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Park S, Yi E, Jeon J, Oh J, Xu Z, Park SH. The Role of Bone Marrow Stromal Cell Antigen 2 (BST2) in the Migration of Dendritic Cells to Lymph Nodes. Int J Mol Sci 2024; 26:149. [PMID: 39796009 PMCID: PMC11720714 DOI: 10.3390/ijms26010149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/24/2024] [Accepted: 12/25/2024] [Indexed: 01/30/2025] Open
Abstract
Bone marrow stromal antigen 2 (BST2) is a host-restriction factor that plays multiple roles in the antiviral defense of innate immune responses, including the inhibition of viral particle release from virus-infected cells. BST2 may also be involved in the endothelial adhesion and migration of monocytes, but its importance in the immune system is still unclear. Immune cell adhesion and migration are closely related to the initiation of immune responses. In this study, we found that the expressions of the lymph node homing marker chemokine receptor 7 (CCR7) and an adhesion molecule intercellular adhesion molecule 1 (ICAM-1) in conventional dendritic cells (cDCs) were associated with BST2 expression. Interestingly, Bst2-/- cDCs showed lower chemotactic ability, including velocity and accumulative distance toward chemokine ligand 19 (CCL19) gradient in vitro, compared to wild-type cDCs. Bst2-/- cDCs also showed reduced migration and reduced retention capacity in draining lymph nodes in vivo. As a result, Bst2-/- cDCs as antigen-presenting cells induced lower antigen-specific B cell and T cell responses compared to Bst2+/+ cDCs. Notably, mice administered the influenza vaccine via Bst2-/- cDCs exhibited substantially inefficient virus clearance compared to mice administered the Bst2+/+ cDCs vaccine. Therefore, we propose that BST2, which plays a critical role in the effective migration and retention of cDCs, is involved in the development of optimal immunological effects in draining lymph nodes.
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Affiliation(s)
| | | | | | | | | | - Se-Ho Park
- College of Life Sciences and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea; (S.P.); (E.Y.); (J.J.); (J.O.); (Z.X.)
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Li R, Li N, Yang Q, Tong X, Wang W, Li C, Zhao J, Jiang D, Huang H, Fang C, Xie K, Yuan J, Chen S, Li G, Luo H, Gao Z, Wu D, Cui X, Jiang W, Guo L, Ma H, Feng Y. Spatial transcriptome profiling identifies DTX3L and BST2 as key biomarkers in esophageal squamous cell carcinoma tumorigenesis. Genome Med 2024; 16:148. [PMID: 39696540 DOI: 10.1186/s13073-024-01422-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 12/05/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Understanding the stepwise progression of esophageal squamous cell carcinoma (ESCC) is crucial for developing customized strategies for early detection and optimal clinical management. Herein, we aimed to unravel the transcriptional and immunologic alterations occurring during malignant transformation and identify clinically significant biomarkers of ESCC. METHODS Digital spatial profiling (DSP) was performed on 11 patients with early-stage ESCC (pT1) to explore the transcriptional alterations in epithelial, immune cell, and non-immune cell stromal compartments across regions of distinct histology, including normal tissues, low- and high-grade dysplasia, and cancerous tissues. Furthermore, single-cell spatial transcriptomics was performed using the CosMx Spatial Molecular Imaging (SMI) system on 4 additional patients with pT1 ESCC. Immunohistochemical (IHC) analysis was performed on consecutive histological sections of 20 pT1 ESCCs. Additionally, public bulk and single-cell RNA-sequencing (scRNA-seq) datasets were analyzed, and in vitro and in vivo functional studies were conducted. RESULTS Spatial transcriptional reprogramming and dynamic cell signaling pathways that determined ESCC progression were delineated. Increased infiltration of macrophages from normal tissues through dysplasia to cancerous tissues occurred. Macrophage subtypes were characterized using the scRNA-seq dataset. Cell-cell communication analysis of scRNA-seq and SMI data indicated that the migration inhibitory factor (MIF)-CD74 axis may exhibit pro-tumor interactions between macrophages and epithelial cells. DSP, SMI, and IHC data demonstrated that DTX3L expression in epithelial cells and BST2 expression in stromal cells increased gradually with ESCC progression. Functional studies demonstrated that DTX3L or BST2 knockdown inhibited ESCC proliferation and migration and decreased M2 polarization of tumor-associated macrophages. CONCLUSIONS Spatial profiling comprehensively characterized the molecular and immunological hallmarks from normal tissue to ESCC, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease and contributing to the prevention of ESCC. Within this exploration, we uncovered biomarkers that exhibit a robust correlation with ESCC progression, offering potential new avenues for insightful therapeutic approaches.
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Affiliation(s)
- Rutao Li
- Department of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
- Institute of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
- Department of Thoracic Surgery, the Fourth Affiliated Hospital Affiliated to Soochow University, Suzhou, 215000, China
| | - Na Li
- Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd, Shenzhen, 518000, China.
| | - Qianqian Yang
- Department of Pathology, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Xing Tong
- Department of Pathology, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Wei Wang
- Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd, Shenzhen, 518000, China
| | - Chang Li
- Department of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
- Institute of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Jun Zhao
- Department of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
- Institute of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Dong Jiang
- Department of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
- Institute of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Haitao Huang
- Department of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
- Institute of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Chen Fang
- Department of Thoracic Surgery, the Fourth Affiliated Hospital Affiliated to Soochow University, Suzhou, 215000, China
| | - Kai Xie
- Department of Thoracic Surgery, the Fourth Affiliated Hospital Affiliated to Soochow University, Suzhou, 215000, China
| | - Jiamin Yuan
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Shaomu Chen
- Department of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
- Institute of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Guangbin Li
- Department of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
- Institute of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Haitao Luo
- Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd, Shenzhen, 518000, China
| | - Zhibo Gao
- Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd, Shenzhen, 518000, China
| | - Dongfang Wu
- Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd, Shenzhen, 518000, China
| | - Xiaoli Cui
- Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd, Shenzhen, 518000, China
| | - Wei Jiang
- Department of Thoracic Surgery, the Fourth Affiliated Hospital Affiliated to Soochow University, Suzhou, 215000, China
| | - Lingchuan Guo
- Department of Pathology, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China.
| | - Haitao Ma
- Department of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China.
- Department of Thoracic Surgery, the Fourth Affiliated Hospital Affiliated to Soochow University, Suzhou, 215000, China.
| | - Yu Feng
- Department of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China.
- Institute of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China.
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Trzaskoma P, Jung S, Kanno Y, O'Shea JJ, Chow CC. Doxorubicin resistance involves modulation of interferon signaling, transcriptional bursting, and gene co-expression patterns of U-ISGF3-related genes. Neoplasia 2024; 58:101071. [PMID: 39405604 PMCID: PMC11574522 DOI: 10.1016/j.neo.2024.101071] [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: 08/29/2024] [Revised: 10/05/2024] [Accepted: 10/08/2024] [Indexed: 11/11/2024]
Abstract
Chemotherapy, although effective in treating cancer, can induce various cellular responses, including senescence and drug resistance. Here, we investigate the transcriptomic alterations induced by doxorubicin (DOX), a commonly used chemotherapeutic agent, in human colon cancer cells. Using single-cell RNA sequencing, we identified distinct cell populations and their transcriptional profiles following subtoxic DOX treatment, revealing cell clusters characterized by differential expression of genes involved in cell cycle regulation and interferon (IFN) signaling. DOX-persisting proliferating cells exhibited upregulation of genes reported to be linked to the unphosphorylated form of ISGF3 (U-ISGF3) transcription factor. Furthermore, we found that HSH2D, a poor prognostic marker, was highly upregulated in doxorubicin-surviving proliferative cells, and its expression was correlated with U-ISGF3-related genes. Analysis of transcription kinetics via mathematical modeling revealed that the number of mRNA molecules produced per transcriptional burst was increased for U-ISGF3-related genes. We also observed altered gene co-expression patterns of U-ISGF3-related genes and others upon DOX treatment, which potentially contributes to chemoresistance of DOX-surviving proliferative cells and may influence cancer cell fate after chemotherapy. Our findings highlight U-ISGF3-related genes and the JAK/STAT pathway as potential therapeutic targets for overcoming chemoresistance in colon cancer.
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Affiliation(s)
- Pawel Trzaskoma
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
| | - SeolKyoung Jung
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Yuka Kanno
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - John J O'Shea
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Carson C Chow
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
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Braun J, Hu Y, Jauch AT, Gronauer TF, Mergner J, Bach NC, Traube FR, Zahler S, Sieber SA. Neocarzilin Inhibits Cancer Cell Proliferation via BST-2 Degradation, Resulting in Lipid Raft-Trapped EGFR. JACS AU 2024; 4:1833-1840. [PMID: 38818080 PMCID: PMC11134574 DOI: 10.1021/jacsau.4c00039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 04/27/2024] [Accepted: 04/29/2024] [Indexed: 06/01/2024]
Abstract
Neocarzilin (NCA) is a natural product exhibiting potent antimigratory as well as antiproliferative effects. While vesicle amine transport protein 1 (VAT-1) was previously shown to inhibit migration upon NCA binding, the molecular mechanisms responsible for impaired proliferation remained elusive. We here introduce a chemical probe closely resembling the structural and stereochemical features of NCA and unravel bone marrow stromal antigen 2 (BST-2) as one of the targets responsible for the antiproliferative effect of NCA in cancer cells. The antiproliferative mechanism of NCA was confirmed in corresponding BST-2 knockout (KO) HeLa cells, which were less sensitive to compound treatment. Vice versa, reconstitution of BST-2 in the KO cells again reduced proliferation upon NCA addition, comparable to that of wild-type (wt) HeLa cells. Whole proteome mass spectrometric (MS) analysis of NCA-treated wt and KO cancer cells revealed regulated pathways and showed reduced levels of BST-2 upon NCA treatment. In-depth analysis of BST-2 levels in response to proteasome and lysosome inhibitors unraveled a lysosomal degradation path upon NCA treatment. As BST-2 mediates the release of epidermal growth factor receptor (EGFR) from lipid rafts to turn on proliferation signaling pathways, reduced BST-2 levels led to attenuated phosphorylation of STAT3. Furthermore, fluorescence microscopy confirmed increased colocalization of EGFR and lipid rafts in the presence of NCA. Overall, NCA represents a versatile anticancer natural product with a unique dual mode of action and unconventional inhibition of proliferation via BST-2 degradation.
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Affiliation(s)
- Josef Braun
- TUM School of Natural Sciences, Department of Bioscience, Chair of Organic Chemistry II, Center for Functional Protein Assemblies (CPA), Technical University of Munich (TUM), Ernst-Otto-Fischer Straße 8, Garching near Munich D-85748, Germany
| | - Yudong Hu
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University in Munich (LMU), Butenandtstraße 5-13, Munich D-81377, Germany
| | - Adrian T Jauch
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University in Munich (LMU), Butenandtstraße 5-13, Munich D-81377, Germany
| | - Thomas F Gronauer
- TUM School of Natural Sciences, Department of Bioscience, Chair of Organic Chemistry II, Center for Functional Protein Assemblies (CPA), Technical University of Munich (TUM), Ernst-Otto-Fischer Straße 8, Garching near Munich D-85748, Germany
- Metabolomics and Proteomics Core (MPC), Helmholtz Zentrum München GmbH German Research Center for Environmental Health, Heidemannstr. 1, Munich D-80939, Germany
| | - Julia Mergner
- Bavarian Center for Biomolecular Mass Spectrometry at Klinikum rechts der Isar (BayBioMS@MRI), Technical University of Munich (TUM), Einsteinstraße 25 Munich, D-81675, Germany
| | - Nina C Bach
- TUM School of Natural Sciences, Department of Bioscience, Chair of Organic Chemistry II, Center for Functional Protein Assemblies (CPA), Technical University of Munich (TUM), Ernst-Otto-Fischer Straße 8, Garching near Munich D-85748, Germany
| | - Franziska R Traube
- Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, Stuttgart D-70569, Germany
| | - Stefan Zahler
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University in Munich (LMU), Butenandtstraße 5-13, Munich D-81377, Germany
| | - Stephan A Sieber
- TUM School of Natural Sciences, Department of Bioscience, Chair of Organic Chemistry II, Center for Functional Protein Assemblies (CPA), Technical University of Munich (TUM), Ernst-Otto-Fischer Straße 8, Garching near Munich D-85748, Germany
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Li J, Yang P, Hong L, Xiao W, Zhang L, Yu Z, Zhang J, Pei M, Peng Y, Wei X, Wu X, Tang W, Zhao Y, Yang J, Lin Z, Jiang P, Xiang L, Zhang H, Lin J, Wang J. BST2 promotes gastric cancer metastasis under the regulation of HOXD9 and PABPC1. Mol Carcinog 2024; 63:663-676. [PMID: 38197534 DOI: 10.1002/mc.23679] [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: 04/14/2023] [Revised: 12/13/2023] [Accepted: 12/28/2023] [Indexed: 01/11/2024]
Abstract
Gastric cancer (GC) constitutes substantial cancer mortality worldwide. Several cancer types aberrantly express bone marrow stromal cell antigen 2 (BST2), yet its functional and underlying mechanisms in GC progression remain unknown. In our study, RNA sequencing data revealed that BST2 was transcriptionally activated by homeobox D9 (HOXD9). BST2 was significantly upregulated in GC tissues and promoted epithelial-mesenchymal transition and metastasis of GC. BST2 knockdown reversed HOXD9's oncogenic effect on GC metastasis. Moreover, BST2 messenger RNA stability could be enhanced by poly(A) binding protein cytoplasmic 1 (PABPC1) through the interaction between BST2 3'-UTR and PABPC1 in GC cells. PABPC1 promoted GC metastasis, which BST2 silencing attenuated in vitro and in vivo. In addition, positive correlations among HOXD9, BST2, and PABPC1 were established in clinical samples. Taken together, increased expression of BST2 induced by HOXD9 synergizing with PABPC1 promoted GC cell migration and invasion capacity.
