [log-rank test, P = 0.000542, HR (in high expression group): 1.856, 95% confidence interval (CI): 1.308 to 2.636]. ROC curves were plotted to analyze the 1-year, 3-year, and 5-year survival rates. The area under the ROC curve values were 0.675 (95%CI: 0.611 to 0.740), 0.623 (95%CI: 0.555 to 0.692), and 0.664 (95%CI: 0.582 to 9.745), respectively. Univariate Cox analysis of CD147 expression and clinical characteristics of HCC and multivariate Cox analysis of CD147 patterns and pathological tumor-node-metastasis stage showed significant differences (univariate Cox, P = 0.00013, HR: 1.424, 95%CI: 1.884 to 1.707 and P = 0.00066, HR: 1.376, 95%CI: 1.145 to 1.654, respectively; multivariate Cox, P = 0.00578, HR: 1.507, 95%CI: 1.126 to 2.018 and P = 0.00336, HR: 1.443, 95%CI: 1.129 to 1.844, respectively). Nomograms were plotted to establish the probability points and predict prognosis. The total points ranged from 0 to 180, and the C-index value was 0.673 (95%CI: 0.600 to 1.000, P < 0.01). CONCLUSION Overexpression of CD147 was correlated with poor prognosis in HCC. The CD147 expression profile combined with clinical characteristics can reliably predict the prognosis of HCC. CD147 can serve as a biomarker to predict the prognosis of HCC.
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Affiliation(s)
- Yun-Ji Xu
- Department of General Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
| | - Hong-Jie He
- Department of General Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
| | - Peng Wu
- Department of General Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
| | - Wen-Bing Li
- Department of General Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
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Hao B, Beningo KA. Regulation of Traction Force through the Direct Binding of Basigin and Calpain 4. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.06.531406. [PMID: 36945510 PMCID: PMC10028868 DOI: 10.1101/2023.03.06.531406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
Traction force and mechanosensing (the ability to sense mechanical attributes of the environment) are two important factors used by a cell to modify behavior during migration. Previously it was determined that the calpain small subunit, calpain 4, regulates the production of traction force independent of its proteolytic holoenzyme. A proteolytic enzyme is formed by calpain4 binding to either of its catalytic partners, calpain 1 and 2. To further understand how calpain 4 regulates traction force, we used two-hybrid analysis to identify more components of the traction pathway. We discovered that basigin, an integral membrane protein and a documented matrix-metalloprotease (MMP) inducer binds to calpain 4 in two-hybrid and pull-down assays. Traction force was deficient when basigin was silenced in MEF cells, and defective in substrate adhesion strength. Consistent with Capn4 -/- MEF cells, the cells deficient in basigin responded to localized stimuli. Together these results implicate basigin in the pathway in which calpain 4 regulates traction force independent of the catalytic large subunits.
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Huang D, Rao D, Jin Q, Lai M, Zhang J, Lai Z, Shen H, Zhong T. Role of CD147 in the development and diagnosis of hepatocellular carcinoma. Front Immunol 2023; 14:1149931. [PMID: 37090718 PMCID: PMC10115957 DOI: 10.3389/fimmu.2023.1149931] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 03/28/2023] [Indexed: 04/25/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and the third leading cause of cancer-related deaths worldwide. HCC is characterized by insidious onset, and most patients are diagnosed at an advanced stage with a poor prognosis. Identification of biomarkers for HCC onset and progression is imperative to development of effective diagnostic and therapeutic strategies. CD147 is a glycoprotein that is involved in tumor cell invasion, metastasis and angiogenesis through multiple mechanisms. In this review, we describe the molecular structure of CD147 and its role in regulating HCC invasion, metastasis and angiogenesis. We highlight its potential as a diagnostic and therapeutic target for HCC.
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Affiliation(s)
- Defa Huang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Dingyu Rao
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Qing Jin
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Mi Lai
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Jiali Zhang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
| | - Zhonghong Lai
- Department of traumatology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Haibin Shen
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- *Correspondence: Haibin Shen, ; Tianyu Zhong,
| | - Tianyu Zhong
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- *Correspondence: Haibin Shen, ; Tianyu Zhong,
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Immunoreactivity of humanized single-chain variable fragment against its functional epitope on domain 1 of CD147. Sci Rep 2022; 12:6719. [PMID: 35468972 PMCID: PMC9038914 DOI: 10.1038/s41598-022-10657-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 04/11/2022] [Indexed: 11/08/2022] Open
Abstract
Domain 1 of CD147 participates in matrix metalloproteinase (MMP) production and is a candidate for targeted therapy to prevent cancer invasion and metastasis. A functional mouse anti-CD147 monoclonal antibody, M6-1B9, was found to recognize domain 1 of CD147, and its respective mouse single-chain variable fragment (ScFvM61B9) was subsequently generated. The EDLGS epitope candidate for M6-1B9 was identified using the phage display peptide technique in this study. For future clinical applications, humanized ScFv specific to domain 1 of CD147 (HuScFvM61B9) was partially adopted from the hypervariable sequences of parental mouse ScFvM61B9 and grafted onto suitable human immunoglobulin frameworks. Molecular modelling and simulation were performed in silico to generate the conformational structure of HuScFvM61B9. These results elucidated the amino acid residues that contributed to the interactions between CDRs and the epitope motif. The expressed HuScFvM61B9 specifically interacted with CD147 at the same epitope as the original mAb, M6-1B9, and retained immunoreactivity against CD147 in SupT1 cells. The reactivity of HuScFvM61B9 was confirmed using CD147 knockout Jurkat cells. In addition, the inhibitory effect of HuScFvM61B9 on OKT3-induced T-cell proliferation as M6-1B9 mAb was preserved. As domain 1 is responsible for cancer invasion and metastasis, HuScFvM61B9 would be a candidate for cancer targeted therapy in the future.
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Küsters N, Grupp K, Grass JK, Bachmann K, Ghadban T, Uzunoglu FG, Tachezy M, Perez D, Reeh M, Izbicki JR, Melling N. CD147 expression lacks prognostic relevance in esophageal cancer. J Cancer Res Clin Oncol 2022; 148:837-844. [PMID: 34997863 PMCID: PMC8930885 DOI: 10.1007/s00432-022-03917-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 01/04/2022] [Indexed: 12/02/2022]
Abstract
Introduction The role of CD147 as an important indicator of tumor prognosis remains controversially discussed in literature. We focused on the prognostic significance of CD147 expression in esophageal cancer patients. While some studies report that CD147 is an unfavorable prognostic factor in esophageal squamous cell carcinoma, others showed no significant correlation. However, only one study draws attention to the significance of CD147 in esophageal adenocarcinoma, which is one of the most rapidly increasing neoplasms in the western world. Methods To finally clarify the impact of CD147 as a prognostic factor, especially for esophageal adenocarcinomas, we analyzed CD147 expression in a tissue microarray of 359 esophageal adenocarcinomas and 254 esophageal squamous cell cancer specimens. For the immuno-histochemical analysis, we used a primary antibody specific for CD147. Staining intensity and proportion of positive tumor cells were scored (negative, weak, moderate, strong staining). These findings were compared to normal esophageal tissue and correlated to the histopathological tumor phenotype and survival data. Results CD147 expression was detectable in weak intensities in benign esophageal tissue (85.78%) and expressed in predominately moderate to strong intensities in esophageal cancer (88.34%). Strong CD147 immunostaining was linked to increased infiltration depth (p = 0.015) and differentiation (p = 0.016) in esophageal squamous cell cancer but revealed no significant correlation with histopathology of adenocarcinoma. Moreover, CD147 intensity was unrelated to overall survival in this collective for both subtypes of esophageal cancer. Conclusion Thus, our data show that CD147 has no prognostic value, neither in esophageal adenocarcinoma nor squamous cell carcinoma.
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Affiliation(s)
- Natalie Küsters
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Katharina Grupp
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julia-Kristin Grass
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kai Bachmann
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tarik Ghadban
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Faik G Uzunoglu
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Tachezy
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Daniel Perez
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Matthias Reeh
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R Izbicki
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nathaniel Melling
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Pishas KI, Cowley KJ, Pandey A, Hoang T, Beach JA, Luu J, Vary R, Smith LK, Shembrey CE, Rashoo N, White MO, Simpson KJ, Bild A, Griffiths JI, Cheasley D, Campbell I, Bowtell DDL, Christie EL. Phenotypic Consequences of SLC25A40-ABCB1 Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer. Cancers (Basel) 2021; 13:cancers13225644. [PMID: 34830797 PMCID: PMC8616176 DOI: 10.3390/cancers13225644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/05/2021] [Accepted: 11/05/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Among the plethora of malignancies affecting the female reproductive tract, those concerning the ovary are the most frequently fatal. In particular, chemotherapy-resistant High-Grade Serous Ovarian Cancer (HGSOC) remains a clinically intractable disease with a high rate of mortality. We previously identified SLC25A40-ABCB1 transcriptional fusions as the driving force behind drug resistance in HGSOC. As success in the clinical arena will only be achieved by enhancing our fundamental understanding of the drivers that mediate cellular drug resistance, this report sought to elucidate the phenotypic, metabolomic and transcriptional consequences of SLC25A40-ABCB1 fusions beyond drug resistance. High-throughput FDA drug screening was also undertaken to identify new therapeutic avenues against drug-resistant cellular populations. Abstract Despite high response rates to initial chemotherapy, the majority of women diagnosed with High-Grade Serous Ovarian Cancer (HGSOC) ultimately develop drug resistance within 1–2 years of treatment. We previously identified the most common mechanism of acquired resistance in HGSOC to date, transcriptional fusions involving the ATP-binding cassette (ABC) transporter ABCB1, which has well established roles in multidrug resistance. However, the underlying biology of fusion-positive cells, as well as how clonal interactions between fusion-negative and positive populations influences proliferative fitness and therapeutic response remains unknown. Using a panel of fusion-negative and positive HGSOC single-cell clones, we demonstrate that in addition to mediating drug resistance, ABCB1 fusion-positive cells display impaired proliferative capacity, elevated oxidative metabolism, altered actin cellular morphology and an extracellular matrix/inflammatory enriched transcriptional profile. The co-culture of fusion-negative and positive populations had no effect on cellular proliferation but markedly altered drug sensitivity to doxorubicin, paclitaxel and cisplatin. Finally, high-throughput screening of 2907 FDA-approved compounds revealed 36 agents that induce equal cytotoxicity in both pure and mixed ABCB1 fusion populations. Collectively, our findings have unraveled the underlying biology of ABCB1 fusion-positive cells beyond drug resistance and identified novel therapeutic agents that may significantly improve the prognosis of relapsed HGSOC patients.
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Affiliation(s)
- Kathleen I. Pishas
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.I.P.); (A.P.); (T.H.); (J.A.B.); (L.K.S.); (C.E.S.); (N.R.); (M.O.W.); (D.C.); (I.C.); (D.D.L.B.)
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia;
| | - Karla J. Cowley
- Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.J.C.); (J.L.); (R.V.)
| | - Ahwan Pandey
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.I.P.); (A.P.); (T.H.); (J.A.B.); (L.K.S.); (C.E.S.); (N.R.); (M.O.W.); (D.C.); (I.C.); (D.D.L.B.)
| | - Therese Hoang
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.I.P.); (A.P.); (T.H.); (J.A.B.); (L.K.S.); (C.E.S.); (N.R.); (M.O.W.); (D.C.); (I.C.); (D.D.L.B.)
| | - Jessica A. Beach
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.I.P.); (A.P.); (T.H.); (J.A.B.); (L.K.S.); (C.E.S.); (N.R.); (M.O.W.); (D.C.); (I.C.); (D.D.L.B.)
| | - Jennii Luu
- Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.J.C.); (J.L.); (R.V.)
| | - Robert Vary
- Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.J.C.); (J.L.); (R.V.)
| | - Lorey K. Smith
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.I.P.); (A.P.); (T.H.); (J.A.B.); (L.K.S.); (C.E.S.); (N.R.); (M.O.W.); (D.C.); (I.C.); (D.D.L.B.)
