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ID 59913
フルテキストURL
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著者
Okusha, Yuka Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kaken ID researchmap
Eguchi, Takanori Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University ORCID Kaken ID researchmap
Tran, Manh T. Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Sogawa, Chiharu Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University ORCID Kaken ID publons researchmap
Yoshida, Kaya Department of Oral Healthcare Education, Institute of Biomedical Sciences, Tokushima University Graduate School
Itagaki, Mami Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Taha, Eman A. Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Ono, Kisho Department of Oral and Maxillofacial Surgery, Okayama University Hospital Kaken ID researchmap
Aoyama, Eriko Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kaken ID researchmap
Okamura, Hirohiko Department of Oral Morphology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine ORCID Kaken ID publons researchmap
Kozaki, Ken-Ichi Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kaken ID researchmap
Calderwood, Stuart K. Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School
Takigawa, Masaharu Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kaken ID publons researchmap
Okamoto, Kuniaki Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kaken ID researchmap
抄録
Matrix metalloproteinase 3 (MMP3) plays multiple roles in extracellular proteolysis as well as intracellular transcription, prompting a new definition of moonlighting metalloproteinase (MMP), according to a definition of protein moonlighting (or gene sharing), a phenomenon by which a protein can perform more than one function. Indeed, connective tissue growth factor (CTGF, aka cellular communication network factor 2 (CCN2)) is transcriptionally induced as well as cleaved by MMP3. Moreover, several members of the MMP family have been found within tumor-derived extracellular vesicles (EVs). We here investigated the roles of MMP3-rich EVs in tumor progression, molecular transmission, and gene regulation. EVs derived from a rapidly metastatic cancer cell line (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich, LuM1-derived EVs were disseminated to multiple organs through body fluid and were pro-tumorigenic in an allograft mouse model, which prompted us to define LuM1-EVs as oncosomes in the present study. Oncosome-derived MMP3 was transferred into recipient cell nuclei and thereby trans-activated the CCN2/CTGF promoter, and induced CCN2/CTGF production in vitro. TRENDIC and other cis-elements in the CCN2/CTGF promoter were essential for the oncosomal responsivity. The CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects such as the inhibition of migration and invasion of tumor cells, and a reduction in CCN2/CTGF promoter activity and fragmentations in vitro. A high expression level of MMP3 or CCN2/CTGF mRNA was prognostic and unfavorable in particular types of cancers including head and neck, lung, pancreatic, cervical, stomach, and urothelial cancers. These data newly demonstrate that oncogenic EVs-derived MMP is a transmissive trans-activator for the cellular communication network gene and promotes tumorigenesis at distant sites.
キーワード
matrix metalloproteinase
moonlighting metalloproteinase (MMP)
protein moonlighting
transcription factor
extracellular vesicles
oncosome
genome editing
CRISPR
cellular communication network factor
CCN2/CTGF
発行日
2020-04-04
出版物タイトル
Cancers
12巻
4号
出版者
MDPI
開始ページ
881
ISSN
2072-6694
資料タイプ
学術雑誌論文
言語
English
OAI-PMH Set
岡山大学
著作権者
© 2020 by the authors.
論文のバージョン
publisher
PubMed ID
DOI
Web of Science KeyUT
関連URL
isVersionOf https://doi.org/10.3390/cancers12040881
ライセンス
http://creativecommons.org/licenses/by/4.0/
助成機関名
日本学術振興会
助成番号
17K17895
17K11642
19H03817
19H04051
17K11643
17K11669
18K09789