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Affiliation(s)
- Jiaying Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Gastroenterology, The Key Laboratory of Advanced Interdisciplinary Studies Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ping Yang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Linjie Hong
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wushuang Xiao
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Luyu Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhen Yu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jieming Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Miaomiao Pei
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Ying Peng
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiangyang Wei
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaosheng Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weimei Tang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yingying Zhao
- Department of Gastroenterology, Panyu District Central Hospital, Guangzhou, China
| | - Juanying Yang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhizhao Lin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ping Jiang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Li Xiang
- Department of Gastroenterology, Longgang District People's Hospital, The Chinese University of Hong Kong, Shenzhen, China
| | - Hui Zhang
- Department of Gastroenterology, Hexian Memorial Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Jianjiao Lin
- Department of Gastroenterology, Longgang District People's Hospital, The Chinese University of Hong Kong, Shenzhen, China
| | - Jide Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Gastroenterology, Longgang District People's Hospital, The Chinese University of Hong Kong, Shenzhen, China
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Yu H, Bian Q, Wang X, Wang X, Lai L, Wu Z, Zhao Z, Ban B. Bone marrow stromal cell antigen 2: Tumor biology, signaling pathway and therapeutic targeting (Review). Oncol Rep 2024; 51:45. [PMID: 38240088 PMCID: PMC10828922 DOI: 10.3892/or.2024.8704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 01/04/2024] [Indexed: 01/23/2024] Open
Abstract
Bone marrow stromal cell antigen 2 (BST2) is a type II transmembrane protein that serves critical roles in antiretroviral defense in the innate immune response. In addition, it has been suggested that BST2 is highly expressed in various types of human cancer and high BST2 expression is related to different clinicopathological parameters in cancer. The molecular mechanism underlying BST2 as a potential tumor biomarker in human solid tumors has been reported on; however, to the best of our knowledge, there has been no review published on the molecular mechanism of BST2 in human solid tumors. The present review focuses on human BST2 expression, structure and functions; the molecular mechanisms of BST2 in breast cancer, hepatocellular carcinoma, gastrointestinal tumor and other solid tumors; the therapeutic potential of BST2; and the possibility of BST2 as a potential marker. BST2 is involved in cell membrane integrity and lipid raft formation, which can activate epidermal growth factor receptor signaling pathways, providing a potential mechanistic link between BST2 and tumorigenesis. Notably, BST2 may be considered a universal tumor biomarker and a potential therapeutical target.
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Affiliation(s)
- Honglian Yu
- Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, P.R. China
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
- Collaborative Innovation Center, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Qiang Bian
- Collaborative Innovation Center, Jining Medical University, Jining, Shandong 272067, P.R. China
- Department of Pathophysiology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Xin Wang
- Department of Urology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Xinzhe Wang
- Department of Urology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Luhao Lai
- Collaborative Innovation Center, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Zhichun Wu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Zhankui Zhao
- Department of Urology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Bo Ban
- Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, P.R. China
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Zhu LH, Yang J, Zhang YF, Yan L, Lin WR, Liu WQ. Identification and validation of a pyroptosis-related prognostic model for colorectal cancer based on bulk and single-cell RNA sequencing data. World J Clin Oncol 2024; 15:329-355. [PMID: 38455135 PMCID: PMC10915942 DOI: 10.5306/wjco.v15.i2.329] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 12/24/2023] [Accepted: 01/15/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Pyroptosis impacts the development of malignant tumors, yet its role in colorectal cancer (CRC) prognosis remains uncertain. AIM To assess the prognostic significance of pyroptosis-related genes and their association with CRC immune infiltration. METHODS Gene expression data were obtained from The Cancer Genome Atlas (TCGA) and single-cell RNA sequencing dataset GSE178341 from the Gene Expression Omnibus (GEO). Pyroptosis-related gene expression in cell clusters was analyzed, and enrichment analysis was conducted. A pyroptosis-related risk model was developed using the LASSO regression algorithm, with prediction accuracy assessed through K-M and receiver operating characteristic analyses. A nomogram predicting survival was created, and the correlation between the risk model and immune infiltration was analyzed using CIBERSORTx calculations. Finally, the differential expression of the 8 prognostic genes between CRC and normal samples was verified by analyzing TCGA-COADREAD data from the UCSC database. RESULTS An effective pyroptosis-related risk model was constructed using 8 genes-CHMP2B, SDHB, BST2, UBE2D2, GJA1, AIM2, PDCD6IP, and SEZ6L2 (P < 0.05). Seven of these genes exhibited differential expression between CRC and normal samples based on TCGA database analysis (P < 0.05). Patients with higher risk scores demonstrated increased death risk and reduced overall survival (P < 0.05). Significant differences in immune infiltration were observed between low- and high-risk groups, correlating with pyroptosis-related gene expression. CONCLUSION We developed a pyroptosis-related prognostic model for CRC, affirming its correlation with immune infiltration. This model may prove useful for CRC prognostic evaluation.
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Affiliation(s)
- Li-Hua Zhu
- Department of Surgical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jun Yang
- Department of Surgical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Yun-Fei Zhang
- Department of Surgical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Li Yan
- Department of Internal Medicine-Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Wan-Rong Lin
- Department of Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Wei-Qing Liu
- Department of Internal Medicine-Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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8
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Hänsch L, Peipp M, Mastall M, Villars D, Myburgh R, Silginer M, Weiss T, Gramatzki D, Vasella F, Manz MG, Weller M, Roth P. Chimeric antigen receptor T cell-based targeting of CD317 as a novel immunotherapeutic strategy against glioblastoma. Neuro Oncol 2023; 25:2001-2014. [PMID: 37335916 PMCID: PMC10628943 DOI: 10.1093/neuonc/noad108] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Indexed: 06/21/2023] Open
Abstract
BACKGROUND Chimeric antigen receptor (CAR) T cell therapy has proven to be successful against hematological malignancies. However, exploiting CAR T cells to treat solid tumors is more challenging for various reasons including the lack of suitable target antigens. Here, we identify the transmembrane protein CD317 as a novel target antigen for CAR T cell therapy against glioblastoma, one of the most aggressive solid tumors. METHODS CD317-targeting CAR T cells were generated by lentivirally transducing human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells toward various glioma cells was assessed in vitro in cell lysis assays. Subsequently, we determined the efficacy of CD317-CAR T cells to control tumor growth in vivo in clinically relevant mouse glioma models. RESULTS We generated CD317-specific CAR T cells and demonstrate strong anti-tumor activity against several glioma cell lines as well as primary patient-derived cells with varying CD317 expression levels in vitro. A CRISPR/Cas9-mediated knockout of CD317 protected glioma cells from CAR T cell lysis, demonstrating the target specificity of the approach. Silencing of CD317 expression in T cells by RNA interference reduced fratricide of engineered T cells and further improved their effector function. Using orthotopic glioma mouse models, we demonstrate the antigen-specific anti-tumor activity of CD317-CAR T cells, which resulted in prolonged survival and cure of a fraction of CAR T cell-treated animals. CONCLUSIONS These data reveal a promising role of CD317-CAR T cell therapy against glioblastoma, which warrants further evaluation to translate this immunotherapeutic strategy into clinical neuro-oncology.
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Affiliation(s)
- Lena Hänsch
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Matthias Peipp
- Division of Antibody-Based Immunotherapy, Department of Internal Medicine II, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
- Division of Antibody-based Immunotherapy, Christian-Albrechts-University, Kiel, Germany
| | - Maximilian Mastall
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Danielle Villars
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Renier Myburgh
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Manuela Silginer
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Tobias Weiss
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Dorothee Gramatzki
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Flavio Vasella
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Department of Neurosurgery, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Markus G Manz
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Michael Weller
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Patrick Roth
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
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9
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Dolton G, Rius C, Wall A, Szomolay B, Bianchi V, Galloway SAE, Hasan MS, Morin T, Caillaud ME, Thomas HL, Theaker S, Tan LR, Fuller A, Topley K, Legut M, Attaf M, Hopkins JR, Behiry E, Zabkiewicz J, Alvares C, Lloyd A, Rogers A, Henley P, Fegan C, Ottmann O, Man S, Crowther MD, Donia M, Svane IM, Cole DK, Brown PE, Rizkallah P, Sewell AK. Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy. Cell 2023; 186:3333-3349.e27. [PMID: 37490916 DOI: 10.1016/j.cell.2023.06.020] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 04/20/2023] [Accepted: 06/24/2023] [Indexed: 07/27/2023]
Abstract
The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide libraries and a proteomic database to reveal the antigen specificities of persistent cancer-specific T cell receptors (TCRs) following successful TIL therapy for stage IV malignant melanoma. Remarkably, individual TCRs could target multiple different tumor types via the HLA A∗02:01-restricted epitopes EAAGIGILTV, LLLGIGILVL, and NLSALGIFST from Melan A, BST2, and IMP2, respectively. Atomic structures of a TCR bound to all three antigens revealed the importance of the shared x-x-x-A/G-I/L-G-I-x-x-x recognition motif. Multi-epitope targeting allows individual T cells to attack cancer in several ways simultaneously. Such "multipronged" T cells exhibited superior recognition of cancer cells compared with conventional T cell recognition of individual epitopes, making them attractive candidates for the development of future immunotherapies.
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Affiliation(s)
- Garry Dolton
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Cristina Rius
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Aaron Wall
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Barbara Szomolay
- Systems Immunology Research Institute, Cardiff, Wales CF14 4XN, UK
| | - Valentina Bianchi
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Sarah A E Galloway
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Md Samiul Hasan
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Théo Morin
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Marine E Caillaud
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Hannah L Thomas
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Sarah Theaker
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Li Rong Tan
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Anna Fuller
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Katie Topley
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Mateusz Legut
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Meriem Attaf
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Jade R Hopkins
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Enas Behiry
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Joanna Zabkiewicz
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Caroline Alvares
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Angharad Lloyd
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Amber Rogers
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Peter Henley
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Christopher Fegan
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Oliver Ottmann
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Stephen Man
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Michael D Crowther
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK; National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Marco Donia
- National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Inge Marie Svane
- National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - David K Cole
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Paul E Brown
- The Zeeman Institute, University of Warwick, Coventry CV4 7AL, UK
| | - Pierre Rizkallah
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK
| | - Andrew K Sewell
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales CF14 4XN, UK; Systems Immunology Research Institute, Cardiff, Wales CF14 4XN, UK.
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10
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Kitao M, Hayashi R, Nomi K, Kobayashi R, Katayama T, Takayanagi H, Oguchi A, Murakawa Y, Nishida K. Identification of BST2 as a conjunctival epithelial stem/progenitor cell marker. iScience 2023; 26:107016. [PMID: 37389178 PMCID: PMC10300367 DOI: 10.1016/j.isci.2023.107016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/25/2023] [Accepted: 05/30/2023] [Indexed: 07/01/2023] Open
Abstract
The conjunctival epithelium consists of conjunctival epithelial cells and goblet cells derived from conjunctival epithelial stem/progenitor cells. However, the source of these cells is not well known because no specific markers for conjunctival epithelial stem/progenitor cells have been discovered. Therefore, to identify conjunctival epithelial stem/progenitor cell markers, we performed single-cell RNA sequencing of a conjunctival epithelial cell population derived from human-induced pluripotent stem cells (hiPSCs). The following conjunctival epithelial markers were identified: BST2, SLC2A3, AGR2, TMEM54, OLR1, and TRIM29. Notably, BST2 was strongly positive in the basal conjunctival epithelium, which is thought to be rich in stem/progenitor cells. Moreover, BST2 was able to sort conjunctival epithelial stem/progenitor cells from hiPSC-derived ocular surface epithelial cell populations. BST2-positive cells were highly proliferative and capable of successfully generating conjunctival epithelial sheets containing goblet cells. In conclusion, BST2 has been identified as a specific marker of conjunctival epithelial stem/progenitor cells.
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Affiliation(s)
- Masahiro Kitao
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Ryuhei Hayashi
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
- Department of Stem Cells and Applied Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka 565-0871, Japan
| | - Kimihito Nomi
- Business Strategy Office, ROHTO Pharmaceutical, Osaka, Osaka 544-0012, Japan
| | - Reiko Kobayashi
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Tomohiko Katayama
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Hiroshi Takayanagi
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
- Department of Stem Cells and Applied Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Akiko Oguchi
- RIKEN-IFOM Joint Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan
| | - Yasuhiro Murakawa
- RIKEN-IFOM Joint Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Kyoto 606-8501, Japan
| | - Kohji Nishida
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka 565-0871, Japan
- Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Suita, Osaka 565-0871, Japan
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11
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Shan F, Shen S, Wang X, Chen G. BST2 regulated by the transcription factor STAT1 can promote metastasis, invasion and proliferation of oral squamous cell carcinoma via the AKT/ERK1/2 signaling pathway. Int J Oncol 2023; 62:54. [PMID: 36929425 PMCID: PMC10019759 DOI: 10.3892/ijo.2023.5502] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 02/22/2023] [Indexed: 03/15/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) is one of the main types of head and neck squamous cell carcinoma. Although progress has been made in treating OSCC, it remains a threat to human health, and novel therapeutic strategies are needed to extend the lifespan of patients with OSCC. The present study, evaluated whether bone marrow stromal antigen 2 (BST2) and STAT1 were potential therapeutic targets in OSCC. Small interfering RNA (siRNA) or overexpression plasmids were used to regulate BST2 or STAT1 expression. Western blotting and reverse transcription‑quantitative PCR were performed to assess changes in the protein and mRNA expression levels of signaling pathway components. The effects of BST2 and STAT1 expression changes on the migration, invasion and proliferation of OSCC cells were assessed using the scratch test assay, Transwell assay and colony formation assay in vitro, respectively. Cell‑derived xenograft models were used to evaluate the impact of BST2 and STAT1 on the occurrence and development of OSCC in vivo. Finally, it was demonstrated that BST2 expression was significantly upregulated in OSCC. Furthermore, it was demonstrated that high expression of BST2 in OSCC contributed to the metastasis, invasion and proliferation of OSCC cells. Moreover, it was demonstrated that the promoter region of BST2 was regulated by the transcription factor STAT1, and that the STAT1/BST2 axis could affect the behavior of OSCC via the AKT/ERK1/2 signaling pathway. In vivo studies also demonstrated that STAT1 downregulation inhibited OSCC growth by down‑regulating BST2 expression via the AKT/ERK1/2 signaling pathway.