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia;
| | - Carolyn E. Shembrey
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.I.P.); (A.P.); (T.H.); (J.A.B.); (L.K.S.); (C.E.S.); (N.R.); (M.O.W.); (D.C.); (I.C.); (D.D.L.B.)
- Department of Clinical Pathology, Faculty of Medicine, Dentistry, and Health Science, The University of Melbourne, Melbourne, VIC 3000, Australia
| | - Nineveh Rashoo
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.I.P.); (A.P.); (T.H.); (J.A.B.); (L.K.S.); (C.E.S.); (N.R.); (M.O.W.); (D.C.); (I.C.); (D.D.L.B.)
| | - Madelynne O. White
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.I.P.); (A.P.); (T.H.); (J.A.B.); (L.K.S.); (C.E.S.); (N.R.); (M.O.W.); (D.C.); (I.C.); (D.D.L.B.)
| | - Kaylene J. Simpson
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia;
- Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.J.C.); (J.L.); (R.V.)
| | - Andrea Bild
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA; (A.B.); (J.I.G.)
| | - Jason I. Griffiths
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA; (A.B.); (J.I.G.)
| | - Dane Cheasley
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.I.P.); (A.P.); (T.H.); (J.A.B.); (L.K.S.); (C.E.S.); (N.R.); (M.O.W.); (D.C.); (I.C.); (D.D.L.B.)
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia;
| | - Ian Campbell
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.I.P.); (A.P.); (T.H.); (J.A.B.); (L.K.S.); (C.E.S.); (N.R.); (M.O.W.); (D.C.); (I.C.); (D.D.L.B.)
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia;
| | - David D. L. Bowtell
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.I.P.); (A.P.); (T.H.); (J.A.B.); (L.K.S.); (C.E.S.); (N.R.); (M.O.W.); (D.C.); (I.C.); (D.D.L.B.)
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia;
| | - Elizabeth L. Christie
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (K.I.P.); (A.P.); (T.H.); (J.A.B.); (L.K.S.); (C.E.S.); (N.R.); (M.O.W.); (D.C.); (I.C.); (D.D.L.B.)
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia;
- Correspondence:
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Kim HS, Kim HJ, Lee MR, Han I. EMMPRIN expression is associated with metastatic progression in osteosarcoma. BMC Cancer 2021; 21:1059. [PMID: 34565336 PMCID: PMC8474954 DOI: 10.1186/s12885-021-08774-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 09/10/2021] [Indexed: 11/10/2022] Open
Abstract
Background Extracellular matrix metalloproteinase inducer (EMMPRIN), a cell-surface glycoprotein, is overexpressed in several cancer types. EMMPRIN induces a metastatic phenotype by triggering the production of matrix metalloproteinase proteins (MMPs) such as MMP1 and MMP2, and vascular endothelial growth factor (VEGF) in cancer cells and the surrounding stromal cells. The purpose of this study was to investigate the expression and role of EMMPRIN in osteosarcoma. Methods The level of EMMPRIN expression was evaluated using reverse transcriptase polymerase chain reaction (RT-PCR) in 6 tumor-derived osteosarcoma cell lines and compared with that in normal osteoblasts. To study the prognostic significance of EMMPRIN expression, immunohistochemistry was carried out in prechemotherapy biopsies of 54 patients. siRNA knockdown of EMMPRIN in SaOS-2 cells was conducted to explore the role of EMMPRIN. To study the role of EMMPRIN in tumor-stromal interaction in MMP production and invasion, co-culture of SaOS-2 cells with osteoblasts and fibroblasts was performed. Osteosarcoma 143B cells were injected into the tail vein of BALB/c mice and lung metastasis was analyzed. Results EMMRIN mRNA expression was significantly higher in 5 of 6 (83%) tumor-derived cells than in MG63 cells. 90% of specimens (50/54) stained positive for EMMPRIN by immunohistochemistry, and higher expression of EMMPRIN was associated with shorter metastasis-free survival (p = 0.023). Co-culture of SaOS-2 with osteoblasts resulted in increased production of pro-MMP2 and VEGF expression, which was inhibited by EMMPRIN-targeting siRNA. siRNA knockdown of EMMPRIN resulted in decreased invasion. EMMPRIN shRNA-transfected 143B cells showed decreased lung metastasis in vivo. Conclusions Our data suggest that EMMPRIN acts as a mediator of osteosarcoma metastasis by regulating MMP and VEGF production in cancer cells as well as stromal cells. EMMPRIN could serve as a therapeutic target in osteosarcoma.
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Affiliation(s)
- Han-Soo Kim
- Department of Orthopaedic Surgery, Seoul National University Hospital, 101 Daehak-ro Jongno-gu, Seoul, 03080, South Korea.,Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Ha Jeong Kim
- Department of Orthopaedic Surgery, Seoul National University Hospital, 101 Daehak-ro Jongno-gu, Seoul, 03080, South Korea
| | - Mi Ra Lee
- Department of Orthopaedic Surgery, Seoul National University Hospital, 101 Daehak-ro Jongno-gu, Seoul, 03080, South Korea
| | - Ilkyu Han
- Department of Orthopaedic Surgery, Seoul National University Hospital, 101 Daehak-ro Jongno-gu, Seoul, 03080, South Korea. .,Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul, South Korea.
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Zhang C, Shen B, Chen X, Gao S, Ying X, Dong P. Identification of a prognostic 4-mRNA signature in laryngeal squamous cell carcinoma. J Cancer 2021; 12:5807-5816. [PMID: 34475994 PMCID: PMC8408111 DOI: 10.7150/jca.47557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/18/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignancy in the respiratory tract and could reduce the quality of life seriously like dyspnea, dysphonia and dysphagia. Moreover, 5-year survival rate has decreased over the past 40 years. This study was designed to identify mRNAs that related to prognosis in LSCC to enable early detection and outcome improvement. Methods: Gene expression profiles from Gene Expression Omnibus (GEO) (GSE59102, GSE84957) and The Cancer Genome Atlas (TCGA) were analyzed to identify differentially expressed genes (DEGs) with the help of bioinformatics tools. Functional enrichment analyses including Gene Ontology (GO) and pathway analysis were carried out to investigate the role of those genes and underlying molecular mechanisms in LSCC. Cox's regression analyses (univariate, LASSO and multivariate in order) were utilized to identify DEGs related with patients' overall survival and a 4-mRNA-based prognostic risk score model was established. Univariate and multivariate Cox's regression analyses were then performed on LSCC data (90 patients left) to identify independent predictors of OS, including the signature and clinicopathologic variables. The prognostic value of the gene signature was further validated and the genes were analyzed by GEPIA to get pan-cancer expression profiles. Results: 444 differentially expressed mRNAs (250 up-regulated, 194 down-regulated) were identified based on the threshold of fold change > 2 and adjusted p value < 0.05. Univariate Cox's regression analysis showed that high risk score (HR: 3.056, 95% confidence interval [CI]: 0.135-0.649, p<0.001) and female (HR: 0.296, 95% CI: 2.020-4.624, p=0.002) were associated with relatively poor prognosis. Further multivariate Cox's regression analysis indicated that risk score and gender were independent prognostic factors (p<0.05). The risk score model could stratify patients into high- and low‑risk groups, which presents significantly differential overall survival (p= 8.252e-04). The AUCs of 1-, 3- and 5-year OS were 0.724, 0.783 and 0.818, respectively. Conclusions: Our study provides evidence that the four-mRNA signature could serve as a biomarker to predict prognosis in LSCC, especially in long-term.
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Affiliation(s)
- Cheng Zhang
- Department of Otorhinolaryngology-head and neck surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Shen
- Department of Otorhinolaryngology-head and neck surgery, Shanghai General Hospital, Shanghai, China
| | - Xinwei Chen
- Department of Otorhinolaryngology-head and neck surgery, Shanghai General Hospital, Shanghai, China
| | - Shang Gao
- Department of Otorhinolaryngology-head and neck surgery, Shanghai General Hospital, Shanghai, China
| | - Xinjiang Ying
- Department of Otorhinolaryngology-head and neck surgery, Shanghai General Hospital, Shanghai, China
| | - Pin Dong
- Department of Otorhinolaryngology-head and neck surgery, Shanghai General Hospital, Shanghai, China
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Bu X, Qu X, Guo K, Meng X, Yang X, Huang Q, Dou W, Feng L, Wei X, Gao J, Sun W, Chao M, Han L, Hu Y, Shen L, Zhang J, Wang L. CD147 confers temozolomide resistance of glioma cells via the regulation of β-TrCP/Nrf2 pathway. Int J Biol Sci 2021; 17:3013-3023. [PMID: 34421346 PMCID: PMC8375226 DOI: 10.7150/ijbs.60894] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/29/2021] [Indexed: 01/15/2023] Open
Abstract
Background: Drug resistance is one of the biggest challenges in cancer therapy. temozolomide (TMZ) represents the most important chemotherapeutic option for glioma treatment. However, the therapeutic efficacy of TMZ remains very limited due to its frequent resistance in glioma, and the underlying mechanisms were not fully addressed. Herein, we demonstrate that the elevated expression of CD147 contributes to TMZ resistance in glioma cells, potentially through the post-translational regulation of Nrf2 expression. Methods: Cell-based assays of CD147 triggered drug resistance were performed through Edu-incorporation assay, CCK8 assay, TUNEL staining assay and flow cytometric assay. Luciferase reporter assay, protein stability related assays, co-immunoprecipitation assay were used to determine CD147 induction of Nrf2 expression through β-TrCP dependent ubiquitin system. Finally, the effect of the CD147/Nrf2 signaling on glioma progression and TMZ resistance were evaluated by functional experiments and clinical samples. Results: Based on the analysis of clinical glioma tissues, CD147 is highly expressed in glioma tissues and positively associated with tumor malignancy. Suppression of CD147 expression increased the inhibitory effect of TMZ on cell survival in both U251 and T98G cells, whereas the gain of CD147 function blocked TMZ-induced ROS production and cell death. Mechanistic study indicates that CD147 inhibited GSK3β/β-TrCP-dependent Nrf2 degradation by promoting Akt activation, and subsequently increased Nrf2-mediated anti-oxidant gene expressions. Supporting the biological significance, the reciprocal relationship between CD147 and Nrf2 was observed in glioma tissues, and associated with patient outcome. Conclusions: Our data provide the first evidence that glioma resistance to TMZ is potentially due to the activation of CD147/Nrf2 axis. CD147 promotes Nrf2 stability through the suppression of GSK3β/β-TrCP dependent Nrf2 protein degradation, which results in the ablation of TMZ induced ROS production. As such, we point out that targeting CD147/Nrf2 axis may provide a new strategy for the treatment of TMZ resistant gliomas.
