Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (<i>CCN2/CTGF</i>): CRISPR against Cancer
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 per...
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MDPI AG
2020-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/4/881 |
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| author | Yuka Okusha Takanori Eguchi Manh T. Tran Chiharu Sogawa Kaya Yoshida Mami Itagaki Eman A. Taha Kisho Ono Eriko Aoyama Hirohiko Okamura Ken-ichi Kozaki Stuart K. Calderwood Masaharu Takigawa Kuniaki Okamoto |
| author_facet | Yuka Okusha Takanori Eguchi Manh T. Tran Chiharu Sogawa Kaya Yoshida Mami Itagaki Eman A. Taha Kisho Ono Eriko Aoyama Hirohiko Okamura Ken-ichi Kozaki Stuart K. Calderwood Masaharu Takigawa Kuniaki Okamoto |
| author_sort | Yuka Okusha |
| collection | DOAJ |
| 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 <i>CCN2/CTGF</i> promoter, and induced CCN2/CTGF production in vitro. TRENDIC and other cis-elements in the <i>CCN2/CTGF</i> 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. |
| first_indexed | 2024-03-10T20:40:24Z |
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| id | doaj.art-c6cdf30212124611a522ca9912d9c0be |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T20:40:24Z |
| publishDate | 2020-04-01 |
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| series | Cancers |
| spelling | doaj.art-c6cdf30212124611a522ca9912d9c0be2023-11-19T20:43:44ZengMDPI AGCancers2072-66942020-04-0112488110.3390/cancers12040881Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (<i>CCN2/CTGF</i>): CRISPR against CancerYuka Okusha0Takanori Eguchi1Manh T. Tran2Chiharu Sogawa3Kaya Yoshida4Mami Itagaki5Eman A. Taha6Kisho Ono7Eriko Aoyama8Hirohiko Okamura9Ken-ichi Kozaki10Stuart K. Calderwood11Masaharu Takigawa12Kuniaki Okamoto13Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, JapanDepartment of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, JapanDepartment of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, JapanDepartment of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, JapanDepartment of Oral Healthcare Education, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8504, JapanDepartment of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, JapanDepartment of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, JapanDepartment of Oral and Maxillofacial Surgery, Okayama University Hospital, Okayama 700-0914, JapanAdvanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, JapanDepartment of Oral Morphology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama 700-8525, JapanDepartment of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, JapanDivision of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USAAdvanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, JapanDepartment of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, JapanMatrix 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 <i>CCN2/CTGF</i> promoter, and induced CCN2/CTGF production in vitro. TRENDIC and other cis-elements in the <i>CCN2/CTGF</i> 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.https://www.mdpi.com/2072-6694/12/4/881matrix metalloproteinasemoonlighting metalloproteinase (MMP)protein moonlightingtranscription factorextracellular vesiclesoncosome |
| spellingShingle | Yuka Okusha Takanori Eguchi Manh T. Tran Chiharu Sogawa Kaya Yoshida Mami Itagaki Eman A. Taha Kisho Ono Eriko Aoyama Hirohiko Okamura Ken-ichi Kozaki Stuart K. Calderwood Masaharu Takigawa Kuniaki Okamoto Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (<i>CCN2/CTGF</i>): CRISPR against Cancer Cancers matrix metalloproteinase moonlighting metalloproteinase (MMP) protein moonlighting transcription factor extracellular vesicles oncosome |
| title | Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (<i>CCN2/CTGF</i>): CRISPR against Cancer |
| title_full | Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (<i>CCN2/CTGF</i>): CRISPR against Cancer |
| title_fullStr | Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (<i>CCN2/CTGF</i>): CRISPR against Cancer |
| title_full_unstemmed | Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (<i>CCN2/CTGF</i>): CRISPR against Cancer |
| title_short | Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (<i>CCN2/CTGF</i>): CRISPR against Cancer |
| title_sort | extracellular vesicles enriched with moonlighting metalloproteinase are highly transmissive pro tumorigenic and trans activates cellular communication network factor i ccn2 ctgf i crispr against cancer |
| topic | matrix metalloproteinase moonlighting metalloproteinase (MMP) protein moonlighting transcription factor extracellular vesicles oncosome |
| url | https://www.mdpi.com/2072-6694/12/4/881 |
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