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Sogawa, Chiharu Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University ORCID Kaken ID
Eguchi, Takanori Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University ORCID Kaken ID researchmap
Okusha, Yuka Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kaken ID
Ono, Kisho Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Ohyama, Kazumi Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Iizuka, Motoharu Research program for undergraduate students, Okayama University Dental School
Kawasaki, Ryu Research program for undergraduate students, Okayama University Dental School
Hamada, Yusaku Research program for undergraduate students, Okayama University Dental School
Takigawa, Masaharu Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Sogawa, Norio Department of Dental Pharmacology, Matsumoto Dental University
Okamoto, Kuniaki Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Kozaki , Ken-ichi Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Abstract
Cancer invasion, metastasis, and therapy resistance are the crucial phenomena in cancer malignancy. The high-expression of matrix metalloproteinase 9 (MMP9) is a biomarker as well as a causal factor of cancer invasiveness and metastatic activity. However, a regulatory mechanism underlying MMP9 expression in cancer is not clarified yet. Additionally, a new strategy for anti-cancer drug discovery is becoming an important clue. In the present study, we aimed (i) to develop a novel reporter system evaluating tumorigenesis, invasiveness, metastasis, and druggability with a combination of three-dimensional (3D) tumoroid model and Mmp9 promoter and (ii) to examine pharmacological actions of anti-cancer medications using this reporter system. High expression and genetic amplification of MMP9 were found in colon cancer cases. We found that proximal promoter sequences of MMP9 in murine and human contained conserved binding sites for transcription factors β-catenin/TCF/LEF, glucocorticoid receptor (GR), and NF-κB. The murine Mmp9 promoter (-569 to +19) was markedly activated in metastatic colon cancer cells and additionally activated by tumoroid formation and by β-catenin signaling stimulator lithium chloride (LiCl). The Mmp9 promoter-driven fluorescent reporter cells enabled the monitoring of activities of MMP9/gelatinase, tumorigenesis, invasion, and metastasis in allogeneic/syngenic transplantation experiments. We also demonstrated pharmacological actions as follows. ids Dexamethasone and hydrocortisone, steroidal medications binding to GR, inhibited the Mmp9 promoter but did not inhibit tumorigenesis. On the other hand, an antimetabolite 5-fluorouracil, a golden standard for colon cancer chemotherapy, inhibited tumoroid formation but did not inhibit Mmp9 promoter activity. Notably, anti-malaria medication artesunate inhibited both tumorigenesis and the Mmp9 promoter in vitro, potentially through inhibition of β-catenin/TCF/LEF signaling. Thus, this novel reporter system enabled monitoring tumorigenesis, invasiveness, metastasis, key regulatory signalings such as β-catenin/MMP9 axis, and druggability.
Keywords
3D tumoroid reporter assay
Wnt/β-catenin signaling
cancer metastasis
metalloproteinase
syngeneic transplantation
tumoroid (tumor organoid)
Note
This is an Accepted Manuscript of an article published by Mary Ann Liebert
This fulltext will be available in Feb 2020
Published Date
2019-02-08
Publication Title
Tissue Engineering Part A.
Volume
volume25
Issue
issue19-20
Publisher
Mary Ann Liebert
Start Page
1413
End Page
1425
ISSN
19373341
NCID
AA12306003
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
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isVersionOf https://doi.org/10.1089/ten.TEA.2018.0348