{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T04:29:40Z","timestamp":1778646580011,"version":"3.51.4"},"reference-count":69,"publisher":"SAGE Publications","issue":"19-20","license":[{"start":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T00:00:00Z","timestamp":1569888000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Tissue Engineering Part A"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:p>\n                    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. In addition, a new strategy for anticancer 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 tumoroid model and\n                    <jats:italic toggle=\"yes\">Mmp9<\/jats:italic>\n                    promoter and (ii) to examine pharmacological actions of anticancer medications using this reporter system. High expression and genetic amplification of\n                    <jats:italic toggle=\"yes\">MMP9<\/jats:italic>\n                    were found in colon cancer cases. We found that proximal promoter sequences of\n                    <jats:italic toggle=\"yes\">MMP9<\/jats:italic>\n                    in murine and human contained conserved binding sites for transcription factors \u03b2-catenin\/TCF\/LEF, glucocorticoid receptor (GR), and nuclear factor kappa-B (NF-\u03baB). The murine\n                    <jats:italic toggle=\"yes\">Mmp9<\/jats:italic>\n                    promoter (\u2212569 to +19) was markedly activated in metastatic colon cancer cells and additionally activated by tumoroid formation and by \u03b2-catenin signaling stimulator lithium chloride. The\n                    <jats:italic toggle=\"yes\">Mmp9<\/jats:italic>\n                    promoter-driven fluorescent reporter cells enabled the monitoring of activities of MMP9\/gelatinase, tumorigenesis, invasion, and metastasis in syngeneic transplantation experiments. We also demonstrated pharmacological actions as follows: dexamethasone and hydrocortisone, steroidal medications binding to GR, inhibited the\n                    <jats:italic toggle=\"yes\">Mmp9<\/jats:italic>\n                    promoter but did not inhibit tumorigenesis. On the contrary, antimetabolite 5-fluorouracil, a gold standard for colon cancer chemotherapy, inhibited tumoroid formation but did not inhibit\n                    <jats:italic toggle=\"yes\">Mmp9<\/jats:italic>\n                    promoter activity. Notably, antimalaria medication artesunate inhibited both tumorigenesis and the\n                    <jats:italic toggle=\"yes\">Mmp9<\/jats:italic>\n                    promoter\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    , potentially through inhibition of \u03b2-catenin\/TCF\/LEF signaling. Thus, this novel reporter system enabled monitoring tumorigenesis, invasiveness, metastasis, key regulatory signalings such as \u03b2-catenin\/MMP9 axis, and druggability.\n                  <\/jats:p>\n                  <jats:sec>\n                    <jats:title>Impact Statement<\/jats:title>\n                    <jats:p>\n                      Cancer invasion and metastasis have been shown to be driven by matrix metalloproteinase 9 (MMP9), whose expression mechanism is not clarified yet. In addition, a new strategy for anticancer drug discovery is becoming important. We established a novel reporter system evaluating tumorigenesis, invasiveness, metastasis, and druggability with a combination of three-dimensional (3D) tumoroid model and\n                      <jats:italic toggle=\"yes\">Mmp9<\/jats:italic>\n                      promoter. Using this reporter system, we demonstrated pharmacological actions of anticancer medications such as antimetabolite 5-fluorouracil (5-FU) and antimalaria medication artesunate (ART), which inhibited both tumorigenesis and \u03b2-catenin\/MMP regulatory signaling. Our study impacts the translational fields of oncology, drug discovery, and organoid model.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/ten.tea.2018.0348","type":"journal-article","created":{"date-parts":[[2019,2,8]],"date-time":"2019-02-08T09:10:42Z","timestamp":1549617042000},"page":"1413-1425","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":18,"title":["A Reporter System Evaluates Tumorigenesis, Metastasis, \u03b2-catenin\/MMP Regulation, and Druggability"],"prefix":"10.1177","volume":"25","author":[{"given":"Chiharu","family":"Sogawa","sequence":"first","affiliation":[{"name":"Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takanori","family":"Eguchi","sequence":"additional","affiliation":[{"name":"Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan."},{"name":"Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuka","family":"Okusha","sequence":"additional","affiliation":[{"name":"Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kisho","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazumi","family":"Ohyama","sequence":"additional","affiliation":[{"name":"Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motoharu","family":"Iizuka","sequence":"additional","affiliation":[{"name":"Research Program for Undergraduate Students, Okayama University Dental School, Okayama, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryu","family":"Kawasaki","sequence":"additional","affiliation":[{"name":"Research Program for Undergraduate Students, Okayama University Dental School, Okayama, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusaku","family":"Hamada","sequence":"additional","affiliation":[{"name":"Research Program for Undergraduate Students, Okayama University Dental School, Okayama, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaharu","family":"Takigawa","sequence":"additional","affiliation":[{"name":"Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norio","family":"Sogawa","sequence":"additional","affiliation":[{"name":"Department of Dental Pharmacology, Matsumoto Dental University, Shiojiri, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuniaki","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken-ichi","family":"Kozaki","sequence":"additional","affiliation":[{"name":"Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 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Lost in translation: animal models and clinical trials in cancer treatment. 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