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Affiliation(s)
- Fayu Shan
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Si Shen
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Xinxing Wang
- Environmental Medicine Laboratory, Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, P.R. China
- Correspondence to: Dr Xinxing Wang, Environmental Medicine Laboratory, Tianjin Institute of Environmental and Operational Medicine, 1 Dali Road, Heping, Tianjin 300050, P.R. China, E-mail:
| | - Gang Chen
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Tianjin Medical University, Tianjin 300070, P.R. China
- Dr Gang Chen, Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Tianjin Medical University, 12 Qi Xinang Tai Road, Heping, Tianjin 300070, P.R. China, E-mail:
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12
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Urata S, Yamaguchi S, Nambu A, Sudo K, Nakae S, Yasuda J. The roles of BST-2 in murine B cell development and on virus propagation. Microbiol Immunol 2023; 67:105-113. [PMID: 36604771 DOI: 10.1111/1348-0421.13049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 12/13/2022] [Accepted: 01/04/2023] [Indexed: 01/07/2023]
Abstract
The bone marrow (BM) stromal cell antigen-2 (BST-2), also known as tetherin, CD317, PDCA-1, or HM1.24, is a membrane protein overexpressed in several types of tumors and may act as a promising target for cancer treatment via antibody-dependent cellular cytotoxicity. BST-2 is also expressed in human BM stromal cells (BMSC), which support B cell development. While the activity of BST-2 as an antiviral factor has been demonstrated, the expression patterns and the role of BST-2 on B-cell development and activation have not been investigated, especially in vivo. In this study, Bst2 knockout (Bst2-/- ) mice were generated to assess the role of BST-2 on B cell development and activation. It was observed that BST-2 was not expressed in BMSC or all B cell progenitors even in wild-type mice and does not play a significant role in B cell development. In addition, the loss of BST-2 had no effect on B cell activation. Furthermore and in contrast to the well-known antiviral role of BST-2, infection of vesicular stomatitis Indiana virus to the BM cells collected from the Bst2-/- mice produced less infectious virus compared with that from the WT mice. These results suggest that murine BST-2 is different from human BST-2 in the expression pattern, physiological function, in vivo, and might possess positive role on VSV replication.
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Affiliation(s)
- Shuzo Urata
- Department of Emerging Infectious Diseases, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.,National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University, Nagasaki, Japan
| | - Sachiko Yamaguchi
- Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
| | - Aya Nambu
- Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Katsuko Sudo
- Pre-clinical Research Center, Tokyo Medical University, Tokyo, Japan
| | - Susumu Nakae
- Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan.,Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama, Japan
| | - Jiro Yasuda
- Department of Emerging Infectious Diseases, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.,National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University, Nagasaki, Japan.,Program for Nurturing Global Leaders in Tropical and Emerging Communicable Diseases, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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13
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He X, Chen H, Zhong X, Wang Y, Hu Z, Huang H, Zhao S, Wei P, Shi D, Li D. BST2 induced macrophage M2 polarization to promote the progression of colorectal cancer. Int J Biol Sci 2023; 19:331-345. [PMID: 36594082 PMCID: PMC9760448 DOI: 10.7150/ijbs.72538] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 10/20/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Tumor-associated macrophages (TAMs) are one of the most prominent tumor-infiltrating immune cells in the tumor microenvironment (TME) of CRC and play a vital role in the progression of CRC. BST2 was predicted to be associated with the infiltration of TAMs. However, its potential function by which CRC cells and TAMs interact with each other still needs further investigation. Methods: The target genes in CRC were selected by bioinformatics screening. The level of bone marrow stromal cell antigen 2 (BST2) in CRC cells and tissues was determined by qRT‒PCR, Western blotting, and immunohistochemistry staining. In vitro and in vivo assays were applied to clarify the function of BST2. Results: In this study, according to bioinformatics analysis, a nomogram based on the risk score (constructed by BST2 and CAV1 (caveolin-1)) and clinical features was built and displayed satisfactory prognostic value. Upregulated BST2 was significantly related to Braf mutation, dMMR/MSI-H, CMS1 subtype, and immune response and was a potential biomarker for predicting immune checkpoint blockade therapy. Silencing BST2 in CRC obviously restrained CRC progression and M2 TAM polarization. The infiltration of TAMs was positively correlated with the high expression of BST2, and depletion of TAMs alleviated the protumoural effect of BST2 in CRC in vivo. In vitro experiments revealed that a reduction in BST2 in CRC inhibited CRC proliferation and migration and also M2 polarization. Conclusion: These findings indicated that BST2 played a vital role in CRC progression and might be a predictable marker for immunotherapy.
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Affiliation(s)
- Xuefeng He
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Huaijun Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyang Zhong
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Yaxian Wang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Zijuan Hu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China,Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China,Institute of Pathology, Fudan University, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Huixia Huang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China,Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China,Institute of Pathology, Fudan University, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Senlin Zhao
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
| | - Ping Wei
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China,Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China,Institute of Pathology, Fudan University, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China,✉ Corresponding authors: Dawei Li, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. . Debing Shi, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. . Ping Wei, Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
| | - Debing Shi
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China,✉ Corresponding authors: Dawei Li, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. . Debing Shi, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. . Ping Wei, Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
| | - Dawei Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China,✉ Corresponding authors: Dawei Li, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. . Debing Shi, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. . Ping Wei, Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
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14
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Human Papillomavirus 16 E6 and E7 Oncoproteins Alter the Abundance of Proteins Associated with DNA Damage Response, Immune Signaling and Epidermal Differentiation. Viruses 2022; 14:v14081764. [PMID: 36016386 PMCID: PMC9415472 DOI: 10.3390/v14081764] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 11/16/2022] Open
Abstract
The high-risk human papillomaviruses are oncogenic viruses associated with almost all cases of cervical carcinomas, and increasing numbers of anal, and oral cancers. Two oncogenic HPV proteins, E6 and E7, are capable of immortalizing keratinocytes and are required for HPV associated cell transformation. Currently, the influence of these oncoproteins on the global regulation of the host proteome is not well defined. Liquid chromatography coupled with quantitative tandem mass spectrometry using isobaric-tagged peptides was used to investigate the effects of the HPV16 oncoproteins E6 and E7 on protein levels in human neonatal keratinocytes (HEKn). Pathway and gene ontology enrichment analyses revealed that the cells expressing the HPV oncoproteins have elevated levels of proteins related to interferon response, inflammation and DNA damage response, while the proteins related to cell organization and epithelial development are downregulated. This study identifies dysregulated pathways and potential biomarkers associated with HPV oncoproteins in primary keratinocytes which may have therapeutic implications. Most notably, DNA damage response pathways, DNA replication, and interferon signaling pathways were affected in cells transduced with HPV16 E6 and E7 lentiviruses. Moreover, proteins associated with cell organization and differentiation were significantly downregulated in keratinocytes expressing HPV16 E6 + E7. High-risk HPV E6 and E7 oncoproteins are necessary for the HPV-associated transformation of keratinocytes. However their influence on the global dysregulation of keratinocyte proteome is not well documented. Here shotgun proteomics using TMT-labeling detected over 2500 significantly dysregulated proteins associated with E6 and E7 expression. Networks of proteins related to interferon response, inflammation and DNA damage repair pathways were altered.
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15
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Single-Cell RNA Sequencing Reveals the Role of Epithelial Cell Marker Genes in Predicting the Prognosis of Colorectal Cancer Patients. DISEASE MARKERS 2022; 2022:8347125. [PMID: 35968507 PMCID: PMC9372514 DOI: 10.1155/2022/8347125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/09/2022] [Accepted: 07/21/2022] [Indexed: 11/17/2022]
Abstract
Single-cell RNA sequencing (scRNA-seq) is increasingly used in studies on gastrointestinal cancers. This study investigated the prognostic value of epithelial cell-associated biomarkers in colorectal cancer (CRC) using scRNA-seq data. We downloaded and analysed scRNA-seq data from four CRC samples from the Gene Expression Omnibus (GEO), and we identified marker genes of malignant epithelial cells (MECs) using CRC transcriptome and clinical data downloaded from The Cancer Genome Atlas (TCGA) and GEO as training and validation cohorts, respectively. In the TCGA training cohort, weighted gene correlation network analysis, univariate Cox proportional hazard model (Cox) analysis, and least absolute shrinkage and selection operator regression analysis were performed on the marker genes of MEC subsets to identify a signature of nine prognostic MEC-related genes (MECRGs) and calculate a risk score based on the signature. CRC patients were divided into high- and low-risk groups according to the median risk score. We found that the MECRG risk score was significantly correlated with the clinical features and overall survival of CRC patients, and that CRC patients in the high-risk group showed a significantly shorter survival time. The univariate and multivariate Cox regression analyses showed that the MECRG risk score can serve as an independent prognostic factor for CRC patients. Gene set enrichment analysis revealed that the MECRG signature genes are involved in fatty acid metabolism, p53 signalling, and other pathways. To increase the clinical application value, we constructed a MECRG nomogram by combining the MECRG risk score with other independent prognostic factors. The validity of the nomogram is based on receiver operating characteristics and calibration curves. The MECRG signature and nomogram models were well validated in the GEO dataset. In conclusion, we established an epithelial cell marker gene-based risk assessment model based on scRNA-seq analysis of CRC samples for predicting the prognosis of CRC patients.
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16
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Jinyu L, Shuying W, Panchan Z, Dan C, Chao C, Xingyu Y, Weiwei C. Bone marrow stromal cell antigen 2(BST2) suppresses the migration and invasion of trophoblasts in preeclampsia by downregulating matrix metallopeptidase 2(MMP2). Bioengineered 2022; 13:13174-13187. [PMID: 35635087 PMCID: PMC9276030 DOI: 10.1080/21655979.2022.2074712] [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] [Indexed: 11/09/2022] Open
Abstract
Preeclampsia is a grievous pregnancy-related complication with an incidence of approximately 5∼7% in pregnant women. Placental abnormalities and decreased placental perfusion associated with impaired trophoblast invasion are early pathological findings of preeclampsia. BST2 is a multifunctional transmembrane protein that plays critical roles in physiological and pathological processes, but its impacts and mechanisms of action in preeclampsia are inadequately understood. The aim of this manuscript was to investigate the functional impacts of BST2 and MMP2 on the biological behavior of trophoblast cells in preeclampsia. The expression of these proteins and their genes was analyzed by qRT-PCR, western blotting and immunohistochemistry. The results showed that the expression of BST2 and MMP2 was significantly downregulated in preeclampsia. The migration and invasion capacities of HTR-8/SVneo and JAR cells with overexpression or knockdown of BST2 were detected by wound healing assay and Transwell assays. It was found that BST2 overexpression could up-regulate MMP2 expression, and enhance the migration and invasion capacity of HTR-8/SVneo and JAR cells. BST2 knockdown could reverse these effects. MMP2 knockdown could downregulate the invasion capacity of HTR-8/SVneo cells, and MMP2 overexpression reversed these effects. Pearson correlation analysis demonstrated that the expression of MMP2 and BST2 were positively correlated. These results indicate that the downregulation of BST2 lowers MMP2 expression and restraint trophoblast functions, which probably explain its role in the pathogenesis of preeclampsia.
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Affiliation(s)
- Liu Jinyu
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China
- Institute of Birth Defects and Rare Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wang Shuying
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zheng Panchan
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chen Dan
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chen Chao
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China
- Institute of Birth Defects and Rare Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yang Xingyu
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China
| | - Cheng Weiwei
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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17
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Characterization of 5-inflammatory-gene signature to affect the immune status and predict prognosis in breast cancer. Cent Eur J Immunol 2022; 47:218-233. [PMID: 36817270 PMCID: PMC9896988 DOI: 10.5114/ceji.2022.121046] [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: 03/18/2022] [Accepted: 09/05/2022] [Indexed: 11/17/2022] Open
Abstract
Introduction Breast cancer (BC) is associated with an inflammatory microenvironment. In BC, epidemiological evidence suggests that inflammation is associated with a poor prognosis. However, approaches to determine the extent of inflammation in the tumor microenvironment remain unclear. Material and methods We downloaded the expression profiles and corresponding clinicopathological information of 1050 BC tissues and 59 cases of normal breast tissue from The Cancer Genome Atlas (TCGA) dataset. Similarly, data of 1050 BC tissues were downloaded from Gene Expression Omnibus (GEO) and 200 inflammation-related genes were downloaded from the MSigDB database. We developed an inflammatory risk model to reflect the immune microenvironment in BC. Results Multivariate Cox analysis showed that the risk score was an independent predictor of overall survival (OS). Inflammatory signature was significantly associated with clinical and molecular features and could serve as an independent prognostic factor for BC patients. Furthermore, most immune cells were significantly less infiltrated in the high-risk group than in the low-risk group. There was a significant difference in survival time between the group with a high and low tumor mutational burden (TMB) score, and the survival time of the patients with a low TMB was significantly higher than that of the high-risk group. The risk scores were significantly lower in patients who responded to immunotherapy (complete response/partial response - CR/PR) than in patients who did not respond to immunotherapy (stable disease/progressive disease - SD/PD). Conclusions We developed and validated an inflammatory risk model, which served as an independent prognostic indicator and reflected immune response intensity in the BC microenvironment.