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Affiliation(s)
- Xin Bu
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Xuan Qu
- Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Kai Guo
- Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Xiangliang Meng
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Xing Yang
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.,JingKai NO. 3 Middle School, Xi'an, 710200, China
| | - Qike Huang
- The 3rd Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Naval Medical University, Shanghai, 200438, China
| | - Wenjie Dou
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Lin Feng
- Basic Medical College, Jiamusi University, Jiamusi, 154002, China
| | - Xinxin Wei
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jiamusi University, Jiamusi, 154002, China
| | - Jiwei Gao
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China
| | - Wei Sun
- Department of Anorectal, the General Hospital of PLA Tibet Military Area Command, Lhasa, 850007, China
| | - Min Chao
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China
| | - Liying Han
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China
| | - Yaqin Hu
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China
| | - Liangliang Shen
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Jian Zhang
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Liang Wang
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China
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Zhou Z, Long J, Wang Y, Li Y, Zhang X, Tang L, Chang Q, Chen Z, Hu G, Hu S, Li Q, Peng C, Chen X. Targeted degradation of CD147 proteins in melanoma. Bioorg Chem 2020; 105:104453. [PMID: 33197849 DOI: 10.1016/j.bioorg.2020.104453] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 09/28/2020] [Accepted: 10/31/2020] [Indexed: 02/07/2023]
Abstract
CD147 is a transmembrane glycoprotein and a member of immunoglobulin superfamily, is strongly expressed in melanoma cells. CD147 has a pivotal role in tumor development. Therefore, it is a potential drug target for melanoma. In this article, we report the discovery of the first CD147 protein proteolysis targeting chimeras (PROTACs) derived from the natural product pseudolaric acid B (PAB). The representative compound 6a effectively induced degradation of CD147 and inhibited melanoma cells in vitro and in vivo. 6a could be used as the novel type of anticancer agent or as a part of the molecular biology research toolkit used in the gain-of-function study of the dynamic roles of CD147 in cancer networks.
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Affiliation(s)
- Zhe Zhou
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jing Long
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuan Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - YaYun Li
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xu Zhang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ling Tang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qi Chang
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - Zhuo Chen
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - GaoYun Hu
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - Shuo Hu
- Department of Nuclear Medicine, XiangYa Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Biological Nanotechnology of National Health Commission, Changsha, Hunan, China
| | - QianBin Li
- Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
| | - Cong Peng
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Xiang Chen
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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16
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Landras A, Mourah S. [CD147: role and therapeutic targeting of a promising molecule in the treatment of cancers]. Med Sci (Paris) 2020; 36 Hors série n° 1:47-49. [PMID: 33052094 DOI: 10.1051/medsci/2020196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Affiliation(s)
- Alexandra Landras
- Université de Paris, Inserm UMRS 976, Hôpital Saint-Louis, 75010 Paris, France
| | - Samia Mourah
- Université de Paris, Inserm UMRS 976, Hôpital Saint-Louis, 75010 Paris, France. - Département de Pharmacologie et Génomique des Tumeurs, APHP, Hôpital Saint-Louis, 75010 Paris, France
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17
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Tseng HC, Xiong W, Badeti S, Yang Y, Ma M, Liu T, Ramos CA, Dotti G, Fritzky L, Jiang JG, Yi Q, Guarrera J, Zong WX, Liu C, Liu D. Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma. Nat Commun 2020; 11:4810. [PMID: 32968061 PMCID: PMC7511348 DOI: 10.1038/s41467-020-18444-2] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 08/20/2020] [Indexed: 12/13/2022] Open
Abstract
Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3-synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3+CD147+), but not single antigen (GPC3-CD147+) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients.
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MESH Headings
- Animals
- Basigin/genetics
- Basigin/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Disease Models, Animal
- Female
- Hep G2 Cells
- Humans
- Immunotherapy, Adoptive/methods
- Killer Cells, Natural
- Liver/pathology
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Male
- Mice
- Mice, Knockout
- Mice, Transgenic
- Receptors, Chimeric Antigen/drug effects
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Hsiang-Chi Tseng
- Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA
| | - Wei Xiong
- Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center, Houston Methodist Research Institute, 6550 Fannin Street, SM8026, Houston, TX, 77030, USA
| | - Saiaditya Badeti
- Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA
| | - Yan Yang
- Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA
| | - Minh Ma
- Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA
| | - Ting Liu
- Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA
| | - Carlos A Ramos
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Gianpietro Dotti
- Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Luke Fritzky
- Imaging core facility, Rutgers University-New Jersey Medical School, 205 South Orange Avenue, Newark, NJ, 07103, USA
| | - Jie-Gen Jiang
- Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA
| | - Qing Yi
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center, Houston Methodist Research Institute, 6550 Fannin Street, SM8026, Houston, TX, 77030, USA
| | - James Guarrera
- Department of Surgery, New Jersey Medical School, Rutgers-The State University of New Jersey, 185 South Orange Avenue, Newark, NJ, 07101, USA
| | - Wei-Xing Zong
- School of Pharmacy, Rutgers-The State University of New Jersey, Newark, 164 Frelinghuysen Road Piscataway, NJ, 08854, USA
| | - Chen Liu
- Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA
| | - Dongfang Liu
- Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA.
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, 185 South Orange Avenue, Newark, NJ, 07101, USA.
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18
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Liu N, Qi M, Li K, Zeng W, Li J, Yin M, Liu H, Chen X, Zhang J, Peng C. CD147 regulates melanoma metastasis via the NFAT1-MMP-9 pathway. Pigment Cell Melanoma Res 2020; 33:731-743. [PMID: 32339381 DOI: 10.1111/pcmr.12886] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 04/11/2020] [Accepted: 04/22/2020] [Indexed: 12/20/2022]
Abstract
Although accumulating evidence had revealed that NFAT1 has oncogenic characteristics, the role of this molecule in melanoma cells remains unclear. Previous studies proved that CD147 plays a crucial function in melanoma cell metastasis and invasion through matrix metalloproteinase 9 (MMP-9) expression; however, the details of how CD147 regulates MMP-9 expression remain elusive. In this study, we demonstrated that CD147 and NFAT1 are overexpressed in the tissues of patients with primary and metastatic melanoma, which has shown a positive correlation. Further, we observed that CD147 regulates NFAT1 activation through the [Ca2+ ]i-calcineurin pathway. Knockdown of NFAT1 significantly suppresses melanoma metastasis, and we demonstrated that CD147 affects melanoma metastasis in an NFAT1-dependent manner. Moreover, we verified that NFAT1 directly binds to MMP-9 promoter. Inhibition of CD147 expression significantly abrogates MMP-9 promoter luciferase gene reporter activity as well as NFAT1 association with MMP-9 promoter. Taken together, this study demonstrated that CD147 affects MMP-9 expression through regulating NFAT1 activity and provided a novel mechanism by which NFAT1 contributes to melanoma metastasis through the regulation of MMP-9.
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Affiliation(s)
- Nian Liu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, China.,Human Engineering Research Center of Skin Health and Disease, Changsha, China
| | - Min Qi
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Keke Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, China.,Human Engineering Research Center of Skin Health and Disease, Changsha, China
| | - Weiqi Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, China.,Human Engineering Research Center of Skin Health and Disease, Changsha, China
| | - Jiaoduan Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, China.,Human Engineering Research Center of Skin Health and Disease, Changsha, China
| | - Mingzhu Yin
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, China.,Human Engineering Research Center of Skin Health and Disease, Changsha, China
| | - Hong Liu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, China.,Human Engineering Research Center of Skin Health and Disease, Changsha, China
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, China.,Human Engineering Research Center of Skin Health and Disease, Changsha, China
| | - JiangLin Zhang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, China.,Human Engineering Research Center of Skin Health and Disease, Changsha, China
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, China.,Human Engineering Research Center of Skin Health and Disease, Changsha, China
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19
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Wang S, Ma F, Feng Y, Liu T, He S. Role of exosomal miR‑21 in the tumor microenvironment and osteosarcoma tumorigenesis and progression (Review). Int J Oncol 2020; 56:1055-1063. [PMID: 32319566 DOI: 10.3892/ijo.2020.4992] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 02/07/2020] [Indexed: 11/06/2022] Open
Abstract
Osteosarcoma is the most common bone tumor affecting both adolescents and children. Early detection is critical for the effective treatment of the disease. Derived from cancer cells, miR‑21 contained within exosomes in the tumor microenvironment may act on both cancer cells and the surrounding tumor microenvironment (TME), including immune cells, endothelial cells and fibroblasts. In human serum and plasm, the level of exosomal miR‑21 between osteosarcoma patients and healthy controls differs, supporting the role of miR‑21 as a biomarker for osteosarcoma. The involvement of a number of miR‑21 target genes in tumor progression suggests that miR‑21 may significantly affect the plasticity of cancer cells, leading to tumor progression, metastasis, angiogenesis and immune escape in osteosarcoma. Understanding the biogenesis and functions of exosomal miR‑21 is of great value for the diagnosis and therapy of cancer, including osteosarcoma. The present review discusses the role of miR‑21 in the tumor microenvironment, and in the development and progression of osteosarcoma, with an aim to summarize the functions of this miRNA in cancer.
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Affiliation(s)
- Shoufeng Wang
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Fang Ma
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Yi Feng
- Ovarian Cancer Research, Perelman School of Medicine, University of Pennsylvania, Philadephia, PA 19104, USA
| | - Tang Liu
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Shasha He
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China
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20
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Zhang X, Huang Z, Guo Y, Xiao T, Tang L, Zhao S, Wu L, Su J, Zeng W, Huang H, Li Z, Tao J, Zhou J, Chen X, Peng C. The phosphorylation of CD147 by Fyn plays a critical role for melanoma cells growth and metastasis. Oncogene 2020; 39:4183-4197. [PMID: 32291412 DOI: 10.1038/s41388-020-1287-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 03/24/2020] [Accepted: 03/26/2020] [Indexed: 12/14/2022]
Abstract
CD147, also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a transmembrane glycoprotein that is highly expressed in tumor cells, particularly melanoma cells, and plays critical roles in tumor cell metastasis through the regulation of matrix metalloprotease (MMP) expression. In this study, we identified Fyn as a novel interacting protein of CD147. Fyn is a member of the Src family of nonreceptor tyrosine kinases that regulates diverse physiological processes, such as T lymphocyte differentiation, through the TCR signaling pathway. Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Two phosphospecific antibodies against Y140 and Y183 were developed to validate the phosphorylation of CD147 by Fyn. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment. In addition, CD147-FF significantly blocked MMP-9 expression as well as cell migration. Moreover, we found that Fyn is overexpressed in clinical melanoma tissues as well as in melanoma cell lines. Knockdown of Fyn expression markedly attenuated the malignant phenotype of melanoma cells in vitro and in vivo through downregulation of CD147 phosphorylation, indicating that Fyn/CD147 is a potential target molecule in melanoma treatment. Finally, through virtual screening, we identified amodiaquine as a potential inhibitor targeting the Fyn/CD147 axis. Amodiaquine treatment dramatically inhibited the phosphorylation of CD147 by Fyn, thus attenuating melanoma cell growth and invasion in vitro and in vivo, suggesting that amodiaquine is a promising inhibitor for melanoma treatment.
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Affiliation(s)
- Xu Zhang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zunnan Huang
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Research Platform Service Management Center, Guangdong Medical University, Dongguan, 523808, Guangdong, China
| | - Yeye Guo
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ta Xiao
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ling Tang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shuang Zhao
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lisha Wu
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Juan Su
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Weiqi Zeng
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hongbin Huang
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Research Platform Service Management Center, Guangdong Medical University, Dongguan, 523808, Guangdong, China
| | - Zheng Li
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Juan Tao
- Department of Dermatology, Affiliated Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianda Zhou
- Department of Plastic Surgery of Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiang Chen
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Cong Peng
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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21
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Tomonobu N, Kinoshita R, Sakaguchi M. S100 Soil Sensor Receptors and Molecular Targeting Therapy Against Them in Cancer Metastasis. Transl Oncol 2020; 13:100753. [PMID: 32193075 PMCID: PMC7078545 DOI: 10.1016/j.tranon.2020.100753] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/25/2020] [Accepted: 02/27/2020] [Indexed: 12/12/2022] Open
Abstract
The molecular mechanisms underlying the ‘seed and soil’ theory are unknown. S100A8/A9 (a heterodimer complex of S100A8 and S100A9 proteins that exhibits a ‘soil signal’) is a ligand for Toll-like receptor 4, causing distant melanoma cells to approach the lung as a ‘seeding’ site. Unknown soil sensors for S100A8/A9 may exist, e.g., extracellular matrix metalloproteinase inducer, neuroplastin, activated leukocyte cell adhesion molecule, and melanoma cell adhesion molecule. We call these receptor proteins ‘novel S100 soil sensor receptors (novel SSSRs).’ Here we review and summarize a crucial role of the S100A8/A9-novel SSSRs' axis in cancer metastasis. The binding of S100A8/A9 to individual SSSRs is important in cancer metastasis via upregulations of the epithelial-mesenchymal transition, cellular motility, and cancer cell invasiveness, plus the formation of an inflammatory immune suppressive environment in metastatic organ(s). These metastatic cellular events are caused by the SSSR-featured signal transductions we identified that provide cancer cells a driving force for metastasis. To deprive cancer cells of these metastatic forces, we developed novel biologics that prevent the interaction of S100A8/A9 with SSSRs, followed by the efficient suppression of S100A8/A9-mediated lung-tropic metastasis in vivo.
