ID | 66979 |
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Gohara, Yuma
Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Tomonobu, Nahoko
Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Kinoshita, Rie
Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
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Futami, Junichiro
Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University
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Audebert, Léna
Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Chen, Youyi
Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Komalasari, Ni Luh Gede Yoni
Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Jiang, Fan
Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Yoshizawa, Chikako
Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Murata, Hitoshi
Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
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Yamamoto, Ken-ichi
Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Watanabe, Masami
Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
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Kumon, Hiromi
Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University
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Sakaguchi, Masakiyo
Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
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Abstract | The adenovirus-REIC/Dkk-3 expression vector (Ad-REIC) has been the focus of numerous clinical studies due to its potential for the quenching of cancers. The cancer-suppressing mechanisms of the REIC/DKK-3 gene depend on multiple pathways that exert both direct and indirect effects on cancers. The direct effect is triggered by REIC/Dkk-3-mediated ER stress that causes cancer-selective apoptosis, and the indirect effect can be classified in two ways: (i) induction, by Ad-REIC-mis-infected cancer-associated fibroblasts, of the production of IL-7, an important activator of T cells and NK cells, and (ii) promotion, by the secretory REIC/Dkk-3 protein, of dendritic cell polarization from monocytes. These unique features allow Ad-REIC to exert effective and selective cancer-preventative effects in the manner of an anticancer vaccine. However, the question of how the REIC/Dkk-3 protein leverages anticancer immunity has remained to be answered. We herein report a novel function of the extracellular REIC/Dkk-3—namely, regulation of an immune checkpoint via modulation of PD-L1 on the cancer-cell surface. First, we identified novel interactions of REIC/Dkk-3 with the membrane proteins C5aR, CXCR2, CXCR6, and CMTM6. These proteins all functioned to stabilize PD-L1 on the cell surface. Due to the dominant expression of CMTM6 among the proteins in cancer cells, we next focused on CMTM6 and observed that REIC/Dkk-3 competed with CMTM6 for PD-L1, thereby liberating PD-L1 from its complexation with CMTM6. The released PD-L1 immediately underwent endocytosis-mediated degradation. These results will enhance our understanding of not only the physiological nature of the extracellular REIC/Dkk-3 protein but also the Ad-REIC-mediated anticancer effects.
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Keywords | Breast cancer
REIC/Dkk-3
PD-L1
Immune checkpoint
Cancer therapy
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Note | The version of record of this article, first published in Journal of Molecular Medicine, is available online at Publisher’s website: http://dx.doi.org/10.1007/s00109-023-02292-w
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Published Date | 2023-03-04
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Publication Title |
Journal of Molecular Medicine
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Volume | volume101
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Issue | issue4
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Publisher | Springer Science and Business Media LLC
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Start Page | 431
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End Page | 447
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ISSN | 0946-2716
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NCID | AA11034065
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Content Type |
Journal Article
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language |
English
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OAI-PMH Set |
岡山大学
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Copyright Holders | © The Author(s) 2023
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File Version | publisher
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Related Url | isVersionOf https://doi.org/10.1007/s00109-023-02292-w
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License | http://creativecommons.org/licenses/by/4.0/
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Citation | Gohara, Y., Tomonobu, N., Kinoshita, R. et al. Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells. J Mol Med 101, 431–447 (2023). https://doi.org/10.1007/s00109-023-02292-w
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Funder Name |
Okayama University
Ministry of Education, Culture, Sports, Science and Technology
Japan Society for the Promotion of Science
Nagase Science and Technology Promotion Foundation
Momotaro-Gene Inc.
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助成番号 | 20H03516
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