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18
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Verma S, Kang AK, Pal R, Gupta SK. BST2 regulates interferon gamma-dependent decrease in invasion of HTR-8/SVneo cells via STAT1 and AKT signaling pathways and expression of E-cadherin. Cell Adh Migr 2021; 14:24-41. [PMID: 31957537 PMCID: PMC6973314 DOI: 10.1080/19336918.2019.1710024] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The mechanism by which interferon-gamma (IFN-γ) downregulates trophoblast invasion needs further investigation. Treatment of HTR-8/SVneo cells with IFN-γ led to a decrease in their invasion concomitant with an increased expression of BST2. Silencing of BST2 by siRNA showed a significant increase in their invasion and spreading after treatment with IFN-γ as well as downregulated expression of E-cadherin. Further, STAT1 silencing inhibited the IFN-γ-dependent increase in the expression of BST2 and E-cadherin. Treatment of HTR-8/SVneo cells with IFN-γ led to the activation of AKT, and its inhibition with PI3K inhibitor abrogated IFN-γ-mediated decrease in invasion/spreading and downregulated BST2 and E-cadherin expression. Collectively, IFN-γ decreases the invasion of HTR-8/SVneo cells by STAT1 and AKT activation via increased expression of BST2 and E-cadherin.
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Affiliation(s)
- Sonam Verma
- Reproductive Cell Biology Laboratory, National Institute of Immunology, New Delhi, India
| | - Amandeep Kaur Kang
- Reproductive Cell Biology Laboratory, National Institute of Immunology, New Delhi, India
| | - Rahul Pal
- Immunoendocrinology Laboratory, National Institute of Immunology, New Delhi, India
| | - Satish Kumar Gupta
- Reproductive Cell Biology Laboratory, National Institute of Immunology, New Delhi, India
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19
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Activation of plasmacytoid dendritic cells promotes AML-cell fratricide. Oncotarget 2021; 12:878-890. [PMID: 33953842 PMCID: PMC8092344 DOI: 10.18632/oncotarget.27949] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 04/06/2021] [Indexed: 12/12/2022] Open
Abstract
Acute myeloid leukemia (AML) is characterized by the proliferation of immature myeloid blasts and a suppressed immune state. Interferons have been previously shown to aid in the clearance of AML cells. Type I interferons are produced primarily by plasmacytoid dendritic cells (pDCs). However, these cells exist in a quiescent state in AML. Because pDCs express TLR 7–9, we hypothesized that the TLR7/8 agonist R848 would be able to reprogram them toward a more active, IFN-producing phenotype. Consistent with this notion, we found that R848-treated pDCs from patients produced significantly elevated levels of IFNβ. In addition, they showed increased expression of the immune-stimulatory receptor CD40. We next tested whether IFNβ would influence antibody-mediated fratricide among AML cells, as our recent work showed that AML cells could undergo cell-to cell killing in the presence of the CD38 antibody daratumumab. We found that IFNβ treatment led to a significant, IRF9-dependent increase in CD38 expression and a subsequent increase in daratumumab-mediated cytotoxicity and decreased colony formation. These findings suggest that the tolerogenic phenotype of pDCs in AML can be reversed, and also demonstrate a possible means of enhancing endogenous Type I IFN production that would promote daratumumab-mediated clearance of AML cells.
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20
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Zhang J, Zheng B, Zhou X, Zheng T, Wang H, Wang Y, Zhang W. Increased BST-2 expression by HBV infection promotes HBV-associated HCC tumorigenesis. J Gastrointest Oncol 2021; 12:694-710. [PMID: 34012659 PMCID: PMC8107608 DOI: 10.21037/jgo-20-356] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 01/11/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The majority of hepatocellular carcinoma (HCC) is closely associated with hepatitis B virus (HBV) infection, while the mechanism of HCC induced by HBV is debatable. Bone marrow stromal cell antigen 2 (BST-2), an N-glycoprotein, has been characterized as an oncogenic factor in several types of cancer. However, whether BST-2 plays an important role in HCC tumorigenesis remains unknown. METHODS A total of 182 HCC tumorous and adjacent nontumor liver tissues were collected. HepG2, Huh7, L02, HepAD38, and HEK293T cell lines were adopted in this study. Tumor proliferation was detected by CCK8, transwell, wound healing, colony formation assays in vitro, and in vivo tumorigenesis was measured by mouse xenografts. NF-κB activation was determined by luciferase assay and Western blot. Protein expression was detected by Western blot, ELISA, or qPCR. Immunoprecipitation was used to confirm the interaction between BST-2 and Syk. RESULTS Here, we observed the higher BST-2 expression in HBV-infected HCC than their paired adjacent tissues and HBV-uninfected HCC tissues, particularly more aberrant non-N-glycosylated BST-2 in HBV-infected HCC tumors. We also observed the increased ER degradation-enhancing α-mannosidase-like protein 3 (EDEM3), which is trimming of N-linked glycans by sequential removal of mannose residues, might result in more non-N-glycosylated form of BST-2. Moreover, we demonstrated that BST-2 and non-N-glycosylated BST-2 N65/92A mutant, not only enhanced the tumor characteristics of hepatoma cell lines in vitro, but also enhanced the growth of mouse xenografts in vivo. Mechanically, N65/92A mutant has stronger ability to promote HCC than BST-2 via NF-κB/ERK1/2 but not NF-κB/anti-apoptotic factors pathway. NF-κB inhibitor attenuated BST-2-mediated tumorigenesis of HCC. CONCLUSIONS Our findings illuminate the novel function of BST-2 as an oncogene of HBV-associated HCC, and highlight the novel relationship of N-glycosylation of BST-2 in regulating HCC tumorigenesis in vitro.
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Affiliation(s)
- Jun Zhang
- Institute of Virology and AIDS Research, the First Hospital of Jilin University, Changchun, China
| | - Baisong Zheng
- Institute of Virology and AIDS Research, the First Hospital of Jilin University, Changchun, China
| | - Xiaolei Zhou
- Institute of Virology and AIDS Research, the First Hospital of Jilin University, Changchun, China
| | - Tianhang Zheng
- Institute of Virology and AIDS Research, the First Hospital of Jilin University, Changchun, China
| | - Hong Wang
- Institute of Virology and AIDS Research, the First Hospital of Jilin University, Changchun, China
| | - Yingchao Wang
- Hepatobiliary Pancreatic Surgery, the First Hospital of Jilin University, Changchun, China
| | - Wenyan Zhang
- Institute of Virology and AIDS Research, the First Hospital of Jilin University, Changchun, China
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21
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Jin H, Zhang L, Wang S, Qian L. BST2 promotes growth and induces gefitinib resistance in oral squamous cell carcinoma via regulating the EGFR pathway. Arch Med Sci 2021; 17:1772-1782. [PMID: 34900059 PMCID: PMC8641506 DOI: 10.5114/aoms.2019.86183] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 04/18/2019] [Indexed: 12/04/2022] Open
Abstract
INTRODUCTION Gefitinib, well known as a new antitumor agent, has been applied in various cancers such as oral squamous cell carcinoma (OSCC). However, most patients eventually acquire resistance to gefitinib, and the molecular mechanism of gefitinib resistance is not well described. Bone marrow stromal cell antigen 2 (BST2) has been reported to promote tumor cell growth and confer chemotherapy resistance in various cancers. However, the roles of BST2 in OSCC still need to be fully understood. MATERIAL AND METHODS We determined the expression of BST2 in OSCC tissues using qRT-PCR, immunohistochemistry and western blot. Next, we used MTT assay, flow cytometry and western blot to determine the roles of BST2 in OSCC cell proliferation, cycle progression and apoptosis, respectively. Furthermore, we evaluated the effect of BST2 on gefitinib resistance in OSCC cells and explored the related molecular mechanism. RESULTS BST2 expression was up-regulated in OSCC tissues compared with the adjacent normal tissues. BST2 overexpression significantly enhanced OSCC cell proliferation, mediated the cell cycle progression and inhibited cell apoptosis. Additionally, the results showed that BST2 overexpression effectively induced gefitinib resistance in OSCC cells. Subsequent analysis revealed that the underlying mechanism was associated with activation of the EGFR pathway. CONCLUSIONS Our study indicated that BST2 promoted growth and induced gefitinib resistance in OSCC cells, at least partially, through regulating the EGFR pathway. Thus, BST2 could be used as a therapeutic target for gefitinib resistance in OSCC.
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Affiliation(s)
- Huang Jin
- Department of Stomatology, Shanghai Songjiang District Central Hospital, Shanghai, China
| | - Lianping Zhang
- Department of Stomatology, Shanghai Songjiang District Central Hospital, Shanghai, China
| | - Shufang Wang
- Department of Stomatology, Shanghai Songjiang District Central Hospital, Shanghai, China
| | - Lei Qian
- Department of Stomatology, Shanghai Songjiang District Central Hospital, Shanghai, China
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22
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Li X, Gou J, Li H, Yang X. Bioinformatic analysis of the expression and prognostic value of chromobox family proteins in human breast cancer. Sci Rep 2020; 10:17739. [PMID: 33082469 PMCID: PMC7576141 DOI: 10.1038/s41598-020-74792-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 10/07/2020] [Indexed: 02/07/2023] Open
Abstract
Chromobox (CBX) family proteins control chromatin structure and gene expression. However, the functions of CBXs in cancer progression, especially breast cancer, are inadequately studied. We assessed the significance of eight CBX proteins in breast cancer. We performed immunohistochemistry and bioinformatic analysis of data from Oncomine, GEPIA Dataset, bcGenExMiner, Kaplan–Meier Plotter, and cBioPortal. We compared mRNA and protein expression levels of eight CBX proteins between breast tumor and normal tissue. The expression difference of CBX7 was the greatest, and CBX7 was downregulated in breast cancer tissues compared with normal breast tissues. The expression of CBX2 was strongly associated with tumor stage. We further analyzed the association between the eight CBX proteins and the following clinicopathological features: menopause age, estrogen receptor (ER), progesterone receptor (PR) and HER-2 receptor status, nodal status, P53 status, triple-negative status, and the Scarff–Bloom–Richardson grade (SBR) and Nottingham prognostic index (NPI). Survival analysis in the Kaplan–Meier Plotter database showed that the eight CBX proteins were significantly associated with prognosis. Moreover, CBX genes in breast cancer patients had a high net alteration frequency of 57%. There were significant co-expression correlations between the following CBX protein pairs: CBX4 positively with CBX8, CBX6 positively with CBX7, and CBX2 negatively with CBX7. We also analyzed the Gene Ontology enrichment of the CBX proteins, including biological processes, cellular components, and molecular functions. CBX 1/2/3/5/8 may be oncogenes for breast cancer, whereas CBX 6 and 7 may be tumor suppressors for breast cancer. All eight CBX proteins may be predictive for prognosis. Clinical trials are needed to confirm the significance of the eight CBX proteins in breast cancer.
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Affiliation(s)
- Xiaomin Li
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China.,Department of Breast Surgery, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu City, Sichuan Province, People's Republic of China
| | - Junhe Gou
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Hongjiang Li
- Department of Breast Surgery, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu City, Sichuan Province, People's Republic of China
| | - Xiaoqin Yang
- Department of Breast Surgery, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu City, Sichuan Province, People's Republic of China.
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23
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Shi H, Luo K, Huang W. Bone Marrow Stromal Antigen 2 is a Potential Unfavorable Prognostic Factor for High-Grade Glioma. Onco Targets Ther 2020; 13:8723-8734. [PMID: 32943880 PMCID: PMC7468947 DOI: 10.2147/ott.s258631] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 07/07/2020] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Bone marrow stromal antigen 2 (BST2) is considered as a transmembrane glycoprotein and plays essential roles in innate immunity. It has been recently reported that up-regulation of BST2 was associated with the development of breast carcinoma. However, the clinical significance of BST2 in glioma has not been identified. The purpose of the present study is to explore the expression pattern and the role of BST2 in the progression of high-grade glioma. METHODS Expression levels of BST2 were tested in glioma tissues by analyzing the GEO database and immunohistochemistry staining. The prognostic role of BST2 in glioma was evaluated through univariate and multivariate analyses. In vitro and in vivo assays were conducted to confirm the role of BST2 on promoting glioma proliferation. RESULTS The mRNA level of BST2 was higher in glioma tissues than that in nontumorous brain tissues. High protein level of BST2 was correlated with larger tumor size and advanced WHO grade. Glioma patients with a high BST2 level had worse overall survival. In addition, BST2 was defined as an independent risk factor for glioma prognosis. Cellular and xenograft studies revealed that BST2 can significantly promote glioma proliferation. CONCLUSION Our study revealed that a high BST2 expression level was closely related to the unfavorable clinical features and poor prognosis of high-grade glioma patients. BST2 may serve as an invaluable prognostic indicator and novel therapeutic target for glioma treatment considering its membrane localization.
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Affiliation(s)
- Haiping Shi
- Department of Neurosurgery, Suining Central Hospital, Suining, Sichuan, People’s Republic of China
| | - Ke Luo
- Department of Neurosurgery, Suining Central Hospital, Suining, Sichuan, People’s Republic of China
| | - Wei Huang
- Department of Neurosurgery, Suining Central Hospital, Suining, Sichuan, People’s Republic of China
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24
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Bruins WSC, Zweegman S, Mutis T, van de Donk NWCJ. Targeted Therapy With Immunoconjugates for Multiple Myeloma. Front Immunol 2020; 11:1155. [PMID: 32636838 PMCID: PMC7316960 DOI: 10.3389/fimmu.2020.01155] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 05/11/2020] [Indexed: 12/15/2022] Open
Abstract
The introduction of proteasome inhibitors (PI) and immunomodulatory drugs (IMiD) has markedly increased the survival of multiple myeloma (MM) patients. Also, the unconjugated monoclonal antibodies (mAb) daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7) have revolutionized MM treatment given their clinical efficacy and safety, illustrating the potential of targeted immunotherapy as a powerful treatment strategy for MM. Nonetheless, most patients eventually develop PI-, IMiD-, and mAb-refractory disease because of the selection of resistant MM clones, which associates with a poor prognosis. Accordingly, these patients remain in urgent need of new therapies with novel mechanisms of action. In this respect, mAbs or mAb fragments can also be utilized as carriers of potent effector moieties to specifically target surface antigens on cells of interest. Such immunoconjugates have the potential to exert anti-MM activity in heavily pretreated patients due to their distinct and pleiotropic mechanisms of action. In addition, the fusion of highly cytotoxic compounds to mAbs decreases the off-target toxicity, thereby improving the therapeutic window. According to the effector moiety, immunoconjugates are classified into antibody-drug conjugates, immunotoxins, immunocytokines, or radioimmunoconjugates. This review will focus on the mechanisms of action, safety and efficacy of several promising immunoconjugates that are under investigation in preclinical and/or clinical MM studies. We will also include a discussion on combination therapy with immunoconjugates, resistance mechanisms, and future developments.