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Affiliation(s)
- Nahoko Tomonobu
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama 700-8558, Japan.
| | - Rie Kinoshita
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama 700-8558, Japan.
| | - Masakiyo Sakaguchi
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama 700-8558, Japan.
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22
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Colangelo NW, Azzam EI. Extracellular vesicles originating from glioblastoma cells increase metalloproteinase release by astrocytes: the role of CD147 (EMMPRIN) and ionizing radiation. Cell Commun Signal 2020; 18:21. [PMID: 32033611 PMCID: PMC7006136 DOI: 10.1186/s12964-019-0494-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 12/04/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Glioblastoma multiforme is an aggressive primary brain tumor that is characterized by local invasive growth and resistance to therapy. The role of the microenvironment in glioblastoma invasiveness remains unclear. While carcinomas release CD147, a protein that signals for increased matrix metalloproteinase (MMP) release by fibroblasts, glioblastoma does not have a significant fibroblast component. We hypothesized that astrocytes release MMPs in response to CD147 contained in glioblastoma-derived extracellular vesicles (EVs) and that ionizing radiation, part of the standard treatment for glioblastoma, enhances this release. METHODS Astrocytes were incubated with EVs released by irradiated or non-irradiated human glioblastoma cells wild-type, knockdown, or knockout for CD147. Levels of CD147 in glioblastoma EVs and MMPs secreted by astrocytes were quantified. Levels of proteins in the mitogen activated protein kinase (MAPK) pathway, which can be regulated by CD147, were measured in astrocytes incubated with EVs from glioblastoma cells wild-type or knockdown for CD147. Immunofluorescence was performed on the glioblastoma cells to identify changes in CD147 localization in response to irradiation, and to confirm uptake of the EVs by astrocytes. RESULTS Immunoblotting and mass spectrometry analyses showed that CD147 levels in EVs were transiently increased when the EVs were from glioblastoma cells that were irradiated with γ rays. Specifically, the highly-glycosylated 45 kDa form of CD147 was preferentially present in the EVs relative to the cells themselves. Immunofluorescence demonstrated that astrocytes incorporate glioblastoma EVs and subsequently increase their secretion of active MMP9. The increase was greater if the EVs were from irradiated glioblastoma cells. Testing MAPK pathway activation, which also regulates MMP expression, showed that JNK signaling, but not ERK1/2 or p38, was increased in astrocytes incubated with EVs from irradiated compared to non-irradiated glioblastoma cells. Knockout of CD147 in glioblastoma cells blocked the increased JNK signaling and the rise in secreted active MMP9 levels. CONCLUSIONS The results support a tumor microenvironment-mediated role of CD147 in glioblastoma invasiveness, and reveal a prominent role for ionizing radiation in enhancing the effect. They provide an improved understanding of glioblastoma intercellular signaling in the context of radiotherapy, and identify pathways that can be targeted to reduce tumor invasiveness. Video abstract.
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Affiliation(s)
- Nicholas W. Colangelo
- Rutgers Biomedical and Health Sciences, New Jersey Medical School, Department of Radiology, 205 South Orange Avenue - Room, Newark, NJ 07103 USA
| | - Edouard I. Azzam
- Rutgers Biomedical and Health Sciences, New Jersey Medical School, Department of Radiology, 205 South Orange Avenue - Room, Newark, NJ 07103 USA
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23
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Landras A, Reger de Moura C, Jouenne F, Lebbe C, Menashi S, Mourah S. CD147 Is a Promising Target of Tumor Progression and a Prognostic Biomarker. Cancers (Basel) 2019; 11:cancers11111803. [PMID: 31744072 PMCID: PMC6896083 DOI: 10.3390/cancers11111803] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 11/13/2019] [Accepted: 11/13/2019] [Indexed: 12/18/2022] Open
Abstract
Microenvironment plays a crucial role in tumor development and progression. Cancer cells modulate the tumor microenvironment, which also contribute to resistance to therapy. Identifying biomarkers involved in tumorigenesis and cancer progression represents a great challenge for cancer diagnosis and therapeutic strategy development. CD147 is a glycoprotein involved in the regulation of the tumor microenvironment and cancer progression by several mechanisms—in particular, by the control of glycolysis and also by its well-known ability to induce proteinases leading to matrix degradation, tumor cell invasion, metastasis and angiogenesis. Accumulating evidence has demonstrated the role of CD147 expression in tumor progression and prognosis, suggesting it as a relevant tumor biomarker for cancer diagnosis and prognosis, as well as validating its potential as a promising therapeutic target in cancers.
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Affiliation(s)
- Alexandra Landras
- INSERM UMRS 976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), University of Paris, 75010 Paris, France; (A.L.); (C.R.d.M.); (F.J.); (C.L.); (S.M.)
| | - Coralie Reger de Moura
- INSERM UMRS 976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), University of Paris, 75010 Paris, France; (A.L.); (C.R.d.M.); (F.J.); (C.L.); (S.M.)
- Pharmacogenomics Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint Louis Hospital, 75010 Paris, France
| | - Fanelie Jouenne
- INSERM UMRS 976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), University of Paris, 75010 Paris, France; (A.L.); (C.R.d.M.); (F.J.); (C.L.); (S.M.)
- Pharmacogenomics Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint Louis Hospital, 75010 Paris, France
| | - Celeste Lebbe
- INSERM UMRS 976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), University of Paris, 75010 Paris, France; (A.L.); (C.R.d.M.); (F.J.); (C.L.); (S.M.)
- Dermatology Department and Centre d’Investigation Clinique (CIC), Assistance Publique-Hôpitaux de Paris (AP-HP), Saint Louis Hospital, 75010 Paris, France
| | - Suzanne Menashi
- INSERM UMRS 976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), University of Paris, 75010 Paris, France; (A.L.); (C.R.d.M.); (F.J.); (C.L.); (S.M.)
- Pharmacogenomics Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint Louis Hospital, 75010 Paris, France
| | - Samia Mourah
- INSERM UMRS 976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), University of Paris, 75010 Paris, France; (A.L.); (C.R.d.M.); (F.J.); (C.L.); (S.M.)
- Pharmacogenomics Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint Louis Hospital, 75010 Paris, France
- Correspondence: ; Tel.: +33-1-42-49-48-85
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24
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Lai TM, Kuo PJ, Lin CY, Chin YT, Lin HL, Chiu HC, Fu MMJ, Fu E. CD147 self-regulates matrix metalloproteinase-2 release in gingival fibroblasts after coculturing with U937 monocytic cells. J Periodontol 2019; 91:651-660. [PMID: 31557319 DOI: 10.1002/jper.19-0278] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 08/11/2019] [Accepted: 08/26/2019] [Indexed: 01/17/2023]
Abstract
BACKGROUND Cluster of differentiation 147 (CD147) is a multifunctional glycoprotein that functions as an inducer of matrix metalloproteinase (MMP) expression in fibroblasts. Synergistically enhanced MMP-2 expression was recently observed in the coculture of human gingival fibroblasts (HGFs) and U937 human monocytic cells; however, the responsible mechanisms have not yet been fully established. The aim of this study was to evaluate the release of soluble CD147 in HGFs after coculturing with U937 cells and its functional effect on the enhancement of MMP-2 expression in HGFs. METHODS Enzyme-linked immunosorbent assay was used to determine the amount of CD147 protein in media, whereas real-time polymerase chain reaction was performed to evaluate the mRNA levels of CD147 and MMP-2 in HGFs and U937 cells. The enzyme activities of MMP-2 released from cells were examined by zymography. Transwell coculturing and conditioned media treatments were selected to rule out the effect of direct contact of HGFs and U937 cells. RESULTS The protein and mRNA expression of CD147 in HGFs were enhanced after transwell coculturing with U937 cells and exposure to U937-conditioned medium. MMP-2 enzyme activities in HGFs were also significantly increased by the coculturing methods. Administration of exogenous CD147 enhanced MMP-2 expression in HGFs, whereas treatment with cyclosporine-A, which inhibited CD147 expression, reduced U937-enhanced MMP-2 expression in HGFs. CONCLUSIONS CD147 can interact with fibroblasts to stimulate the expression of MMPs associated with periodontal extracellular matrix degradation. This study has demonstrated that CD147 released from fibroblasts might play a role in monocyte-enhanced MMP-2 expression in HGFs.
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Affiliation(s)
- Tat-Ming Lai
- Dental Department, Cardinal Tien Hospital, New Taipei City, Taiwan
| | - Po-Jan Kuo
- Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan
| | - Chi-Yu Lin
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.,Center for Teeth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan
| | - Yu-Tang Chin
- Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
| | - Hsiao-Lun Lin
- Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan
| | - Hsien-Chung Chiu
- Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan
| | - Martin M J Fu
- Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan
| | - Earl Fu
- Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.,Department of Dentistry, Taipei Tzu Chi Hospital, New Taipei City, Taiwan
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25
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Aoki M, Koga K, Miyazaki M, Hamasaki M, Koshikawa N, Oyama M, Kozuka-Hata H, Seiki M, Toole BP, Nabeshima K. CD73 complexes with emmprin to regulate MMP-2 production from co-cultured sarcoma cells and fibroblasts. BMC Cancer 2019; 19:912. [PMID: 31510956 PMCID: PMC6739984 DOI: 10.1186/s12885-019-6127-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 09/03/2019] [Indexed: 12/14/2022] Open
Abstract
Background Interaction between cancer cells and fibroblasts mediated by extracellular matrix metalloproteinase inducer (emmprin, CD147) is important in the invasion and proliferation of cancer cells. However, the exact mechanism of emmprin mediated stimulation of matrix metalloprotease-2 (MMP-2) production from fibroblasts has not been elucidated. Our previous studies using an inhibitory peptide against emmprin suggested the presence of a molecule on the cell membrane which forms a complex with emmprin. Here we show that CD73 expressed on fibroblasts interacts with emmprin and is a required factor for MMP-2 production in co-cultures of sarcoma cells with fibroblasts. Methods CD73 along with CD99 was identified by mass spectrometry analysis as an emmprin interacting molecule from a co-culture of cancer cells (epithelioid sarcoma cell line FU-EPS-1) and fibroblasts (immortalized fibroblasts cell line ST353i). MMP-2 production was measured by immunoblot and ELISA. The formation of complexes of CD73 with emmprin was confirmed by immunoprecipitation, and their co-localization in tumor cells and fibroblasts was shown by fluorescent immunostaining and proximity ligation assays. Results Stimulated MMP-2 production in co-culture of cancer cells and fibroblasts was completely suppressed by siRNA knockdown of CD73, but not by CD99 knockdown. MMP-2 production was not suppressed by CD73-specific enzyme inhibitor (APCP). However, MMP-2 production was decreased by CD73 neutralizing antibodies, suggesting that CD73-mediated suppression of MMP-2 production is non-enzymatic. In human epithelioid sarcoma tissues, emmprin was immunohistochemically detected to be mainly expressed in tumor cells, and CD73 was expressed in fibroblasts and tumor cells: emmprin and CD73 were co-localized predominantly on tumor cells. Conclusion This study provides a novel insight into the role of CD73 in emmprin-mediated regulation of MMP-2 production.
