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ID 115042
Author
Okusha, Yuka Okayama University|Harvard Medical School
Eguchi, Takanori Okayama University
Tran, Manh T. Okayama University
Sogawa, Chiharu Okayama University
Itagaki, Mami Okayama University
Taha, Eman A. Okayama University|Ain Shams University
Ono, Kisho Okayama University
Aoyama, Eriko Okayama University
Kozaki, Ken-ichi Okayama University
Calderwood, Stuart K. Harvard Medical School
Takigawa, Masaharu Okayama University
Okamoto, Kuniaki Okayama University
Keywords
matrix metalloproteinase
moonlighting metalloproteinase (MMP)
protein moonlighting
transcription factor
extracellular vesicles
oncosome
genome editing
CRISPR
cellular communication network factor
CCN2/CTGF
Content Type
Journal Article
Description
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.
Journal Title
Cancers
ISSN
20726694
Publisher
MDPI
Volume
12
Issue
4
Start Page
881
Published Date
2020-04-04
Rights
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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language
eng
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departments
Oral Sciences