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Affiliation(s)
- Wassilis S C Bruins
- Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Sonja Zweegman
- Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Tuna Mutis
- Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Niels W C J van de Donk
- Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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25
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Xu X, Wang Y, Xue F, Guan E, Tian F, Xu J, Zhang H. BST2 Promotes Tumor Growth via Multiple Pathways in Hepatocellular Carcinoma. Cancer Invest 2020; 38:329-337. [PMID: 32427495 DOI: 10.1080/07357907.2020.1769125] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Bone marrow stromal antigen 2 (BST2) is a transmembrane glycoprotein and plays an essential role in innate immunity. Here we firstly found that BST2 expression was significantly elevated in hepatocellular carcinoma (HCC) tissues. High BST2 was closely related to the larger tumor size and more tumor number. Moreover, HCC patients with higher expression of BST2 had poorer overall survival and BST2 was identified as an independent unfavorable prognosis factor. Finally, we demonstrated that BST2 can promote proliferation capacity of tumor cells. In conclusion, HCC patients with higher BST2 expression were more predisposed to poorer clinical symptoms and unfavorable prognosis.
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Affiliation(s)
- Xiaoguang Xu
- Department of Gastroenterology, Linyi Central Hospital, Shandong, Linyi, China
| | - Yu Wang
- Department of Gastroenterology, Linyi Central Hospital, Shandong, Linyi, China
| | - Fangxi Xue
- Department of Gastroenterology, Linyi Central Hospital, Shandong, Linyi, China
| | - Encui Guan
- Department of Gastroenterology, Linyi Central Hospital, Shandong, Linyi, China
| | - Feng Tian
- Department of Gastroenterology, Linyi Central Hospital, Shandong, Linyi, China
| | - Jian Xu
- Department of Gastroenterology, Linyi Central Hospital, Shandong, Linyi, China
| | - Hongjin Zhang
- Department of Endocrinology and Nephrology, The Third People's Hospital of Linyi, Shandong, Linyi, China
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Waheed AA, Swiderski M, Khan A, Gitzen A, Majadly A, Freed EO. The viral protein U (Vpu)-interacting host protein ATP6V0C down-regulates cell-surface expression of tetherin and thereby contributes to HIV-1 release. J Biol Chem 2020; 295:7327-7340. [PMID: 32291285 PMCID: PMC7247306 DOI: 10.1074/jbc.ra120.013280] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/09/2020] [Indexed: 12/11/2022] Open
Abstract
Host proteins with antiviral activity have evolved as first-line defenses to suppress viral replication. The HIV-1 accessory protein viral protein U (Vpu) enhances release of the virus from host cells by down-regulating the cell-surface expression of the host restriction factor tetherin. However, the exact mechanism of Vpu-mediated suppression of antiviral host responses is unclear. To further understand the role of host proteins in Vpu's function, here we carried out yeast two-hybrid screening and identified the V0 subunit C of vacuolar ATPase (ATP6V0C) as a Vpu-binding protein. To examine the role of ATP6V0C in Vpu-mediated tetherin degradation and HIV-1 release, we knocked down ATP6V0C expression in HeLa cells and observed that ATP6V0C depletion impairs Vpu-mediated tetherin degradation, resulting in defective HIV-1 release. We also observed that ATP6V0C overexpression stabilizes tetherin expression. This stabilization effect was specific to ATP6V0C, as overexpression of another subunit of the vacuolar ATPase, ATP6V0C″, had no effect on tetherin expression. ATP6V0C overexpression did not stabilize CD4, another target of Vpu-mediated degradation. Immunofluorescence localization experiments revealed that the ATP6V0C-stabilized tetherin is sequestered in a CD63- and lysosome-associated membrane protein 1 (LAMP1)-positive intracellular compartment. These results indicate that the Vpu-interacting protein ATP6V0C plays a role in down-regulating cell-surface expression of tetherin and thereby contributes to HIV-1 assembly and release.
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Affiliation(s)
- Abdul A Waheed
- Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702.
| | - Maya Swiderski
- Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702
| | - Ali Khan
- Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702
| | - Ariana Gitzen
- Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702
| | - Ahlam Majadly
- Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702
| | - Eric O Freed
- Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702
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Coleman DJ, Sampson DA, Sehrawat A, Kumaraswamy A, Sun D, Wang Y, Schwartzman J, Urrutia J, Lee AR, Coleman IM, Nelson PS, Dong X, Morrissey C, Corey E, Xia Z, Yates JA, Alumkal JJ. Alternative splicing of LSD1+8a in neuroendocrine prostate cancer is mediated by SRRM4. Neoplasia 2020; 22:253-262. [PMID: 32403054 PMCID: PMC7218227 DOI: 10.1016/j.neo.2020.04.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 04/06/2020] [Indexed: 02/06/2023] Open
Abstract
Neuroendocrine prostate cancer (NEPC) is the most virulent form of prostate cancer. Importantly, our recent work examining metastatic biopsy samples demonstrates NEPC is increasing in frequency. In contrast to prostate adenocarcinomas that express a luminal gene expression program, NEPC tumors express a neuronal gene expression program. Despite this distinction, the diagnosis of NEPC is often challenging, demonstrating an urgent need to identify new biomarkers and therapeutic targets. Our prior work demonstrated that the histone demethylase LSD1 (KDM1A) is important for survival of prostate adenocarcinomas, but little was known about LSD1's role in NEPC. Recently, a neural-specific transcript variant of LSD1-LSD1+8a-was discovered and demonstrated to activate neuronal gene expression in neural cells. The splicing factor SRRM4 was previously shown to promote LSD1+8a splicing in neuronal cells, and SRRM4 promotes NEPC differentiation and cell survival. Therefore, we sought to determine if LSD1+8a might play a role in NEPC and whether LSD1+8a splicing was linked to SRRM4. To investigate a potential role for LSD1+8a in NEPC, we examined a panel of prostate adenocarcinoma and NEPC patient-derived xenografts and metastatic biopsies. LSD1+8a was expressed exclusively in NEPC samples and correlated significantly with elevated expression of SRRM4. Using SRRM4-overexpressing cell lines, we determined that SRRM4 mediates alternative splicing of LSD1+8a. Finally, using gain of function studies, we confirmed that LSD1+8a and SRRM4 co-regulate target genes distinct from canonical LSD1. Our findings suggest further study of the interplay between SRRM4 and LSD1+8a and mechanisms by which LSD1+8a regulates gene expression in NEPC is warranted.
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Affiliation(s)
- Daniel J Coleman
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - David A Sampson
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Archana Sehrawat
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Anbarasu Kumaraswamy
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Duanchen Sun
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Computational Biology Program, Oregon Health & Science University, Portland, OR, USA
| | - Yuzhuo Wang
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - Jacob Schwartzman
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Joshua Urrutia
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Ahn R Lee
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - Ilsa M Coleman
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Peter S Nelson
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Xuesen Dong
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - Colm Morrissey
- Department of Urology, University of Washington, Seattle, WA, USA
| | - Eva Corey
- Department of Urology, University of Washington, Seattle, WA, USA
| | - Zheng Xia
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Computational Biology Program, Oregon Health & Science University, Portland, OR, USA
| | - Joel A Yates
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Joshi J Alumkal
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
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Development and Characterization of the Shortest Anti-Adhesion Peptide Analogue of B49Mod1. Molecules 2020; 25:molecules25051188. [PMID: 32155736 PMCID: PMC7179399 DOI: 10.3390/molecules25051188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/25/2020] [Accepted: 02/29/2020] [Indexed: 02/07/2023] Open
Abstract
Inhibition of cancer cell adhesion is an effective approach to killing adherent cancer cells. B49 and its analog B49Mod1 peptides, derived from the extracellular domain (ECD) of bone marrow stromal antigen 2 (BST-2), display anti-adhesion activity on breast cancer cells. However, the minimal sequence required for this anti-adhesion activity is unknown. Here, we further characterized the anti-adhesion activity of B49Mod1. We show that the anti-adhesion activity of B49Mod1 may require cysteine-linked disulfide bond and that the peptide is susceptible to proteolytic deactivation. Using structure-activity relationship studies, we identified an 18-Mer sequence (B18) as the minimal peptide sequence mediating the anti-adhesion activity of B49Mod1. Atomistic molecular dynamic (MD) simulations reveal that B18 forms a stable complex with the ECD of BST-2 in aqueous solution. MD simulations further reveal that B18 may cause membrane defects that facilitates peptide translocation across the bilayer. Placement of four B18 chains as a transmembrane bundle results in water channel formation, indicating that B18 may impair membrane integrity and form pores. We hereby identify B18 as the minimal peptide sequence required for the anti-adhesion activity of B49Mod1 and provide atomistic insight into the interaction of B18 with BST-2 and the cell membrane.
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Zhang H, Sun X, Lu Y, Wu J, Feng J. DNA-methylated gene markers for colorectal cancer in TCGA database. Exp Ther Med 2020; 19:3042-3050. [PMID: 32256791 PMCID: PMC7086203 DOI: 10.3892/etm.2020.8565] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 11/21/2019] [Indexed: 12/21/2022] Open
Abstract
Colorectal cancer (CRC) is characterized by the accumulation of genetic and epigenetic alterations in neoplastic processes. DNA methylation, as an important epigenetic process, contributes to the development of CRC. In the present study, the epigenetic landscape of genes in CRC was characterized by analyzing the dataset from The Cancer Genome Atlas database and 177 DNA-methylated genes were screened based on the criterion of the Pearson correlation (R) between expression and methylation levels being >0.4. Pathway enrichment analysis revealed prominent pathways, including transcription and metabolism, further implying their significant role in tumorigenesis. Among the methylated genes, only zinc finger protein (ZNF)726 with aberrant expression was determined to affect overall survival (OS) as well as disease-free survival of patients with CRC. In addition, ZNF726 was identified as an independent prognostic risk factor for OS in patients with CRC. The methylation-based regulation of ZNF726 expression in CRC cells was further assessed using the Cancer Cell Line Encyclopedia database. Finally, the CpG island methylation of the ZNF726 promoter was evaluated to further elucidate its role in the development of CRC. In conclusion, the epigenetic landscape of genes in terms of promoter methylation in CRC was characterized, revealing that aberrant expression of ZNF726 may be an independent prognostic risk factor for OS in patients with CRC.
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Affiliation(s)
- Hui Zhang
- Research Center for Clinical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210000, P.R. China
| | - Xun Sun
- Research Center for Clinical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210000, P.R. China
| | - Ya Lu
- Research Center for Clinical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210000, P.R. China
| | - Jianzhong Wu
- Research Center for Clinical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210000, P.R. China
| | - Jifeng Feng
- Research Center for Clinical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210000, P.R. China
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Monti M, Consoli F, Vescovi R, Bugatti M, Vermi W. Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma. Cells 2020; 9:E417. [PMID: 32054102 PMCID: PMC7072514 DOI: 10.3390/cells9020417] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 02/05/2020] [Accepted: 02/07/2020] [Indexed: 12/12/2022] Open
Abstract
The prognosis of metastatic melanoma (MM) patients has remained poor for a long time. However, the recent introduction of effective target therapies (BRAF and MEK inhibitors for BRAFV600-mutated MM) and immunotherapies (anti-CTLA-4 and anti-PD-1) has significantly improved the survival of MM patients. Notably, all these responses are highly dependent on the fitness of the host immune system, including the innate compartment. Among immune cells involved in cancer immunity, properly activated plasmacytoid dendritic cells (pDCs) exert an important role, bridging the innate and adaptive immune responses and directly eliminating cancer cells. A distinctive feature of pDCs is the production of high amount of type I Interferon (I-IFN), through the Toll-like receptor (TLR) 7 and 9 signaling pathway activation. However, published data indicate that melanoma-associated escape mechanisms are in place to hijack pDC functions. We have recently reported that pDC recruitment is recurrent in the early phases of melanoma, but the entire pDC compartment collapses over melanoma progression. Here, we summarize recent advances on pDC biology and function within the context of melanoma immunity.
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Affiliation(s)
- Matilde Monti
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.M.); (R.V.); (M.B.)
| | - Francesca Consoli
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia at ASST-Spedali Civili, 25123 Brescia, Italy;
| | - Raffaella Vescovi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.M.); (R.V.); (M.B.)
| | - Mattia Bugatti
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.M.); (R.V.); (M.B.)
| | - William Vermi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.M.); (R.V.); (M.B.)
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Han Y, Nakayama J, Hayashi Y, Jeong S, Futakuchi M, Ito E, Watanabe S, Semba K. Establishment and characterization of highly osteolytic luminal breast cancer cell lines by intracaudal arterial injection. Genes Cells 2020; 25:111-123. [PMID: 31849141 DOI: 10.1111/gtc.12743] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 11/18/2019] [Accepted: 12/05/2019] [Indexed: 01/01/2023]
Abstract
Bone is one of the most common metastatic sites of breast cancer, and bone metastasis profoundly affects the quality of life of breast cancer patients. Bone metastasis is commonly observed among all the subtypes of breast cancer; however, its molecular mechanism has been analyzed only in triple-negative subtype of breast cancer (TNBC). To characterize the molecular mechanisms of bone metastasis of luminal breast cancer, we established a bone-metastatic model of the MCF7, luminal breast cancer cell line, with enhanced osteolytic activity by intracaudal arterial injection (CAI). Pathological analysis of the established cell lines revealed that they exhibited fierce osteolytic ability by promoting osteoclast differentiation and activity. The signature genes extracted from highly osteolytic MCF7 cell lines were differed from those of bone-metastatic TNBC cell lines. Our results suggest that unique mechanisms of osteolysis in bone-metastatic lesions of luminal breast cancer. In addition, several up-regulated genes in MCF7-BM (Bone Metastasis) 02 cell lines correlated with poor prognosis with luminal breast cancer patients. Our findings support further study on the bone-metastatic mechanisms of luminal breast cancer.