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Affiliation(s)
- M Aoki
- Department of Pathology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - K Koga
- Department of Pathology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - M Miyazaki
- Department of Pathology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - M Hamasaki
- Department of Pathology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - N Koshikawa
- Division of Cancer Cell Research, Kanagawa Cancer Center Research Institute, Yokohama, Japan.,Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - M Oyama
- Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - H Kozuka-Hata
- Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - M Seiki
- Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - B P Toole
- Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, USA
| | - K Nabeshima
- Department of Pathology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
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26
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Wang S, Li M, Xing L, Yu J. High expression level of peptidylprolyl isomerase A is correlated with poor prognosis of liver hepatocellular carcinoma. Oncol Lett 2019; 18:4691-4702. [PMID: 31611978 PMCID: PMC6781733 DOI: 10.3892/ol.2019.10846] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 08/20/2019] [Indexed: 12/19/2022] Open
Abstract
Peptidylprolyl isomerase A (PPIA) has been reported to be correlated with cancer. The present study investigated the prognostic values of PPIA expression levels in cancer by comparing different types of cancer using databases. High expression levels of PPIA were observed in 17 out of 17 cancer types compared with normal adjacent tissues. High expression levels of PPIA were associated with decreased overall survival in low grade glioma, acute myeloid leukemia, lung adenocarcinoma, skin cutaneous melanoma and liver hepatocellular carcinoma (LIHC). The prognostic effect of PPIA expression in LIHC was independent of tumor grade. High expression levels of PPIA were of particular prognostic value in stage 3, American Joint Committee on Cancer Tumor 3, hepatitis B virus negative and sorafenib-administered subgroups in LIHC. The expression level of PPIA was significantly associated with levels of basigin and signal transducer and activator of transcription 3, which may be major effectors of PPIA in the progression of the cancer.
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Affiliation(s)
- Shilong Wang
- Department of Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.,Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong 250117, P.R. China
| | - Minghuan Li
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong 250117, P.R. China.,Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Ligang Xing
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong 250117, P.R. China.,Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong 250117, P.R. China.,Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
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27
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Kumar D, Vetrivel U, Parameswaran S, Subramanian KK. Structural insights on druggable hotspots in CD147: A bull's eye view. Life Sci 2019; 224:76-87. [DOI: 10.1016/j.lfs.2019.03.044] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/11/2019] [Accepted: 03/19/2019] [Indexed: 12/13/2022]
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28
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Wu XD, Zhang MY, Chen YT, Yao H, Zhang Q, Wang WJ, Fu DF, Wei RJ, Zhang JY, Li Y, Dang D, Bian HJ, Xu J, Chen ZN. Generation and Characterization of Fibroblast-Specific Basigin Knockout Mice. Mol Biotechnol 2019; 61:111-121. [PMID: 30539414 DOI: 10.1007/s12033-018-0141-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Basigin is a well-known extracellular stimulator of fibroblasts and may confer resistance to apoptosis of fibroblasts in vitro under some pathological status, but its exact function in fibroblasts and the underlying mechanism remain poorly understood. The systematic Basigin gene knockout leads to the perinatal lethality of mice, which limits the delineation of its function in vivo. In this study, we generated a fibroblast-specific Basigin knock-out mouse model and demonstrated the successful deletion of Basigin in fibroblasts. The fibroblast-specific deletion of Basigin did not influence the growth, fertility and the general condition of the mice. No obvious differences were found in the size, morphology, and histological structure of the major organs, including heart, liver, spleen, lung and kidney, between the knockout mice and the control mice. The deletion of Basigin in fibroblasts did not induce apoptosis in the tissues of the major organs. These results provide the first evidence that the fibroblast-specific Basigin knock-out mice could be a useful tool for exploring the function of Basigin in fibroblasts in vivo.
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Affiliation(s)
- Xiao-Dong Wu
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an, 710032, China.,Center of Anesthesiology & Operation, Chinese PLA General Hospital, Beijing, 100853, China
| | - Meng-Yao Zhang
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an, 710032, China.,Beijing Institute of Biotechnology, Beijing, 100071, China
| | - Ya-Tong Chen
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an, 710032, China
| | - Hui Yao
- Department of Radiation Oncology, The First Peoples' Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, 213000, China
| | - Qing Zhang
- Institute of Liver Surgery, General Hospital of Chinese People's Armed Police Forces, Beijing, 100039, China
| | - Wen-Jing Wang
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an, 710032, China
| | - Da-Fu Fu
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an, 710032, China
| | - Ren-Ji Wei
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an, 710032, China
| | - Jia-Yu Zhang
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an, 710032, China
| | - Yin Li
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an, 710032, China
| | - Dan Dang
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an, 710032, China
| | - Hui-Jie Bian
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an, 710032, China
| | - Jing Xu
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an, 710032, China.
| | - Zhi-Nan Chen
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an, 710032, China.
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29
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Guindolet D, Gabison EE. Role of CD147 (EMMPRIN/Basigin) in Tissue Remodeling. Anat Rec (Hoboken) 2019; 303:1584-1589. [DOI: 10.1002/ar.24089] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 10/31/2018] [Accepted: 11/07/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Damien Guindolet
- Fondation Ophtalmologique A. de Rothschild 25 rue Manin, 75019, Paris France
| | - Eric E. Gabison
- Fondation Ophtalmologique A. de Rothschild 25 rue Manin, 75019, Paris France
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30
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Bojić-Trbojević Ž, Jovanović Krivokuća M, Vilotić A, Kolundžić N, Stefanoska I, Zetterberg F, Nilsson UJ, Leffler H, Vićovac L. Human trophoblast requires galectin-3 for cell migration and invasion. Sci Rep 2019; 9:2136. [PMID: 30765738 PMCID: PMC6376043 DOI: 10.1038/s41598-018-38374-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 12/20/2018] [Indexed: 12/12/2022] Open
Abstract
Invasive extravillous cytotrophoblast of the human placenta expresses galectins-1, -3, and -8 in vivo and in vitro. This study aimed to investigate the potential role of galectin-3 in cell migration and invasion, using recombinant human galectin-3 (rhgalectin-3), small molecule galectin inhibitor I47, and galectin-3 silencing. HTR-8/SVneo cell migration was stimulated by rhgalectin-3 and reduced by I47, which could be neutralised by rhgalectin-3. Inhibitor specificity and selectivity for the galectins expressed in extravillous trophoblast were validated in solid phase assays using recombinant galectin-1, -3, -8, confirming selectivity for galectin-3. HTR-8/SVneo cell migration and invasion, and invasion by isolated trophoblast cells in primary culture were significantly reduced in the presence of I47, which could be restored by rhgalectin-3. Upon HTR-8/SVneo cell treatment with galectin-3 siRNA both LGALS3 and galectin-3 protein were dramatically decreased. Silencing of galectin-3 induced significant reduction in cell migration and invasion, which was restored by rhgalectin-3. The influence on known mediators of cell invasion, MMP2 and -9, and integrins α1, α5, and β1 was followed in silenced cells, showing lower levels of MMPs and a large reduction in integrin subunit β1. These results show that galectin-3 acts as a pro-invasive autocrine/paracrine factor in trophoblast in vitro.
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Affiliation(s)
- Ž Bojić-Trbojević
- Laboratory for Biology of Reproduction, Institute for the Application of Nuclear Energy, University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia
| | - M Jovanović Krivokuća
- Laboratory for Biology of Reproduction, Institute for the Application of Nuclear Energy, University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia
| | - A Vilotić
- Laboratory for Biology of Reproduction, Institute for the Application of Nuclear Energy, University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia
| | - N Kolundžić
- Laboratory for Biology of Reproduction, Institute for the Application of Nuclear Energy, University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia.,King's College London, Faculty of Life Sciences & Medicine, Department of Women & Children's Health, Guy's Hospital, London SE1 9RT, London, United Kingdom
| | - I Stefanoska
- Laboratory for Biology of Reproduction, Institute for the Application of Nuclear Energy, University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia
| | - F Zetterberg
- Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8A, 413 46, Gothenburg, Sweden
| | - U J Nilsson
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University, POB 124, SE-22100, Lund, Sweden
| | - H Leffler
- Section MIG, Department of Laboratory Medicine Lund University, BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden
| | - Lj Vićovac
- Laboratory for Biology of Reproduction, Institute for the Application of Nuclear Energy, University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia.
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31
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Rai A, Greening DW, Chen M, Xu R, Ji H, Simpson RJ. Exosomes Derived from Human Primary and Metastatic Colorectal Cancer Cells Contribute to Functional Heterogeneity of Activated Fibroblasts by Reprogramming Their Proteome. Proteomics 2019; 19:e1800148. [PMID: 30582284 DOI: 10.1002/pmic.201800148] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 12/05/2018] [Indexed: 12/18/2022]
Abstract
Cancer-associated fibroblasts (CAFs) are a heterogeneous population of activated fibroblasts that constitute a dominant cellular component of the tumor microenvironment (TME) performing distinct functions. Here, the role of tumor-derived exosomes (Exos) in activating quiescent fibroblasts into distinct functional subtypes is investigated. Proteomic profiling and functional dissection reveal that early- (SW480) and late-stage (SW620) colorectal cancer (CRC) cell-derived Exos both activated normal quiescent fibroblasts (α-SMA- , CAV+ , FAP+ , VIM+ ) into CAF-like fibroblasts (α-SMA+ , CAV- , FAP+ , VIM+ ). Fibroblasts activated by early-stage cancer-exosomes (SW480-Exos) are highly pro-proliferative and pro-angiogenic and display elevated expression of pro-angiogenic (IL8, RAB10, NDRG1) and pro-proliferative (SA1008, FFPS) proteins. In contrast, fibroblasts activated by late-stage cancer-exosomes (SW620-Exos) display a striking ability to invade through extracellular matrix through upregulation of pro-invasive regulators of membrane protrusion (PDLIM1, MYO1B) and matrix-remodeling proteins (MMP11, EMMPRIN, ADAM10). Conserved features of Exos-mediated fibroblast activation include enhanced ECM secretion (COL1A1, Tenascin-C/X), oncogenic transformation, and metabolic reprogramming (downregulation of CAV-1, upregulation of glycogen metabolism (GAA), amino acid biosynthesis (SHMT2, IDH2) and membrane transporters of glucose (GLUT1), lactate (MCT4), and amino acids (SLC1A5/3A5)). This study highlights the role of primary and metastatic CRC tumor-derived Exos in generating phenotypically and functionally distinct subsets of CAFs that may facilitate tumor progression.
