{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:20:38Z","timestamp":1791408038213,"version":"4.3.3"},"reference-count":39,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T00:00:00Z","timestamp":1669334400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T00:00:00Z","timestamp":1669334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21gm5010001"],"award-info":[{"award-number":["JP21gm5010001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JPMJMS2022"],"award-info":[{"award-number":["JPMJMS2022"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ror1 plays a crucial role in cancer progression by regulating cell proliferation and migration. Ror1 is expressed abundantly in various types of cancer cells and cancer stem\u2010like cells. However, the molecular mechanisms regulating expression of <jats:italic>Ror1<\/jats:italic> in these cells remain largely unknown. <jats:italic>Ror1<\/jats:italic> and its putative ligand Wnt5a are expressed highly in malignant gliomas, especially in glioblastomas, and the extents of <jats:italic>Ror1<\/jats:italic> expression are correlated positively with poorer prognosis in patients with gliomas. We show that <jats:italic>Ror1<\/jats:italic> expression can be upregulated in glioblastoma cells under spheroid culture, but not adherent culture conditions. Notch and hypoxia signaling pathways have been shown to be activated in spheroid\u2010forming glioblastoma stem\u2010like cells (GSCs), and <jats:italic>Ror1<\/jats:italic> expression in glioblastoma cells is indeed suppressed by inhibiting either Notch or hypoxia signaling. Meanwhile, either forced expression of the Notch intracellular domain (NICD) in or hypoxic culture of glioblastoma cells result in enhanced expression of <jats:italic>Ror1<\/jats:italic> in the cells. Consistently, we show that both NICD and hypoxia\u2010inducible factor 1 alpha bind to upstream regions within the <jats:italic>Ror1<\/jats:italic> gene more efficiently in GSCs under spheroid culture conditions. Furthermore, we provide evidence indicating that binding of Wnt5a to Ror1, upregulated by Notch and hypoxia signaling pathways in GSCs, might promote their spheroid\u2010forming ability. Collectively, these findings indicate for the first time that Notch and hypoxia signaling pathways can elicit a Wnt5a\u2013Ror1 axis through transcriptional activation of <jats:italic>Ror1<\/jats:italic> in glioblastoma cells, thereby promoting their stem cell\u2010like property.<\/jats:p>","DOI":"10.1111\/cas.15630","type":"journal-article","created":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T08:26:32Z","timestamp":1667204792000},"page":"561-573","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell\u2010like property of glioblastoma cells"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0539-7372","authenticated-orcid":false,"given":"Tomohiro","family":"Ishikawa","sequence":"first","affiliation":[{"name":"Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine Kobe University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuka","family":"Ogura","sequence":"additional","affiliation":[{"name":"Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine Kobe University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Medicine Kobe University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Nagashima","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Medicine Kobe University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5593-9045","authenticated-orcid":false,"given":"Takashi","family":"Sasayama","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Medicine Kobe University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuharu","family":"Endo","sequence":"additional","affiliation":[{"name":"Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine Kobe University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3514-4285","authenticated-orcid":false,"given":"Yasuhiro","family":"Minami","sequence":"additional","affiliation":[{"name":"Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine Kobe University  Kobe 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