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Affiliation(s)
- Yuxuan Han
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Jun Nakayama
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.,Computational Bio-Big Data Open Innovation Lab. (CBBD-OIL), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
| | - Yusuke Hayashi
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Seongmoon Jeong
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Mitsuru Futakuchi
- Department of Pathology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Emi Ito
- Department of Biomolecular Profiling, Translational Research Center, Fukushima Medical University, Fukushima, Japan
| | - Shinya Watanabe
- Department of Biomolecular Profiling, Translational Research Center, Fukushima Medical University, Fukushima, Japan
| | - Kentaro Semba
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.,Department of Cell Factory, Translational Research Center, Fukushima Medical University, Fukushima, Japan
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Pidugu VK, Pidugu HB, Wu MM, Liu CJ, Lee TC. Emerging Functions of Human IFIT Proteins in Cancer. Front Mol Biosci 2019; 6:148. [PMID: 31921891 PMCID: PMC6930875 DOI: 10.3389/fmolb.2019.00148] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 12/04/2019] [Indexed: 12/14/2022] Open
Abstract
Interferon-induced protein with tetratricopeptide repeats (IFIT) genes are prominent interferon-stimulated genes (ISGs). The human IFIT gene family consists of four genes named IFIT1, IFIT2, IFIT3, and IFIT5. The expression of IFIT genes is very low in most cell types, whereas their expression is greatly enhanced by interferon treatment, viral infection, and pathogen-associated molecular patterns (PAMPs). The proteins encoded by IFIT genes have multiple tetratricopeptide repeat (TPR) motifs. IFIT proteins do not have any known enzymatic roles. However, they execute a variety of cellular functions by mediating protein-protein interactions and forming multiprotein complexes with cellular and viral proteins through their multiple TPR motifs. The versatile tertiary structure of TPR motifs in IFIT proteins enables them to be involved in distinct biological functions, including host innate immunity, antiviral immune response, virus-induced translation initiation, replication, double-stranded RNA signaling, and PAMP recognition. The current understanding of the IFIT proteins and their role in cellular signaling mechanisms is limited to the antiviral immune response and innate immunity. However, recent studies on IFIT protein functions and their involvement in various molecular signaling mechanisms have implicated them in cancer progression and metastasis. In this article, we focused on critical molecular, biological and oncogenic functions of human IFIT proteins by reviewing their prognostic significance in health and cancer. Research suggests that IFIT proteins could be novel therapeutic targets for cancer therapy.
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Affiliation(s)
| | | | - Meei-Maan Wu
- Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chung-Ji Liu
- Department of Oral and Maxillofacial Surgery, Mackay Memorial Hospital, Taipei, Taiwan
| | - Te-Chang Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
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Moloudizargari M, Abdollahi M, Asghari MH, Zimta AA, Neagoe IB, Nabavi SM. The emerging role of exosomes in multiple myeloma. Blood Rev 2019; 38:100595. [PMID: 31445775 DOI: 10.1016/j.blre.2019.100595] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 08/01/2019] [Accepted: 08/06/2019] [Indexed: 12/18/2022]
Abstract
Multiple myeloma (MM), one of the most prevalent hematological malignancies, accounts for approximately 10% of all blood cancers. In spite of the recent advancements in MM therapy, this malignancy of terminally differentiated plasma cells (PCs) continues to remain a hard-to-cure disease due to the emergence of drug resistance and frequent relapses. It is now well-established that the tumor-supportive involvement of the bone marrow microenvironment (BMM) including the cellular and non-cellular elements are the major causes behind treatment failures of MM as well as its main complications such as osteolytic bone loss. Exosomes (EXs) are membranous structures that carry signaling molecules and have recently received a great deal of attention as important mediators of inter-cellular communication in health and disease. EXs involve in the growth and drug resistance of many tumors via delivering their rich contents of bioactive molecules including miRNAs, growth factors, cytokines, signaling molecules, etc. With regard to MM, many studies have reported that EXs are among the main culprits playing key roles in the vicious network within the BMM of these patients. The main producers of EXs that largely contribute to MM pathogenesis are bone marrow stromal cells (BMSCs) as well as MM cells themselves. These cell types produce large amounts of EXs that affect a variety of target cells including natural killer (NK) cells, osteoclasts (OCs) and osteoblasts (OBs) to the advantage of tumor survival and progression. These EXs contain a different profile of proteins and miRNAs from that of EXs obtained from their counterparts in healthy individuals. MM patients exhibit distinguishable elevations in some of their contents such as miR-21, miR-146a, let-7b and miR-18a, while some molecules like miR-15a are markedly downregulated in EXs of MM patients compared to healthy individuals. These findings make EXs desirable biomarkers for early prediction of disease progression and drug resistance in the context of MM. On the other hand, due to the tumor-supportive role of EXs, targeting these structures in parallel to the conventional therapeutic regimens may be a promising approach to a successful anti-MM therapy. In the present work, an extensive review of the literature has been carried out to highlight the recent advances in the field.
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Affiliation(s)
- Milad Moloudizargari
- Department of Immunology, School of Medicine, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Asghari
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Sciences, Babol, Iran.
| | - Alina Andreea Zimta
- MedFuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Ioana Berindan Neagoe
- MedFuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Alshabi AM, Vastrad B, Shaikh IA, Vastrad C. Identification of Crucial Candidate Genes and Pathways in Glioblastoma Multiform by Bioinformatics Analysis. Biomolecules 2019; 9:biom9050201. [PMID: 31137733 PMCID: PMC6571969 DOI: 10.3390/biom9050201] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/17/2019] [Accepted: 05/23/2019] [Indexed: 02/07/2023] Open
Abstract
The present study aimed to investigate the molecular mechanisms underlying glioblastoma multiform (GBM) and its biomarkers. The differentially expressed genes (DEGs) were diagnosed using the limma software package. The ToppGene (ToppFun) was used to perform pathway and Gene Ontology (GO) enrichment analysis of the DEGs. Protein-protein interaction (PPI) networks, extracted modules, miRNA-target genes regulatory network and TF-target genes regulatory network were used to obtain insight into the actions of DEGs. Survival analysis for DEGs was carried out. A total of 590 DEGs, including 243 up regulated and 347 down regulated genes, were diagnosed between scrambled shRNA expression and Lin7A knock down. The up-regulated genes were enriched in ribosome, mitochondrial translation termination, translation, and peptide biosynthetic process. The down-regulated genes were enriched in focal adhesion, VEGFR3 signaling in lymphatic endothelium, extracellular matrix organization, and extracellular matrix. The current study screened the genes in the PPI network, extracted modules, miRNA-target genes regulatory network, and TF-target genes regulatory network with higher degrees as hub genes, which included NPM1, CUL4A, YIPF1, SHC1, AKT1, VLDLR, RPL14, P3H2, DTNA, FAM126B, RPL34, and MYL5. Survival analysis indicated that the high expression of RPL36A and MRPL35 were predicting longer survival of GBM, while high expression of AP1S1 and AKAP12 were predicting shorter survival of GBM. High expression of RPL36A and AP1S1 were associated with pathogenesis of GBM, while low expression of ALPL was associated with pathogenesis of GBM. In conclusion, the current study diagnosed DEGs between scrambled shRNA expression and Lin7A knock down samples, which could improve our understanding of the molecular mechanisms in the progression of GBM, and these crucial as well as new diagnostic markers might be used as therapeutic targets for GBM.
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Affiliation(s)
- Ali Mohamed Alshabi
- Department of Clinical Pharmacy, College of Pharmacy, Najran University, Najran 61441, Saudi Arabia.
| | - Basavaraj Vastrad
- Department of Pharmaceutics, SET`S College of Pharmacy, Dharwad, Karnataka 580002, India.
| | - Ibrahim Ahmed Shaikh
- Department of Pharmacology, College of Pharmacy, Najran University, Najran 61441, Saudi Arabia.
| | - Chanabasayya Vastrad
- Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karnataka, India.
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Oue N, Sentani K, Sakamoto N, Uraoka N, Yasui W. Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells. Int J Clin Oncol 2019; 24:771-778. [PMID: 30980196 DOI: 10.1007/s10147-019-01443-9] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 04/02/2019] [Indexed: 12/13/2022]
Abstract
Gastric cancer (GC), one of the most common human cancers, is a heterogeneous disease with different phenotypes, prognoses, and responses to treatment. Understanding the pathogenesis of GC at the molecular level is important for prognosis prediction and determining treatments. Microsatellite instability (MSI), silencing of MLH1, MGMT, and CDKN2A genes by DNA hypermethylation, KRAS mutation, APC mutation, and ERBB2 amplification are frequently found in intestinal type GC. Inactivation of CDH1 and RARB by DNA hypermethylation, and amplification of FGFR and MET, are frequently detected in diffuse type GC. In addition, BST2 and PCDHB9 genes are overexpressed in intestinal type GC. Both genes are associated with GC progression. GC can be divided into gastric/intestinal mucin phenotypes according to mucin expression. MSI, alterations of TP73, CDH1 mutation, and DNA methylation of MLH are detected frequently in the gastric mucin phenotype. TP53 mutation, deletion of APC, and DNA methylation of MGMT are detected frequently in the intestinal mucin phenotype. FKTN is overexpressed in the intestinal mucin phenotype, and IQGAP3 is overexpressed in the gastric mucin phenotype. These genes are involved in GC progression. To characterize cancer stem cells, a useful method is spheroid colony formation. KIFC1 and KIF11 genes show more than twofold higher expression in spheroid-forming cells than that in parental cells. Both KIF genes are overexpressed in GC, and knockdown of these genes inhibits spheroid formation. Alterations of these molecules may be useful to understand gastric carcinogenesis. Specific inhibitors of these molecules may also be promising anticancer drugs.
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Affiliation(s)
- Naohide Oue
- Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Kazuhiro Sentani
- Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Naoya Sakamoto
- Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Naohiro Uraoka
- Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
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Zhang G, Li X, Chen Q, Li J, Ruan Q, Chen YH, Yang X, Wan X. CD317 Activates EGFR by Regulating Its Association with Lipid Rafts. Cancer Res 2019; 79:2220-2231. [PMID: 30890618 DOI: 10.1158/0008-5472.can-18-2603] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 01/24/2019] [Accepted: 03/14/2019] [Indexed: 12/21/2022]
Abstract
EGFR regulates various fundamental cellular processes, and its constitutive activation is a common driver for cancer. Anti-EGFR therapies have shown benefit in cancer patients, yet drug resistance almost inevitably develops, emphasizing the need for a better understanding of the mechanisms that govern EGFR activation. Here we report that CD317, a surface molecule with a unique topology, activated EGFR in hepatocellular carcinoma (HCC) cells by regulating its localization on the plasma membrane. CD317 was upregulated in HCC cells, promoting cell-cycle progression and enhancing tumorigenic potential in a manner dependent on EGFR. Mechanistically, CD317 associated with lipid rafts and released EGFR from these ordered membrane domains, facilitating the activation of EGFR and the initiation of downstream signaling pathways, including the Ras-Raf-MEK-ERK and JAK-STAT pathways. Moreover, in HCC mouse models and patient samples, upregulation of CD317 correlated with EGFR activation. These results reveal a previously unrecognized mode of regulation for EGFR and suggest CD317 as an alternative target for treating EGFR-driven malignancies. SIGNIFICANCE: Activation of EGFR by CD317 in hepatocellular carcinoma cells suggests CD317 as an alternative target for treating EGFR-dependent tumors.
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Affiliation(s)
- Guizhong Zhang
- Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Xin Li
- Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Qian Chen
- Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Junxin Li
- Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Qingguo Ruan
- Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Youhai H Chen
- Department of Pathology and Laboratory of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Xiaolu Yang
- Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Xiaochun Wan
- Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People's Republic of China.
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Sharma A, Lal SK. Is tetherin a true antiviral: The influenza a virus controversy. Rev Med Virol 2019; 29:e2036. [DOI: 10.1002/rmv.2036] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 12/17/2018] [Accepted: 12/18/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Anshika Sharma
- School of ScienceMonash University, Sunway Campus Bandar Sunway Malaysia
| | - Sunil K. Lal
- School of ScienceMonash University, Sunway Campus Bandar Sunway Malaysia
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CBX6 is negatively regulated by EZH2 and plays a potential tumor suppressor role in breast cancer. Sci Rep 2019; 9:197. [PMID: 30655550 PMCID: PMC6336801 DOI: 10.1038/s41598-018-36560-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 11/22/2018] [Indexed: 12/21/2022] Open
Abstract
Chromobox 6 (CBX6) is a subunit of Polycomb Repressive Complex 1 (PRC1) that mediates epigenetic gene repression and acts as an oncogene or tumor suppressor in a cancer type-dependent manner. The specific function of CBX6 in breast cancer is currently undefined. In this study, a comprehensive analysis of The Cancer Genome Atlas (TCGA) dataset led to the identification of CBX6 as a consistently downregulated gene in breast cancer. We provided evidence showing enhancer of zeste homolog 2 (EZH2) negatively regulated CBX6 expression in a Polycomb Repressive Complex 2 (PRC2)-dependent manner. Exogenous overexpression of CBX6 inhibited cell proliferation and colony formation, and induced cell cycle arrest along with suppression of migration and invasion of breast cancer cells in vitro. Microarray analyses revealed that CBX6 governs a complex gene expression program. Moreover, CBX6 induced significant downregulation of bone marrow stromal cell antigen-2 (BST2), a potential therapeutic target, via interactions with its promoter region. Our collective findings support a tumor suppressor role of CBX6 in breast cancer.