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Affiliation(s)
- Alin Rai
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
| | - David W Greening
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
| | - Maoshan Chen
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
| | - Rong Xu
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
| | - Hong Ji
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
| | - Richard J Simpson
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
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32
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Peng C, Chen X. CD147 Is a Novel Chemotherapy or Prevention Target in Melanoma. J Investig Dermatol Symp Proc 2018; 19:S91-S93. [PMID: 30471763 DOI: 10.1016/j.jisp.2018.10.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
CD147, also named as BSG, was first identified from F9 embryonal carcinoma cells (Miyauchi et al., 1990) and the human BSG locus on chromosome 19p13.3 containing 10 exons (Belton et al., 2008; Kaname et al., 1993; Liao et al., 2011), which encodes four alternatively spliced transcripts:CD147/Bsg-1,2,3,4 (Kaname et al., 1993; Liao et al., 2011). Bsg-1 has three Ig-like domains (CD147/Bsg-1) (Hanna et al., 2003; Ochrietor et al., 2003), while CD147/Bsg-3,4 contains a single Ig-like domain (Belton et al., 2008; Liao et al., 2011). Evidence shows that CD147/Bsg-2 is the most abundant and best characterized splice product, which contains two Ig-like domains (Weidle et al., 2010). Analysis of amino acids showed that CD147 contains a single-chain type I transmembrane domain composed of a 21-amino acid signal sequence, an extracellular domain consisting of 186 amino acids with two Ig-like domains and a cytoplasmic domain of 41 residues (Kanekura et al., 2010; Yurchenko et al., 2005). There are three glycosylation sites at three conserved asparagine (Asn 44, 152, and 186) in the CD147 N-terminal domain (Fadool et al., 1993; Tang et al., 2004; Yu et al., 2006), which could explain the molecular mass of CD147 shifts from a predicted molecular weight of about 27 kDa to 40-65 kDa with Western blotting. Inhibition of glycosylation by specific inhibitors showed that on carbohydrate side groups bearing β-1,6-branched, polylactosamine-type sugars, fucosylations are the major glycosylation type in N-glycosylation of CD147 (Ni et al., 2014; Riethdorf et al., 2006; Tang et al., 2004). In addition, N-glycosylation of CD147 has been identified as low glycosylated (approximately 32 kDa) or high glycosylated (approximately 45-65 kDa). The fully glycosylated mature CD147 (high-glycosylated CD147) is translocated to the plasma membrane, while low-glycosylated CD147 is the precursor of high-glycosylated CD147 in the endoplasmic reticulum, which requires additional modification in the Golgi prior to being expressed on the cell surface; high levels of glycosylation are a primary biochemical property of CD147 (Jia et al., 2006; Jiang et al., 2014; Ni et al., 2014; Tang et al., 2004).
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Affiliation(s)
- Cong Peng
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Xiang Chen
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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33
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Updegraff BL, Zhou X, Guo Y, Padanad MS, Chen PH, Yang C, Sudderth J, Rodriguez-Tirado C, Girard L, Minna JD, Mishra P, DeBerardinis RJ, O'Donnell KA. Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism. Cell Rep 2018; 25:2223-2233.e6. [PMID: 30463017 PMCID: PMC6338450 DOI: 10.1016/j.celrep.2018.10.100] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 07/04/2018] [Accepted: 10/25/2018] [Indexed: 01/19/2023] Open
Abstract
Pathways underlying metabolic reprogramming in cancer remain incompletely understood. We identify the transmembrane serine protease TMPRSS11B as a gene that promotes transformation of immortalized human bronchial epithelial cells (HBECs). TMPRSS11B is upregulated in human lung squamous cell carcinomas (LSCCs), and high expression is associated with poor survival of non-small cell lung cancer patients. TMPRSS11B inhibition in human LSCCs reduces transformation and tumor growth. Given that TMPRSS11B harbors an extracellular (EC) protease domain, we hypothesized that catalysis of a membrane-bound substrate modulates tumor progression. Interrogation of a set of soluble receptors revealed that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporter MCT4. Basigin release mediated by TMPRSS11B enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. These findings establish an oncogenic role for TMPRSS11B and provide support for the development of therapies that target this enzyme at the surface of cancer cells.
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Affiliation(s)
- Barrett L Updegraff
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA
| | - Xiaorong Zhou
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Department of Immunology, Nantong University School of Medicine, Nantong 226001, China
| | - Yabin Guo
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Mahesh S Padanad
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA
| | - Pei-Hsuan Chen
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Chendong Yang
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jessica Sudderth
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Carla Rodriguez-Tirado
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA
| | - Luc Girard
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA
| | - John D Minna
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA
| | - Prashant Mishra
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ralph J DeBerardinis
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Kathryn A O'Donnell
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
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34
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Preisner F, Leimer U, Sandmann S, Zoernig I, Germann G, Koellensperger E. Impact of Human Adipose Tissue-Derived Stem Cells on Malignant Melanoma Cells in An In Vitro Co-culture Model. Stem Cell Rev Rep 2018; 14:125-140. [PMID: 29064018 DOI: 10.1007/s12015-017-9772-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
This study focuses on the interactions of human adipose tissue-derived stem cells (ADSCs) and malignant melanoma cells (MMCs) with regard to future cell-based skin therapies. The aim was to identify potential oncological risks as ADSCs could unintentionally be sited within the proximity of the tumor microenvironment of MMCs. An indirect co-culture model was used to analyze interactions between ADSCs and four different established melanoma cell lines (G-361, SK-Mel-5, MeWo and A2058) as well as two low-passage primary melanoma cell cultures (M1 and M2). Doubling time, migration and invasion, angiogenesis, quantitative real-time PCR of 229 tumor-associated genes and multiplex protein assays of 20 chemokines and growth factors and eight matrix metalloproteinases (MMPs) were evaluated. Co-culture with ADSCs significantly increased migration capacity of G-361, SK-Mel-5, A2058, MeWo and M1 and invasion capacity of G-361, SK-Mel-5 and A2058 melanoma cells. Furthermore, conditioned media from all ADSC-MMC-co-cultures induced tube formation in an angiogenesis assay in vitro. Gene expression analysis of ADSCs and MMCs, especially of low-passage melanoma cell cultures, revealed an increased expression of various genes with tumor-promoting activities, such as CXCL12, PTGS2, IL-6, and HGF upon ADSC-MMC-co-culture. In this context, a significant increase (up to 5,145-fold) in the expression of numerous tumor-associated proteins could be observed, e.g. several pro-angiogenic factors, such as VEGF, IL-8, and CCL2, as well as different matrix metalloproteinases, especially MMP-2. In conclusion, the current report clearly demonstrates that a bi-directional crosstalk between ADSCs and melanoma cells can enhance different malignant properties of melanoma cells in vitro.
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Affiliation(s)
- Fabian Preisner
- ETHIANUM - Clinic for Plastic, Aesthetic and Reconstructive Surgery, Spine, Orthopedic and Hand Surgery, Preventive Medicine, Voßstraße 6, 69115, Heidelberg, Germany
| | - Uwe Leimer
- ETHIANUM - Clinic for Plastic, Aesthetic and Reconstructive Surgery, Spine, Orthopedic and Hand Surgery, Preventive Medicine, Voßstraße 6, 69115, Heidelberg, Germany
| | - Stefanie Sandmann
- ETHIANUM - Clinic for Plastic, Aesthetic and Reconstructive Surgery, Spine, Orthopedic and Hand Surgery, Preventive Medicine, Voßstraße 6, 69115, Heidelberg, Germany
| | - Inka Zoernig
- Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Im Neuenheimer Feld 460, 60120, Heidelberg, Germany
| | - Guenter Germann
- ETHIANUM - Clinic for Plastic, Aesthetic and Reconstructive Surgery, Spine, Orthopedic and Hand Surgery, Preventive Medicine, Voßstraße 6, 69115, Heidelberg, Germany
| | - Eva Koellensperger
- ETHIANUM - Clinic for Plastic, Aesthetic and Reconstructive Surgery, Spine, Orthopedic and Hand Surgery, Preventive Medicine, Voßstraße 6, 69115, Heidelberg, Germany.
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35
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Hu X, Su J, Zhou Y, Xie X, Peng C, Yuan Z, Chen X. Repressing CD147 is a novel therapeutic strategy for malignant melanoma. Oncotarget 2018; 8:25806-25813. [PMID: 28445958 PMCID: PMC5421970 DOI: 10.18632/oncotarget.15709] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 01/22/2017] [Indexed: 12/21/2022] Open
Abstract
CD147/basigin, a transmembrane protein, is a member of the immunoglobulin super family. Accumulating evidence has revealed the role of CD147 in the development and progression of various cancers, including malignant melanoma (MM). MM is a malignancy of pigment-producing cells that causes the greatest number of skin cancer-related deaths worldwide. CD147 is overexpressed in MM and plays an important role in cell viability, apoptosis, proliferation, invasion, and metastasis, probably by mediating vascular endothelial growth factor (VEGF) production, glycolysis, and multi-drug resistance (MDR). As a matrix metalloproteinase (MMP) inducer, CD147 could also promote surrounding fibroblasts to secrete abundant MMPs to further stimulate tumor cell invasion. Targeting CD147 has been shown to suppress MM in vitro and in vivo, highlighting the therapeutic potential of CD147 silencing in MM treatment. In this review article, we discuss CD147 and its biological roles, regulatory mechanisms, and potential application as a molecular target for MM.
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Affiliation(s)
- Xing Hu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
| | - Juan Su
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
| | - Youyou Zhou
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyun Xie
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
| | - Zhimin Yuan
- Department of Genetics and Complex Diseases, Harvard T.H Chan School of Public Health, Boston, MA, USA
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
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36
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Matsumoto T, Nagashio R, Ryuge S, Igawa S, Kobayashi M, Fukuda E, Goshima N, Ichinoe M, Jiang SX, Satoh Y, Masuda N, Murakumo Y, Saegusa M, Sato Y. Basigin expression as a prognostic indicator in stage I pulmonary adenocarcinoma. Pathol Int 2018; 68:232-240. [PMID: 29431238 DOI: 10.1111/pin.12646] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 01/09/2018] [Indexed: 02/06/2023]
Abstract
We established the KU-Lu-8 monoclonal antibody (MoAb) using a lung cancer cell line as an antigen and a random immunization method. The KU-Lu-8 MoAb recognizes basigin (BSG), which is a transmembrane-type glycoprotein that is strongly expressed on the cell membranes of lung cancer cells. This study aimed to clarify the relationships between BSG expression and clinicopathological parameters and determine the prognostic significance of BSG expression in pulmonary adenocarcinoma (AC) patients. To evaluate the significance of BSG expression in lung cancer, we immunohistochemically analyzed 113 surgically resected pulmonary adenocarcinomas, and the associations between BSG expression and various clinicopathological parameters were evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to investigate the effects of BSG expression on survival. Clinicopathologically, BSG expression was significantly associated with tumor differentiation, vascular invasion, lymphatic invasion, and a poor prognosis. In particular, BSG expression was significantly correlated with poorer survival in patients with stage I AC. The high BSG expression group (compared with the low BSG expression group) exhibited adjusted hazard ratios for mortality of 4.694. BSG expression is indicative of a poor prognosis in AC patients, particularly in those with stage I disease.
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Affiliation(s)
- Toshihide Matsumoto
- Department of Pathology, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Ryo Nagashio
- Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University, Kanagawa, Japan
| | - Shinichiro Ryuge
- Department of Respiratory Medicine, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Satoshi Igawa
- Department of Respiratory Medicine, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Makoto Kobayashi
- Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University, Kanagawa, Japan
| | - Eriko Fukuda
- Division of Quantitative Proteomics Team, Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
| | - Naoki Goshima
- Division of Quantitative Proteomics Team, Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
| | - Masaaki Ichinoe
- Department of Pathology, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Shi-Xu Jiang
- Department of Pathology, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Yukitoshi Satoh
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Noriyuki Masuda
- Department of Respiratory Medicine, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Yoshiki Murakumo
- Department of Pathology, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Makoto Saegusa
- Department of Pathology, School of Medicine, Kitasato University, Kanagawa, Japan
| | - Yuichi Sato
- Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University, Kanagawa, Japan
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Extracellular Matrix Metalloproteinase Inducer EMMPRIN (CD147) in Cardiovascular Disease. Int J Mol Sci 2018; 19:ijms19020507. [PMID: 29419744 PMCID: PMC5855729 DOI: 10.3390/ijms19020507] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 01/31/2018] [Accepted: 02/01/2018] [Indexed: 12/22/2022] Open
Abstract
The receptor EMMPRIN is involved in the development and progression of cardiovascular diseases and in the pathogenesis of myocardial infarction. There are several binding partners of EMMPRIN mediating the effects of EMMPRIN in cardiovascular diseases. EMMPRIN interaction with most binding partners leads to disease progression by mediating cytokine or chemokine release, the activation of platelets and monocytes, as well as the formation of monocyte-platelet aggregates (MPAs). EMMPRIN is also involved in atherosclerosis by mediating the infiltration of pro-inflammatory cells. There is also evidence that EMMPRIN controls energy metabolism of cells and that EMMPRIN binding partners modulate intracellular glycosylation and trafficking of EMMPRIN towards the cell membrane. In this review, we systematically discuss these multifaceted roles of EMMPRIN and its interaction partners, such as Cyclophilins, in cardiovascular disease.
