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Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell‐like property of glioblastoma cells
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‐like cells. However, the molecular mechanisms regulating expression of Ror1 in these cells remain largely unknown. Ror1 and it...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899608/ https://www.ncbi.nlm.nih.gov/pubmed/36314076 http://dx.doi.org/10.1111/cas.15630 |
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author | Ishikawa, Tomohiro Ogura, Yasuka Tanaka, Kazuhiro Nagashima, Hiroaki Sasayama, Takashi Endo, Mitsuharu Minami, Yasuhiro |
author_facet | Ishikawa, Tomohiro Ogura, Yasuka Tanaka, Kazuhiro Nagashima, Hiroaki Sasayama, Takashi Endo, Mitsuharu Minami, Yasuhiro |
author_sort | Ishikawa, Tomohiro |
collection | PubMed |
description | 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‐like cells. However, the molecular mechanisms regulating expression of Ror1 in these cells remain largely unknown. Ror1 and its putative ligand Wnt5a are expressed highly in malignant gliomas, especially in glioblastomas, and the extents of Ror1 expression are correlated positively with poorer prognosis in patients with gliomas. We show that Ror1 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‐forming glioblastoma stem‐like cells (GSCs), and Ror1 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 Ror1 in the cells. Consistently, we show that both NICD and hypoxia‐inducible factor 1 alpha bind to upstream regions within the Ror1 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‐forming ability. Collectively, these findings indicate for the first time that Notch and hypoxia signaling pathways can elicit a Wnt5a–Ror1 axis through transcriptional activation of Ror1 in glioblastoma cells, thereby promoting their stem cell‐like property. |
format | Online Article Text |
id | pubmed-9899608 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98996082023-02-09 Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell‐like property of glioblastoma cells Ishikawa, Tomohiro Ogura, Yasuka Tanaka, Kazuhiro Nagashima, Hiroaki Sasayama, Takashi Endo, Mitsuharu Minami, Yasuhiro Cancer Sci ORIGINAL ARTICLES 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‐like cells. However, the molecular mechanisms regulating expression of Ror1 in these cells remain largely unknown. Ror1 and its putative ligand Wnt5a are expressed highly in malignant gliomas, especially in glioblastomas, and the extents of Ror1 expression are correlated positively with poorer prognosis in patients with gliomas. We show that Ror1 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‐forming glioblastoma stem‐like cells (GSCs), and Ror1 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 Ror1 in the cells. Consistently, we show that both NICD and hypoxia‐inducible factor 1 alpha bind to upstream regions within the Ror1 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‐forming ability. Collectively, these findings indicate for the first time that Notch and hypoxia signaling pathways can elicit a Wnt5a–Ror1 axis through transcriptional activation of Ror1 in glioblastoma cells, thereby promoting their stem cell‐like property. John Wiley and Sons Inc. 2022-11-25 /pmc/articles/PMC9899608/ /pubmed/36314076 http://dx.doi.org/10.1111/cas.15630 Text en © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | ORIGINAL ARTICLES Ishikawa, Tomohiro Ogura, Yasuka Tanaka, Kazuhiro Nagashima, Hiroaki Sasayama, Takashi Endo, Mitsuharu Minami, Yasuhiro Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell‐like property of glioblastoma cells |
title | Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell‐like property of glioblastoma cells |
title_full | Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell‐like property of glioblastoma cells |
title_fullStr | Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell‐like property of glioblastoma cells |
title_full_unstemmed | Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell‐like property of glioblastoma cells |
title_short | Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell‐like property of glioblastoma cells |
title_sort | ror1 is expressed inducibly by notch and hypoxia signaling and regulates stem cell‐like property of glioblastoma cells |
topic | ORIGINAL ARTICLES |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899608/ https://www.ncbi.nlm.nih.gov/pubmed/36314076 http://dx.doi.org/10.1111/cas.15630 |
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