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Liu J, Guo Y, Huang Y, Xue H, Bai S, Zhu J, Xia X, Shen B, Fang W. Effects of insulin-like growth factor binding protein 3 on apoptosis of cutaneous squamous cell carcinoma cells. Onco Targets Ther 2018; 11:6569-6577. [PMID: 30323629 PMCID: PMC6178943 DOI: 10.2147/ott.s167187] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Background Cutaneous squamous cell carcinoma (CSCC) is the second most common carcinoma worldwide. Clinical treatment for patients with CSCC remains non-ideal. Insulin-like growth factor binding protein 3 (IGFBP3), a member of the insulin-like growth (IGF) system, participates in several biological processes, including cellular proliferation and apoptosis. Here, we explored the functional role of IGFBP3 in apoptosis and proliferation of A431 cells, a human CSCC cell line. Materials and methods Differential expression analysis, immunohistochemistry, immunoblotting, TUNEL assay, and CCK8 assay techniques were used to investigate the IGFBP3 expression levels in both A431 cells and CSCC tissue surgically obtained from humans as well as to explore the functional role of IGFBP3 in the apoptosis and proliferation of A431 cells. Results By using normal epidermal keratinocytes for comparison, we identified the top 10 ranked differentially upregulated genes expressed in human cutaneous squamous cell carcinoma cell lines. Among these 10 genes, IGFBP3 was ranked number 1. By using immunohistochemistry, we found that the expression level of IGFBP3 was significantly elevated in CSCC tissue compared with that in normal human skin tissue. Knockdown of IGFBP3 in A431 cells by transfection with IGFBP3-specific siRNA markedly altered the expression of proteins that contribute to apoptosis via mitochondrial pathways, significantly suppressing the expression of Bax and active caspase-3, while significantly increasing B-cell lymphoma-2 expression. TUNEL assay confirmed the effect of knockdown of IGFBP3 on the apoptosis as well. In addition, knockdown of IGFBP3 inhibited the proliferation of A431 cells. Conclusion IGFBP3 is overexpressed in both CSCC cell lines and tissue. Knockdown of IGFBP3 enhanced the apoptosis via a mitochondrial pathway and inhibited the proliferation of A431 cells. These findings indicate that IGFBP3 may be a biomarker and a potential therapeutic target for CSCC.
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Affiliation(s)
- Jinli Liu
- Department of Dermatology, Anhui Provincial Hospital, Hefei 230001, Anhui, China
| | - Yuanyuan Guo
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China
| | - Yuanyuna Huang
- Department of Gastroenterology and Hepatology, The Fourth Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui, China
| | - Haowei Xue
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Suwen Bai
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China
| | - Jinhang Zhu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China
| | - Xianming Xia
- Department of Gastroenterology and Hepatology, The Fourth Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui, China
| | - Bing Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China
| | - Wei Fang
- Department of ICU, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266071, China,
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Kim SC, Hong CW, Jang SG, Kim YA, Yoo BC, Shin YK, Jeong SY, Ku JL, Park JG. Establishment and Characterization of Paired Primary and Peritoneal Seeding Human Colorectal Cancer Cell Lines: Identification of Genes That Mediate Metastatic Potential. Transl Oncol 2018; 11:1232-1243. [PMID: 30114595 PMCID: PMC6097464 DOI: 10.1016/j.tranon.2018.07.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 07/23/2018] [Indexed: 01/10/2023] Open
Abstract
Peritoneal metastasis is one of the major patterns of unresectability in colorectal cancer (CRC) and a cause of death in advanced CRC. Identification of distinct gene expressions between primary CRC and peritoneal seeding metastasis is to predict the metastatic potential of primary human CRC. Three pairs of primary CRC (SNU-2335A, SNU-2404A, and SNU-2414A) and corresponding peritoneal seeding (SNU-2335D, SNU-2404B, and SNU-2414B) cell lines were established to determine the different gene expressions and resulting aberrated signaling pathways in peritoneal metastasis tumor using whole exome sequencing and microarray. Whole exome sequencing detected that mutation in CYP2A7 was exclusively shared in peritoneal seeding cell lines. Microarray identified that there were five upregulated genes (CNN3, SORBS1, BST2, EPSTI1, and KLHL5) and two downregulated genes (TRY6 and STYL5) in the peritoneal metastatic cell lines. CNN3 expression was highly augmented in both mRNA and protein levels in peritoneal metastasis cells. Knockdown of Calponin 3 resulted in augmented level of E-cadherin in peritoneal metastasis cells, and migration and invasiveness decreased accordingly. We suggest that CNN3 takes part in cell projection and movement, and the detection and distribution of CNN3 may render prognostic information for predicting peritoneal seeding metastasis from primary colorectal cancer.
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Affiliation(s)
- Soon-Chan Kim
- Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Chang-Won Hong
- Colorectal Cancer Branch, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 10408, Korea
| | - Sang-Geun Jang
- Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Ye-Ah Kim
- Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Byong-Chul Yoo
- Colorectal Cancer Branch, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 10408, Korea
| | - Young-Kyoung Shin
- Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Seung-Yong Jeong
- Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea; Department of Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Yeongeon-dong, Jongno-gu, Seoul 03080, Korea
| | - Ja-Lok Ku
- Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.
| | - Jae-Gahb Park
- Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea; Department of Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Yeongeon-dong, Jongno-gu, Seoul 03080, Korea.
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41
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Liu W, Cao Y, Guan Y, Zheng C. BST2 promotes cell proliferation, migration and induces NF-κB activation in gastric cancer. Biotechnol Lett 2018; 40:1015-1027. [PMID: 29774441 DOI: 10.1007/s10529-018-2562-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 05/03/2018] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To investigate the functional roles of bone marrow stromal cell antigen 2 (BST2) in gastric cancer (GC) cells and its implications in the development of GC patients. RESULTS BST2 was frequently overexpressed in GC tissues compared with the adjacent non-tumorous tissues, and high BST2 expression was correlated with tumor stage and lymphatic metastasis. Furthermore, in vitro experiments demonstrated that knockdown of BST2 by siRNA inhibited cell proliferation, induced apoptosis and repressed cell motility in GC cells. In addition, the pro-tumor function of BST2 in GC was mediated partly through the NF-κB signaling. CONCLUSION BST2 possesses the oncogenic potential in GC by regulating the proliferation, apoptosis, and migratory ability of GC cells, thereby BST2 could be a potential therapeutic target for the treatment of GC.
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Affiliation(s)
- Weiyu Liu
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang, 110022, People's Republic of China
- Department of Gastroenterology, The People's Hospital of Liaoning Province, Shenyang, 110013, People's Republic of China
| | - Yong Cao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang, 110022, People's Republic of China
| | - Yadi Guan
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang, 110022, People's Republic of China
| | - Changqing Zheng
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang, 110022, People's Republic of China.
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42
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Yang LL, Wu L, Yu GT, Zhang WF, Liu B, Sun ZJ. CD317 Signature in Head and Neck Cancer Indicates Poor Prognosis. J Dent Res 2018; 97:787-794. [PMID: 29486141 DOI: 10.1177/0022034518758604] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Targeted therapy using monoclonal antibodies (mAbs) has emerged as a widely used form of immunotherapy in head and neck squamous cell carcinoma (HNSCC). Membrane-associated glycoprotein CD317 has been preferentially overexpressed by multiple myeloma cells, and its humanized mAb has been previously used in clinical trials. However, overexpression of CD317 in HNSCC and its correlation with tumor immunity is still uncertain. Here, the immunoreactivity of CD317 was detected in human HNSCC tissue microarrays, which contained 43 oral mucosa samples, 48 dysplasia samples, and 165 primary HNSCC. We found that CD317 expression was up-regulated in HNSCC tumor cells, and the CD317 expression level was independent of the histological grade, tumor size, and lymph node metastasis. Moreover, Kaplan–Meier survival curve analysis showed that patients with high expression of CD317 had a poor prognosis compared with patients with low expression. Furthermore, CD317 overexpression in HNSCC was correlated with immune checkpoint molecules PD-L1, B7-H3, and B7-H4 and tumor-associated macrophage markers (CD68 and CD163). We also observed that CD317 was overexpressed in immunocompetent mouse HNSCC tissue compared with normal tissue. Taken together, our findings demonstrate that CD317 overexpression indicates poor prognosis and is correlated with immune-related components in this patient cohort. CD317 may serve as a potential target for effective immunotherapy of HNSCC.
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Affiliation(s)
- L.-L. Yang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - L. Wu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - G.-T. Yu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - W.-F. Zhang
- Department of Oral Maxillofacial–Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - B. Liu
- Department of Oral Maxillofacial–Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Z.-J. Sun
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral Maxillofacial–Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
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43
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Waheed AA, Gitzen A, Swiderski M, Freed EO. High-Mannose But Not Complex-Type Glycosylation of Tetherin Is Required for Restriction of HIV-1 Release. Viruses 2018; 10:v10010026. [PMID: 29303997 PMCID: PMC5795439 DOI: 10.3390/v10010026] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 12/28/2017] [Accepted: 12/31/2017] [Indexed: 11/16/2022] Open
Abstract
Tetherin is an interferon-inducible antiviral protein that inhibits the release of a broad spectrum of enveloped viruses by retaining virions at the surface of infected cells. While the role of specific tetherin domains in antiviral activity is clearly established, the role of glycosylation in tetherin function is not clear. In this study, we carried out a detailed investigation of this question by using tetherin variants in which one or both sites of N-linked glycosylation were mutated (N65A, N92A, and N65,92A), and chemical inhibitors that prevent glycosylation at specific stages of oligosaccharide were added or modified. The single N-linked glycosylation mutants, N65A and N92A, efficiently inhibited the release of Vpu-defective human immunodeficiency virus type 1 (HIV-1). In contrast, the non-glycosylated double mutant, N65,92A, lost its ability to block HIV-1 release. The inability of the N65,92A mutant to inhibit HIV-1 release is associated with a lack of cell-surface expression. A role for glycosylation in cell-surface tetherin expression is supported by tunicamycin treatment, which inhibits the first step of N-linked glycosylation and impairs both cell-surface expression and antiviral activity. Inhibition of complex-type glycosylation with kifunensine, an inhibitor of the oligosaccharide processing enzyme mannosidase 1, had no effect on either the cell-surface expression or antiviral activity of tetherin. These results demonstrate that high-mannose modification of a single asparagine residue is necessary and sufficient, while complex-type glycosylation is dispensable, for cell-surface tetherin expression and antiviral activity.
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Affiliation(s)
- Abdul A Waheed
- Virus-Cell Interaction Section, HIV Dynamics and Replication Program, National Cancer Institute, Bldg. 535, Room 108B, 1050 Boyles St., Frederick, MD 21702-1201, USA.
| | - Ariana Gitzen
- Virus-Cell Interaction Section, HIV Dynamics and Replication Program, National Cancer Institute, Bldg. 535, Room 108B, 1050 Boyles St., Frederick, MD 21702-1201, USA.
| | - Maya Swiderski
- Virus-Cell Interaction Section, HIV Dynamics and Replication Program, National Cancer Institute, Bldg. 535, Room 108B, 1050 Boyles St., Frederick, MD 21702-1201, USA.
| | - Eric O Freed
- Virus-Cell Interaction Section, HIV Dynamics and Replication Program, National Cancer Institute, Bldg. 535, Room 108B, 1050 Boyles St., Frederick, MD 21702-1201, USA.
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Structural determinant of BST-2-mediated regulation of breast cancer cell motility: a role for cytoplasmic tail tyrosine residues. Oncotarget 2017; 8:110221-110233. [PMID: 29299143 PMCID: PMC5746378 DOI: 10.18632/oncotarget.22753] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 11/09/2017] [Indexed: 01/25/2023] Open
Abstract
There is now irrefutable evidence that overexpression of the innate immunity protein―BST-2, in breast cancer cells is implicated in tumor growth and progression. The cellular mechanisms that control BST-2-mediated effect in tumor progression involve enhancement of cancer cell motility―migration/invasion. However, the distinct structural elements of BST-2 that mediate breast cancer cell motility remain unknown. Here, we used various motility assays and different variants of BST-2 to examine the cellular and structural mechanisms controlling BST-2-mediated cell motility. We show that BST-2 silencing in various cancer cell lines inhibits cell motility. Restoration of BST-2 expression using construct expressing wild type BST-2 rescues cell motility. Mutational analysis identifies the cytoplasmic tail of BST-2 as a novel regulator of cancer cell motility, because cell motility was significantly abrogated by substitution of the BST-2 cytoplasmic tail tyrosine residues to alanine residues. Furthermore, in a spheroid invasion model, BST-2-expressing tumor spheroids are highly invasive inside 3D Matrigel matrices. In this model, the spreading distance of BST-2-expressing spheroids was significantly higher than that of BST-2-suppressed spheroids. Collectively, our data reveal that i) BST-2-expressing breast cancer cells in spheroids are more motile than their BST-2-supressed counterparts; ii) BST-2 cytoplasmic tail regulates non-proteolytic (migration) and proteolytic (invasion) mechanisms of breast cancer cell motility; and iii) replacement of the tyrosine residues at positions 6 and 8 in the cytoplasmic tail of BST-2 with alanine residues inhibits cell motility.