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Aragon-Sanabria V, Kim GB, Dong C. From Cancer Immunoediting to New Strategies in Cancer Immunotherapy: The Roles of Immune Cells and Mechanics in Oncology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1092:113-138. [PMID: 30368751 DOI: 10.1007/978-3-319-95294-9_7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
For the last three decades, the concept of immunoediting has evolved to characterize our increasing understanding of the interactions between cells from the immune system and cancer development. Elucidating the role of immune cells in the progression of cancer has been very challenging due to their dual role; the immune system can either suppress tumor formation by killing cancer cells, or it can also promote tumor growth. Revealing how immune cells are hampered by the tumor microenvironment and how they aid tumor progression has signaled strategies to reverse these effects and control cancer cell growth; this has been the advent of immunotherapy design. More recently, the role of physical forces in the process of immunoediting has been highlighted by multiple studies focusing on understanding how force changes in the stiffness of the extracellular matrix and fluid flow shear stress contribute to tumor development. Using models in vitro that incorporate biomechanical components, it has been shown that these physical aspects are not only important during the formation and growth of primary tumors, but in the metastatic process as well. In this way, we have also gained insight into the interactions occurring within the vascular system, which are highly affected by the dynamics of physical collisions between cells and by shear forces. Here, we review the concept of cancer immunoediting with an emphasis on biomechanics and conclude with a summary on current immunotherapies and potential new strategies.
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Affiliation(s)
- Virginia Aragon-Sanabria
- Department of Biomedical Engineering, Pennsylvania State University, University Park, State College, PA, USA
| | - Gloria B Kim
- Department of Biomedical Engineering, Pennsylvania State University, University Park, State College, PA, USA
| | - Cheng Dong
- Department of Biomedical Engineering, Pennsylvania State University, University Park, State College, PA, USA.
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Aoki M, Koga K, Hamasaki M, Egawa N, Nabeshima K. Emmprin, released as a microvesicle in epithelioid sarcoma, interacts with fibroblasts. Int J Oncol 2017; 50:2229-2235. [PMID: 28498412 DOI: 10.3892/ijo.2017.3986] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 03/20/2017] [Indexed: 11/05/2022] Open
Abstract
Emmprin (extracellular matrix metalloproteinase inducer, CD147) is a glycosylated transmembrane protein, consisting of two immunoglobulin domains, that stimulates the production of matrix metalloproteinases (MMPs) by tumor-associated fibroblasts. These effects play important roles in tumor invasion and metastasis. However, the precise mechanisms by which emmprin acts on fibroblasts have not been fully elucidated, especially in sarcoma cells. Previously, we demonstrated that emmprin, expressed in conditioned medium collected from the epithelioid sarcoma cell line (FU-EPS-1), stimulates MMP-2 production via interactions with fibroblasts. In this study, we used microvesicles derived from sarcoma cells, and determined whether emmprin exists in the microvesicles, which enhance the production of MMP-2 via fibroblasts. Microvesicles released from FU-EPS-1 cells were shown to contain full-length emmprin, identified as a 45-kDa protein characterized by polylactosamine glycosylation. Microvesicles collected from FU-EPS-1 cells transfected with emmprin-specific siRNA or transduced with shRNA displayed significantly reduced MMP-2 production by fibroblasts compared with those from control-transfected cells. Our findings show that emmprin is released through microvesicle shedding in sarcoma cells, and emmprin in microvesicles regulates MMP-2 production by influencing the activity of fibroblasts located at sites distant from the tumor cells.
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Affiliation(s)
- Mikiko Aoki
- Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan
| | - Kaori Koga
- Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan
| | - Makoto Hamasaki
- Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan
| | - Nagayasu Egawa
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK
| | - Kazuki Nabeshima
- Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan
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40
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Zhou Y, Wu B, Li JH, Nan G, Jiang JL, Chen ZN. Rab22a enhances CD147 recycling and is required for lung cancer cell migration and invasion. Exp Cell Res 2017; 357:9-16. [PMID: 28433697 DOI: 10.1016/j.yexcr.2017.04.020] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Revised: 04/01/2017] [Accepted: 04/18/2017] [Indexed: 10/25/2022]
Abstract
Rab22a is a member of the Ras-related small GTPase family, which plays a key role in regulating the recycling of cargo proteins entering cells through clathrin-independent endocytosis (CIE). Rab22a is overexpressed in different cancer types, including liver cancer, malignant melanoma, ovarian cancer and osteosarcoma. However, its oncogenic role remains unknown. In this study, we found that silencing of Rab22a suppressed the migration and invasion of lung cancer cells. Furthermore, Rab22a interacts with CD147, and knockdown of Rab22a blocks CD147 recycling and promotes CD147 degradation. Taken together, our findings indicate that Rab22a enhances recycling of CD147, which is required for lung cancer cell migration and invasion,and targeting CD147 recycling may be a rational strategy for lung cancer therapy.
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Affiliation(s)
- Yang Zhou
- National Translational Science Center for Molecular Medicine, Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, PR China.
| | - Bo Wu
- National Translational Science Center for Molecular Medicine, Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, PR China.
| | - Jiang-Hua Li
- National Translational Science Center for Molecular Medicine, Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, PR China.
| | - Gang Nan
- National Translational Science Center for Molecular Medicine, Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, PR China.
| | - Jian-Li Jiang
- National Translational Science Center for Molecular Medicine, Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, PR China.
| | - Zhi-Nan Chen
- National Translational Science Center for Molecular Medicine, Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, PR China.
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Intasai N, Tragoolpua K, Pingmuang P, Khunkaewla P, Moonsom S, Kasinrerk W, Lieber A, Tayapiwatana C. Potent inhibition of OKT3-induced T cell proliferation and suppression of CD147 cell surface expression in HeLa cells by scFv-M6-1B9. Immunobiology 2017; 214:410-21. [PMID: 19264376 DOI: 10.1016/j.imbio.2008.12.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2008] [Revised: 12/11/2008] [Accepted: 12/12/2008] [Indexed: 12/20/2022]
Abstract
CD147, a multifunctional type I transmembrane glycoprotein, has been implicated in various physiological and pathological processes. It is involved in signal transduction pathways and also plays a crucial role in the invasive and metastatic activity of malignant tumor cells. Diminished expression of this molecule has been shown to be beneficial in suppression of tumor progression. In a previous study, we generated and characterized a recombinant antibody fragment, scFv, which reacted specifically to CD147. In the present study, we further investigated the biological properties, function and the effect of generated scFv on CD147 expression. The in vitro study showed that soluble scFv-M6-1B9 produced from E. coli HB2151 bound to CD147 surface molecule and inhibited OKT3-induced T cell proliferation. Furthermore, soluble lysate of scFv-M6-1B9 from 293A cells, transduced with a scFv-M6-1B9 expressing adenovirus vector, recognized both recombinant and native CD147. These results indicate that scFv-M6-1B9 binds with high efficiency and specificity. Importantly, scFv-M6-1B9 intrabody reduced the expression of CD147 on the cell surface of HeLa cells suggesting that scFv-M6-1B9 is biologically active. In conclusion, our present study demonstrated that scFv-M6-1B9 has a great potential to target both the intracellular and the extracellular CD147. The generated scFv-M6-1B9 may be an effective agent to clarify the cellular function of CD147 and may aid in efforts to develop a novel treatment in various human carcinomas.
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Affiliation(s)
- Nutjeera Intasai
- Division ofClinicalMicroscopy,DepartmentofMedicalTechnology,FacultyofAssociatedMedicalSciences, Chiang MaiUniversity,ChiangMai50200,Thailand
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CD147 as a Novel Prognostic Biomarker for Hepatocellular Carcinoma: A Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5019367. [PMID: 28386553 PMCID: PMC5366185 DOI: 10.1155/2017/5019367] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 12/19/2016] [Indexed: 01/06/2023]
Abstract
We conducted a meta-analysis to investigate the controversial association of CD147 expression with HCC prognosis and clinicopathological characteristics. Eight studies from PubMed (1966–2016), EMBASE (1980–2016), Cochrane Library (1996–2016), Web of Science (1945–2016), China National Knowledge Infrastructure (1982–2016), and Wanfang databases (1988–2016) were considered. The associations between CD147 expression and clinicopathological parameters and overall survival (OS) or DFS/RFS were reassessed using the meta-analysis for odds ratio (OR) or hazard ratio (HR) and 95% confidence interval (CI). CD147 expression was associated with DFS/RFS (HR = 3.26; 95% CI: 1.82–5.83; P < 0.0001) but not with OS (HR = 1.35; 95% CI: 0.56–3.29; P = 0.51). We also delved deeper into the association between median survival time and CD147 expression owing to significant heterogeneity and found significant differences between high and low CD147 expression groups with respect to median survival time. CD147 expression was closely associated with the TNM stage (OR = 0.18; 95% CI: 0.04–0.85; P = 0.03) and venous invasion (OR = 6.29; 95% CI: 1.70–23.20; P = 0.006). In contrast, there was no association between CD147 expression and tumor stage, cirrhosis, differentiation, lymph node metastasis, HBsAg, and serum AFP levels. Thus, CD147 expression is potentially closely related to HCC survival and associated clinicopathological parameters, paving the way for further research.
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43
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Luo Z, Zhang X, Zeng W, Su J, Yang K, Lu L, Lim CB, Tang W, Wu L, Zhao S, Jia X, Peng C, Chen X. TRAF6 regulates melanoma invasion and metastasis through ubiquitination of Basigin. Oncotarget 2016; 7:7179-92. [PMID: 26769849 PMCID: PMC4872777 DOI: 10.18632/oncotarget.6886] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 01/02/2016] [Indexed: 01/01/2023] Open
Abstract
TRAF6 plays a crucial role in the regulation of the innate and adaptive immune responses. Although studies have shown that TRAF6 has oncogenic activity, the role of TRAF6 in melanoma is unclear. Here, we report that TRAF6 is overexpressed in primary as well as metastatic melanoma tumors and melanoma cell lines. Knockdown of TRAF6 with shRNA significantly suppressed malignant phenotypes including cell proliferation, anchorage-independent cell growth and metastasis in vitro and in vivo. Notably, we demonstrated that Basigin (BSG)/CD147, a critical molecule for cancer cell invasion and metastasis, is a novel interacting partner of TRAF6. Furthermore, depletion of TRAF6 by shRNA reduced the recruitment of BSG to the plasma membrane and K63-linked ubiquitination, in turn, which impaired BSG-dependent MMP9 induction. Taken together, our findings indicate that TRAF6 is involved in regulating melanoma invasion and metastasis, suggesting that TRAF6 may be a potential target for therapy or chemo-prevention in melanoma.
