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Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

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Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
2
Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
3
Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
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Department of Oral Healthcare Education, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8504, Japan
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Research program for undergraduate students, Okayama University Dental School, Okayama 700-8525, Japan
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Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan
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Department of Biochemistry, Ain Shams University Faculty of Science, Cairo 11566, Egypt
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Department of Oral and Maxillofacial Surgery, Okayama University Hospital, Okayama 700-0914, Japan
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Department of Oral Morphology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8525, Japan
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(4), 881; https://doi.org/10.3390/cancers12040881
Received: 19 February 2020 / Revised: 24 March 2020 / Accepted: 2 April 2020 / Published: 4 April 2020
(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)
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. View Full-Text
Keywords: matrix metalloproteinase; moonlighting metalloproteinase (MMP); protein moonlighting; transcription factor; extracellular vesicles; oncosome; genome editing; CRISPR; cellular communication network factor; CCN2/CTGF matrix metalloproteinase; moonlighting metalloproteinase (MMP); protein moonlighting; transcription factor; extracellular vesicles; oncosome; genome editing; CRISPR; cellular communication network factor; CCN2/CTGF
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MDPI and ACS Style

Okusha, Y.; Eguchi, T.; Tran, M.T.; Sogawa, C.; Yoshida, K.; Itagaki, M.; Taha, E.A.; Ono, K.; Aoyama, E.; Okamura, H.; Kozaki, K.-i.; Calderwood, S.K.; Takigawa, M.; Okamoto, K. Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer. Cancers 2020, 12, 881. https://doi.org/10.3390/cancers12040881

AMA Style

Okusha Y, Eguchi T, Tran MT, Sogawa C, Yoshida K, Itagaki M, Taha EA, Ono K, Aoyama E, Okamura H, Kozaki K-i, Calderwood SK, Takigawa M, Okamoto K. Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer. Cancers. 2020; 12(4):881. https://doi.org/10.3390/cancers12040881

Chicago/Turabian Style

Okusha, Yuka; Eguchi, Takanori; Tran, Manh T.; Sogawa, Chiharu; Yoshida, Kaya; Itagaki, Mami; Taha, Eman A.; Ono, Kisho; Aoyama, Eriko; Okamura, Hirohiko; Kozaki, Ken-ichi; Calderwood, Stuart K.; Takigawa, Masaharu; Okamoto, Kuniaki. 2020. "Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer" Cancers 12, no. 4: 881. https://doi.org/10.3390/cancers12040881

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