Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Extracellular Oncosomes Rich in Moonlighting Metalloproteinase (MMP3) Are Transmissive, Pro-Tumorigenic, and Induces Cellular Communication Network Factor 2 (CCN2/CTGF): CRISPR against Cancer

Version 1 : Received: 19 February 2020 / Approved: 19 February 2020 / Online: 19 February 2020 (11:52:42 CET)

A peer-reviewed article of this Preprint also exists.

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. 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.

Journal reference: Cancers 2020, 12, 881
DOI: 10.3390/cancers12040881

Abstract

Matrix metalloproteinase 3 (MMP3) plays multiple roles in pro-tumorigenic proteolysis and in intracellular transcription. These include inducing connective tissue growth factor [CTGF, also known as cellular communication network factor 2 (CCN2)] and prompting a new definition of MMP3 as a moonlighting metalloproteinase. Members of the MMP family have been found within tumor-derived extracellular vesicles (EVs) such as oncosomes or exosomes. We here investigated the roles of MMP3-rich oncosomes in tumor progression, molecular transmission, and gene regulation. MMP3 and CCN2/CTGF were significantly co-expressed in tumor samples derived from patients suffering from colorectal adenocarcinoma. We found that oncosomes derived from a rapidly metastatic colon cancer cells (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich oncosomes were highly transmissive into recipient cells and were pro-tumorigenic in an allograft mouse model. Oncosome-derived MMP3 was transmissive into recipient cell nuclei, trans-activated CCN2/CTGF promoter, and induced CCN2/CTGF production at 1 to 6 hours after the addition of oncosomes to culture media. In addition, CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects, including inhibition of migration and invasion of LuM1 cells in vitro, inhibition of tumor growth in vivo, and reduction of CCN2/CTGF and its promoter activity in vitro. These data newly demonstrate that the oncosome-derived moonlighting metalloproteinase promotes metastasis and is pro-tumorigenic at distant sites as well as a transmissive trans-activator for the cellular communication network gene.

Subject Areas

matrix metalloproteinase (MMP); moonlighting metalloproteinase; extracellular vesicles; oncosome; genome editing; cell communication network factor 2 (CCN2/CTGF); transcription factor; cancer

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