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Affiliation(s)
- Zhongling Luo
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xu Zhang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Weiqi Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Juan Su
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Keda Yang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lixia Lu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chuan Bian Lim
- Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Wen Tang
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lisha Wu
- Institute of Medical Science Research, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shuang Zhao
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xuekun Jia
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Yang S, Qi F, Tang C, Wang H, Qin H, Li X, Li J, Wang W, Zhao C, Gao H. CD147 promotes the proliferation, invasiveness, migration and angiogenesis of human lung carcinoma cells. Oncol Lett 2016; 13:898-904. [PMID: 28356976 DOI: 10.3892/ol.2016.5502] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 05/05/2016] [Indexed: 11/06/2022] Open
Abstract
Cluster of differentiation (CD) 147 is a transmembrane glycoprotein that is highly expressed at the tumor cell surface, which stimulates fibroblasts to produce a large number of matrix metalloproteinases and promotes tumor invasion and metastasis and tumor-induced angiogenesis. The present study investigated the functions and the role of CD147 in the human lung carcinoma A549 cell line. The present study constructed expression and interference [small interfering (si) RNA] lentiviral vectors of CD147, which established stable overexpression and low expression of CD147 in the A549 cell line, named A549-CD147 and A549-siCD147, respectively. The differences in biological features between various levels of CD147 expression in A549 cells was investigated by cell counting kit-8 (CCK-8), Transwell, scratch and lumen formation assays. The results of the CCK-8 assay revealed that A549-CD147 cell proliferation was significantly increased and A549-siCD147 cell proliferation was decreased compared with the control groups. The A549-CD147 cells had the largest number of cells penetrating the Matrigel in the Transwell assay, which indicates that upregulation of CD147 expression increases the infiltration capacity of cells. The scratch assay revealed that A549-CD147 cells have the highest capacity for migration, while A549-siCD147 cells have the lowest. Quantitative polymerase chain reaction and western blot analysis demonstrated that vascular endothelial growth factor (VEGF) expression was proportional to the expression level of CD147 at the mRNA and protein level. The lumen formation assay revealed that the number of vessel lumens that human umbilical vein endothelial cells formed in the A549-CD147 cell supernatant was increased compared with the A549-siCD147 cells. Collectively, the present results suggest that CD147 is important in the promotion of lung carcinoma cell proliferation, invasion and metastasis and the upregulation of VEGF, which stimulates the angiogenesis of lung carcinoma. In conclusion, CD147 may be a potential target in the treatment of lung carcinoma.
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Affiliation(s)
- Shaoxing Yang
- Department of Pulmonary Oncology, Affiliated Hospital, Academy of Military Medical Science, Beijing 100071, P.R. China
| | - Fei Qi
- Department of Respiratory Medicine, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Chuanhao Tang
- Department of Pulmonary Oncology, Affiliated Hospital, Academy of Military Medical Science, Beijing 100071, P.R. China
| | - Hong Wang
- Department of Pulmonary Oncology, Affiliated Hospital, Academy of Military Medical Science, Beijing 100071, P.R. China
| | - Haifeng Qin
- Department of Pulmonary Oncology, Affiliated Hospital, Academy of Military Medical Science, Beijing 100071, P.R. China
| | - Xiaoyan Li
- Department of Pulmonary Oncology, Affiliated Hospital, Academy of Military Medical Science, Beijing 100071, P.R. China
| | - Jianjie Li
- Department of Pulmonary Oncology, Affiliated Hospital, Academy of Military Medical Science, Beijing 100071, P.R. China
| | - Weixia Wang
- Department of Pulmonary Oncology, Affiliated Hospital, Academy of Military Medical Science, Beijing 100071, P.R. China
| | - Changyun Zhao
- Department of Pulmonary Oncology, Affiliated Hospital, Academy of Military Medical Science, Beijing 100071, P.R. China
| | - Hongjun Gao
- Department of Pulmonary Oncology, Affiliated Hospital, Academy of Military Medical Science, Beijing 100071, P.R. China
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45
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Yuan S, Wang L, Chen X, Fan B, Yuan Q, Zhang H, Yang D, Wang S. Triptolide inhibits the migration and invasion of human prostate cancer cells via Caveolin-1/CD147/MMPs pathway. Biomed Pharmacother 2016; 84:1776-1782. [DOI: 10.1016/j.biopha.2016.10.104] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 10/25/2016] [Accepted: 10/30/2016] [Indexed: 12/15/2022] Open
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Nambiar J, Bose C, Venugopal M, Banerji A, Patel TB, Kumar GB, Nair BG. Anacardic acid inhibits gelatinases through the regulation of Spry2, MMP-14, EMMPRIN and RECK. Exp Cell Res 2016; 349:139-151. [PMID: 27737732 DOI: 10.1016/j.yexcr.2016.10.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Revised: 09/24/2016] [Accepted: 10/09/2016] [Indexed: 01/31/2023]
Abstract
Earlier studies from our laboratory have identified Anacardic acid (AA) as a potent inhibitor of gelatinases (MMP-2 and 9), which are over-expressed in a wide variety of cancers (Omanakuttan et al., 2012). Disruption of the finely tuned matrix metalloproteinase (MMP) activator/inhibitor balance plays a decisive role in determining the fate of the cell. The present study demonstrates for the first time, that in addition to regulating the expression as well as activity of gelatinases, AA also inhibits the expression of its endogenous activators like MMP-14 and Extracellular Matrix MetalloProteinase Inducer (EMMPRIN) and induces the expression of its endogenous inhibitor, REversion-inducing Cysteine-rich protein with Kazal motifs (RECK). In addition to modulating gelatinases, AA also inhibits the expression of various components of the Epidermal Growth Factor (EGF) pathway like EGF, Protein Kinase B (Akt) and Mitogen-activated protein kinases (MAPK). Furthermore, AA also activates the expression of Sprouty 2 (Spry2), a negative regulator of EGF pathway, and silencing Spry2 results in up-regulation of expression of gelatinases as well as MMP-14. The present study thus elucidates a novel mechanism of action of AA and provides a strong basis for utilizing this molecule as a template for cancer therapeutics.
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Affiliation(s)
- Jyotsna Nambiar
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India
| | - Chinchu Bose
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India
| | - Meera Venugopal
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India
| | - Asoke Banerji
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India
| | - Tarun B Patel
- Albany College of Pharmacy and Health Sciences, New York, USA
| | - Geetha B Kumar
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India
| | - Bipin G Nair
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India.
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Kuo PJ, Lin HL, Lin CY, Chin YT, Tu HP, Lai TM, Chiu HC, Fu E. Crosstalk Between Human Monocytic U937 Cells and Gingival Fibroblasts in Coculturally Enhanced Matrix Metalloproteinase-2 Expression. J Periodontol 2016; 87:1228-37. [PMID: 27294432 DOI: 10.1902/jop.2016.140653] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Po-Jan Kuo
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Department of Periodontology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, Republic of China
| | - Hsiao-Lun Lin
- Department of Periodontology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, Republic of China
| | - Chi-Yu Lin
- Department of Periodontology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, Republic of China
| | - Yu-Tang Chin
- Department of Periodontology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, Republic of China
- Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, Republic of China
| | - Hsiao-Pei Tu
- Department of Periodontology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, Republic of China
| | - Tat-Ming Lai
- Department of Periodontology, Cardinal Tien Hospital, New Taipei City, Taiwan, Republic of China
| | - Hsien-Chung Chiu
- Department of Periodontology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, Republic of China
| | - Earl Fu
- Department of Periodontology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, Republic of China
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Piovesana S, Capriotti AL, Colapicchioni V, Ferraris F, La Barbera G, Ventura S. Membrane proteome functional characterization of breast cancer-initiating cells subjected to bone morphogenetic protein signaling inhibition by dorsomorphin. Med Chem Res 2016. [DOI: 10.1007/s00044-016-1657-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Somno A, Anuchapreeda S, Chruewkamlow N, Pata S, Kasinrerk W, Chiampanichayakul S. Involvement of CD147 on multidrug resistance through the regulation of P-glycoprotein expression in K562/ADR leukemic cell line. Leuk Res Rep 2016; 6:33-8. [PMID: 27656412 PMCID: PMC5021772 DOI: 10.1016/j.lrr.2016.08.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 08/25/2016] [Indexed: 11/29/2022] Open
Abstract
The relationship between P-gp and CD147 in the regulation of MDR in leukemic cells has not been reported. This study aimed to investigate the correlation between CD147 and P-gp in the regulation of drug resistance in the K562/ADR leukemic cell line. The results showed that drug-resistant K562/ADR cells expressed significantly higher P-gp and CD147 levels than drug-free K562/ADR cells. To determine the regulatory effect of CD147 on P-gp expression, anti-CD147 antibody MEM-M6/6 significantly decreased P-gp and CD147 mRNA and protein levels. This is the first report to show that CD147 mediates MDR in leukemia through the regulation of P-gp expression.
High expression levels of P-gp and CD147 in drug-resistant cells. MEM-M6/6 antibody decreases both CD147 and P-gp expression. CD147 mediates MDR phenotype in leukemia through the regulation of P-gp expression.
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Affiliation(s)
- Aoranit Somno
- Division of Clinical Microscopy, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Songyot Anuchapreeda
- Division of Clinical Microscopy, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Nuttapol Chruewkamlow
- Biomedical Technology Research Center, National Center for Genetic Engineering and Biotechnology, National Sciences and Technology Development Agency at the Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Supansa Pata
- Division of Clinical Immunology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; Biomedical Technology Research Center, National Center for Genetic Engineering and Biotechnology, National Sciences and Technology Development Agency at the Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Watchara Kasinrerk
- Division of Clinical Immunology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; Biomedical Technology Research Center, National Center for Genetic Engineering and Biotechnology, National Sciences and Technology Development Agency at the Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Sawitree Chiampanichayakul
- Division of Clinical Microscopy, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; Biomedical Technology Research Center, National Center for Genetic Engineering and Biotechnology, National Sciences and Technology Development Agency at the Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
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50
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Ismail R, Allaudin ZN, Abdullah R, Mohd Lila MA, Nik Abd Rahman NMA, Abdul Rahman SO. Combination of VP3 and CD147-knockdown enhance apoptosis and tumor growth delay index in colorectal tumor allograft. BMC Cancer 2016; 16:461. [PMID: 27411985 PMCID: PMC4944445 DOI: 10.1186/s12885-016-2530-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 07/06/2016] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Cancer therapies that kill cancer cells without affecting normal cells is the ultimate mode of treating cancers. The VP3, an avian virus-derived protein, can specifically initiate cell death through several signal transduction pathways leading to apoptosis. In cancer, chemoresistance and cell survivability implicate the cell surface protein, CD147. METHODS In this study, transfection of VP3 and silencing of CD147 genes was achieved through the treatment of tumors with pVIVO1-GFP/VP3 (VP3), psiRNA-CD147/2 (shCD147/2), and their combination of CT26 colon cancer cell-induced in mice. The effectiveness of tumor-treatment was ascertained by electrophoresis, TUNEL assay, and flow cytometry analysis. While histopathological and biochemical analysis were used as toxic side effect identification. RESULTS The tumor growth delay index (TGDI) after treatment with VP3, shCD147/2, and their combination treatments increased by 1.3-, 1.2-, 2.0- and 2.3-fold respectively, over untreated control. The VP3-shCD147/2 combination treatment was more efficacious then either VP3 or shCD147/2 alone in the retardation of mouse CT26 colorectal cell tumor allograft. CONCLUSION The antitumor effect of the combination treatment is the result of synergistic effects of VP3 and shCD147/2 on the tumor cells resulting in apoptosis. Thus, the study shows that combination of VP3 and shCD147/2 treatment can be developed into a potential approach for anticolorectal cancer treatment regimen.
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Affiliation(s)
- Ruzila Ismail
- Laboratory of Immunotherapeutic and Vaccines, Institute of Bioscience, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Zeenathul Nazariah Allaudin
- Laboratory of Immunotherapeutic and Vaccines, Institute of Bioscience, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia. .,Department of Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
| | - Rasedee Abdullah
- Department of Veterinary Laboratory Diagnosis, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Mohd-Azmi Mohd Lila
- Department of Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Nik-Mohd-Afizan Nik Abd Rahman
- Laboratory of Immunotherapeutic and Vaccines, Institute of Bioscience, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Sheikh-Omar Abdul Rahman
- Department of Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
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