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45
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Arabzadeh A, McGregor K, Breton V, Van Der Kraak L, Akavia UD, Greenwood CMT, Beauchemin N. EphA2 signaling is impacted by carcinoembryonic antigen cell adhesion molecule 1-L expression in colorectal cancer liver metastasis in a cell context-dependent manner. Oncotarget 2017; 8:104330-104346. [PMID: 29262644 PMCID: PMC5732810 DOI: 10.18632/oncotarget.22236] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 10/05/2017] [Indexed: 12/12/2022] Open
Abstract
We have shown that carcinoembryonic antigen cell adhesion molecule 1 long isoform (CEACAM1-L) expression in MC38 metastatic colorectal cancer (CRC) cells results in liver metastasis inhibition via CCL2 and STAT3 signaling. But other molecular mechanisms orchestrating CEACAM1-L-mediated metastasis inhibition remain to be defined. We screened a panel of mouse and human CRC cells and evaluated their metastatic outcome after CEACAM1 overexpression or downregulation. An unbiased transcript profiling and a phospho-receptor tyrosine kinase screen comparing MC38 CEACAM1-L-expressing and non-expressing (CT) CRC cells revealed reduced ephrin type-A receptor 2 (EPHA2) expression and activity. An EPHA2-specific inhibitor reduced EPHA2 downstream signaling in CT cells similar to that in CEACAM1-L cells with decreased proliferation and migration. Human CRC patients exhibiting high CEACAM1 in combination with low EPHA2 expression benefited from longer time to first recurrence/metastasis compared to those with high EPHA2 expression. With the added interaction of CEACAM6, we denoted that CEACAM1 high- and EPHA2 low-expressing patient samples with lower CEACAM6 expression also exhibited a longer time to first recurrence/metastasis. In HT29 human CRC cells, down-regulation of CEACAM1 along with CEA and CEACAM6 up-regulation led to higher metastatic burden. Overall, CEACAM1-L expression in poorly differentiated CRC can inhibit liver metastasis through cell context-dependent EPHA2-mediated signaling. However, CEACAM1’s role should be considered in the presence of other CEACAM family members.
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Affiliation(s)
- Azadeh Arabzadeh
- Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | - Kevin McGregor
- Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, QC, Canada
| | - Valérie Breton
- Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | - Lauren Van Der Kraak
- Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.,Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - Uri David Akavia
- Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.,Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - Celia M T Greenwood
- Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, QC, Canada.,Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.,Departments of Oncology and Human Genetics, McGill University, Montreal, QC, Canada
| | - Nicole Beauchemin
- Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.,Department of Biochemistry, McGill University, Montreal, QC, Canada.,Departments of Medicine and Oncology, McGill University, Montreal, QC, Canada
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Januchowski R, Sterzyńska K, Zawierucha P, Ruciński M, Świerczewska M, Partyka M, Bednarek-Rajewska K, Brązert M, Nowicki M, Zabel M, Klejewski A. Microarray-based detection and expression analysis of new genes associated with drug resistance in ovarian cancer cell lines. Oncotarget 2017; 8:49944-49958. [PMID: 28611294 PMCID: PMC5564819 DOI: 10.18632/oncotarget.18278] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 04/24/2017] [Indexed: 12/24/2022] Open
Abstract
PURPOSE The present study is to discover a new genes associated with drug resistance development in ovarian cancer. METHODS We used microarray analysis to determine alterations in the level of expression of genes in cisplatin- (CisPt), doxorubicin- (Dox), topotecan- (Top), and paclitaxel- (Pac) resistant variants of W1 and A2780 ovarian cancer cell lines. Immunohistochemistry assay was used to determine protein expression in ovarian cancer patients. RESULTS We observed alterations in the expression of 22 genes that were common to all three cell lines that were resistant to the same cytostatic drug. The level of expression of 13 genes was upregulated and that of nine genes was downregulated. In the CisPt-resistant cell line, we observed downregulated expression of ABCC6, BST2, ERAP2 and MCTP1; in the Pac-resistant cell line, we observe upregulated expression of ABCB1, EPHA7 and RUNDC3B and downregulated expression of LIPG, MCTP1, NSBP1, PCDH9, PTPRK and SEMA3A. The expression levels of three genes, ABCB1, ABCB4 and IFI16, were upregulated in the Dox-resistant cell lines. In the Top-resistant cell lines, we observed increased expression levels of ABCG2, HERC5, IFIH1, MYOT, S100A3, SAMD4A, SPP1 and TGFBI and decreased expression levels of MCTP1 and PTPRK. The expression of EPHA7, IFI16, SPP1 and TGFBI was confirmed at protein level in analyzed ovarian cancer patients.. CONCLUSIONS The expression profiles of the investigated cell lines indicated that new candidate genes are related to the development of resistance to the cytostatic drugs that are used in first- and second-line chemotherapy of ovarian cancer.
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Affiliation(s)
- Radosław Januchowski
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | - Karolina Sterzyńska
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | - Piotr Zawierucha
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
- Department of Anatomy, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | - Marcin Ruciński
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | - Monika Świerczewska
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | - Małgorzata Partyka
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | | | - Maciej Brązert
- Division of Infertility and Reproductive Endocrinology, Department of Gynecology, Obstetrics and Gynecological Oncology, Poznań University of Medical Sciences, Poznań, 60-535, Poland
| | - Michał Nowicki
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | - Maciej Zabel
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
- Department of Histology and Embryology, Wrocław Medical University, Wrocław, 50-368, Poland
| | - Andrzej Klejewski
- Department of Nursing, Poznań University of Medical Sciences, Poznań, 60-179, Poland
- Departament of Obstetrics and Womens Dieseases, Poznań University of Medical Sciences, Poznań, 60-535, Poland
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BST2 confers cisplatin resistance via NF-κB signaling in nasopharyngeal cancer. Cell Death Dis 2017; 8:e2874. [PMID: 28617432 PMCID: PMC5520926 DOI: 10.1038/cddis.2017.271] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 04/28/2017] [Accepted: 05/09/2017] [Indexed: 11/26/2022]
Abstract
Concurrent/adjuvant cisplatin-based chemoradiotherapy is regarded as the standard of treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, patients who do not respond to cisplatin suffer, rather than benefit, from chemotherapy treatment. The goal of this study was to identify molecules involved in cisplatin resistance and to clarify their molecular mechanisms, which would help in the discovery of potential therapeutic targets and in developing a personalized and precise treatment approach for NPC patients. We previously generated a cisplatin-sensitive NPC cell line, S16, from CNE2 cells and found that eIF3a, ASNS and MMP19 are upregulated in S16 cells, which contributes to their cisplatin sensitivity. In this study, we found that BST2 is downregulated in cisplatin-sensitive S16 cells compared with CNE2 cells. Knockdown of BST2 in NPC cells sensitized their response to cisplatin and promoted cisplatin-induced apoptosis, whereas exogenous overexpression of BST2 increased their cisplatin resistance and inhibited cisplatin-induced apoptosis. Further investigation demonstrated that BST2-mediated cisplatin resistance depended on the activation of the NF-κB signaling pathway and consequent upregulation of anti-apoptotic genes, such as Bcl-XL and livin. Moreover, an analysis of clinical data revealed that a high BST2 level might serve as an independent indicator of poor prognosis in patients with locally advanced NPC treated with platinum-based chemoradiotherapy. These findings suggest that BST2 likely mediates platinum resistance in NPC, offering guidance for personalized and precise treatment strategies for patients with NPC.
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Shigematsu Y, Oue N, Nishioka Y, Sakamoto N, Sentani K, Sekino Y, Mukai S, Teishima J, Matsubara A, Yasui W. Overexpression of the transmembrane protein BST-2 induces Akt and Erk phosphorylation in bladder cancer. Oncol Lett 2017; 14:999-1004. [PMID: 28693265 DOI: 10.3892/ol.2017.6230] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 03/07/2017] [Indexed: 11/05/2022] Open
Abstract
Bladder cancer, the majority of which is urothelial carcinoma (UC), is a common malignancy worldwide. Genes encoding transmembrane/secretory proteins expressed specifically in certain cancers may be ideal biomarkers for cancer diagnosis and may represent therapeutic targets. In the present study, the expression and function of the bone marrow stromal cell antigen 2 (BST2) gene was analyzed in UC. Reverse transcription-quantitative polymerase chain reaction demonstrated that expression of BST2 in normal tissue samples was the highest in liver tissue. However, expression of BST2 in UC tissue samples was higher than in normal liver. Immunohistochemical analysis revealed weak or no staining of BST-2 in non-neoplastic mucosa, whereas UC tissue exhibited stronger and more extensive staining compared with non-neoplastic mucosa. BST-2 staining was observed mainly on UC cell membranes. In total, 28 (41%) of 69 UC cases were positive for BST-2. UC cases positive for BST-2 were more frequently T2/3/4 cases [so-called muscle-invasive bladder cancer (MIBC)] than Ta/is/1 cases (P=0.0001). However, Kaplan-Meier analysis demonstrated no association between BST-2 expression and survival. BST2 small interfering RNA (siRNA)-transfected T24 cells exhibited significantly reduced cell growth relative to negative control siRNA-transfected T24 cells. The levels of phosphorylated Akt and extracellular signal-regulated kinase were lower in BST2 siRNA-transfected T24 cells than in control cells. These results suggest the involvement of BST-2 in the pathogenesis of UC. Since BST-2 is expressed on the cell membrane, BST-2 may be a good therapeutic target for MIBC.
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Affiliation(s)
- Yoshinori Shigematsu
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan.,Department of Urology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Naohide Oue
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Yuri Nishioka
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Naoya Sakamoto
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Kazuhiro Sentani
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Yohei Sekino
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan.,Department of Urology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Shoichiro Mukai
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Jun Teishima
- Department of Urology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Akio Matsubara
- Department of Urology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
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Bellanger A, Donini CF, Vendrell JA, Lavaud J, Machuca-Gayet I, Ruel M, Vollaire J, Grisard E, Győrffy B, Bièche I, Peyruchaud O, Coll JL, Treilleux I, Maguer-Satta V, Josserand V, Cohen PA. The critical role of the ZNF217 oncogene in promoting breast cancer metastasis to the bone. J Pathol 2017; 242:73-89. [PMID: 28207159 DOI: 10.1002/path.4882] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 11/10/2016] [Accepted: 01/18/2017] [Indexed: 12/24/2022]
Abstract
Bone metastasis affects >70% of patients with advanced breast cancer. However, the molecular mechanisms underlying this process remain unclear. On the basis of analysis of clinical datasets, and in vitro and in vivo experiments, we report that the ZNF217 oncogene is a crucial mediator and indicator of bone metastasis. Patients with high ZNF217 mRNA expression levels in primary breast tumours had a higher risk of developing bone metastases. MDA-MB-231 breast cancer cells stably transfected with ZNF217 (MDA-MB-231-ZNF217) showed the dysregulated expression of a set of genes with bone-homing and metastasis characteristics, which overlapped with two previously described 'osteolytic bone metastasis' gene signatures, while also highlighting the bone morphogenetic protein (BMP) pathway. The latter was activated in MDA-MB-231-ZNF217 cells, and its silencing by inhibitors (Noggin and LDN-193189) was sufficient to rescue ZNF217-dependent cell migration, invasion or chemotaxis towards the bone environment. Finally, by using non-invasive multimodal in vivo imaging, we found that ZNF217 increases the metastatic growth rate in the bone and accelerates the development of severe osteolytic lesions. Altogether, the findings of this study highlight ZNF217 as an indicator of the emergence of breast cancer bone metastasis; future therapies targeting ZNF217 and/or the BMP signalling pathway may be beneficial by preventing the development of bone metastases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Aurélie Bellanger
- Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.,Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Caterina F Donini
- Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.,Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France.,Unité Cancer et Environnement, Centre Léon Bérard, Lyon, France
| | - Julie A Vendrell
- Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.,Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Jonathan Lavaud
- INSERM U1209, Institut Albert Bonniot, Grenoble, France.,Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France
| | - Irma Machuca-Gayet
- Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France.,INSERM, Unit 1033 (Faculté de Médecine Lyon Est), Lyon, France
| | - Maëva Ruel
- Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.,Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Julien Vollaire
- INSERM U1209, Institut Albert Bonniot, Grenoble, France.,Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France
| | - Evelyne Grisard
- Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.,Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Balázs Győrffy
- MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.,Second Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Ivan Bièche
- Unit of Pharmacogenetics, Department of Genetics, Institut Curie, Paris, France
| | - Olivier Peyruchaud
- Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France.,INSERM, Unit 1033 (Faculté de Médecine Lyon Est), Lyon, France
| | - Jean-Luc Coll
- INSERM U1209, Institut Albert Bonniot, Grenoble, France.,Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France
| | | | - Véronique Maguer-Satta
- Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
| | - Véronique Josserand
- INSERM U1209, Institut Albert Bonniot, Grenoble, France.,Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France
| | - Pascale A Cohen
- Univ. Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.,Univ. Lyon, Université Claude Bernard Lyon 1, Lyon, France
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Mahauad-Fernandez WD, Okeoma CM. Cysteine-linked dimerization of BST-2 confers anoikis resistance to breast cancer cells by negating proapoptotic activities to promote tumor cell survival and growth. Cell Death Dis 2017; 8:e2687. [PMID: 28300825 PMCID: PMC5386562 DOI: 10.1038/cddis.2017.68] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 12/23/2016] [Accepted: 01/03/2017] [Indexed: 12/11/2022]
Abstract
Almost all breast tumors express the antiviral protein BST-2 with 67%, 25% and 8.2% containing high, medium or low levels of BST-2, respectively. Breast tumor cells and tissues that contain elevated levels of BST-2 are highly aggressive. Suppression of BST-2 expression reprograms tumorigenic properties of cancer cells and diminishes cancer cell aggressiveness. Using structure/function studies, we report that dimerization of BST-2 through cysteine residues located in the BST-2 extracellular domain (ECD), leads to anoikis resistance and cell survival through proteasome-mediated degradation of BIM—a key proapoptotic factor. Importantly, BST-2 dimerization promotes tumor growth in preclinical breast cancer models in vitro and in vivo. Furthermore, we demonstrate that restoration of the ECD cysteine residues is sufficient to rescue cell survival and tumor growth via a previously unreported pathway—BST-2/GRB2/ERK/BIM/Cas3. These findings suggest that disruption of BST-2 dimerization offers a potential therapeutic approach for breast cancer.
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Affiliation(s)
| | - Chioma M Okeoma
- Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.,Interdisciplinary Graduate Program in Molecular and Cellular Biology (MCB), University of Iowa, Iowa City, IA, USA
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