ID | 60127 |
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Author |
Du, Juan
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Xu, Yanning
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Sasada, Saki
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Oo, Aung Ko Ko
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Hassan, Ghmkin
Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University
ORCID
publons
Mahmud, Hafizah
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
ORCID
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Khayrani, Apriliana Cahya
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Alam, Md Jahangir
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Kumon, Kazuki
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Uesaki, Ryo
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Afify, Said M.
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
ORCID
Mansour, Hager M.
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Nair, Neha
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Zahra, Maram H.
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Seno, Akimasa
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
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Okada, Nobuhiro
Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University
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Chen, Ling
Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics
Yan, Ting
Department of Pathology, Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University
Seno, Masaharu
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
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Abstract | Cancer stem cells (CSCs) are a class of cancer cells characterized by self-renewal, differentiation and tumorigenic potential. We previously established a model of CSCs by culturing mouse induced pluripotent stem cells (miPSCs) for four weeks in the presence of a conditioned medium (CM) of cancer cell lines, which functioned as the tumor microenvironment. Based on this methodology of developing CSCs from miPSCs, we assessed the risk of 110 non-mutagenic chemical compounds, most of which are known as inhibitors of cytoplasmic signaling pathways, as potential carcinogens. We treated miPSCs with each compound for one week in the presence of a CM of Lewis lung carcinoma (LLC) cells. However, one-week period was too short for the CM to convert miPSCs into CSCs. Consequently, PDO325901 (MEK inhibitor), CHIR99021 (GSK-3 beta inhibitor) and Dasatinib (Abl, Src and c-Kit inhibitor) were found to confer miPSCs with the CSC phenotype in one week. The tumor cells that survived exhibited stemness markers, spheroid formation and tumorigenesis in Balb/c nude mice. Hence, we concluded that the three signal inhibitors accelerated the conversion of miPSCs into CSCs. Similarly to our previous study, we found that the PI3K-Akt signaling pathway was upregulated in the CSCs. Herein, we focused on the expression of relative genes after the treatment with these three inhibitors. Our results demonstrated an increased expression of pik3ca, pik3cb, pik3r5 and pik3r1 genes indicating class IA PI3K as the responsible signaling pathway. Hence, AKT phosphorylation was found to be up-regulated in the obtained CSCs. Inhibition of Erk1/2, tyrosine kinase, and/or GSK-3 beta was implied to be involved in the enhancement of the PI3K-AKT signaling pathway in the undifferentiated cells, resulting in the sustained stemness, and subsequent conversion of miPSCs into CSCs in the tumor microenvironment.
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Keywords | 2020-06-22
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Published Date | 2020-06-22
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Publication Title |
Scientific Reports
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Volume | volume10
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Issue | issue1
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Publisher | NATURE PUBLISHING GROUP
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Start Page | 9955
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ISSN | 2045-2322
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Content Type |
Journal Article
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language |
English
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OAI-PMH Set |
岡山大学
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Copyright Holders | © The Author(s) 2020
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File Version | publisher
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PubMed ID | |
DOI | |
Web of Science KeyUT | |
Related Url | isVersionOf https://doi.org/10.1038/s41598-020-66471-2
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License | http://creativecommons.org/licenses/by/4.0/
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Citation | Du J, Xu Y, Sasada S, et al. Signaling Inhibitors Accelerate the Conversion of mouse iPS Cells into Cancer Stem Cells in the Tumor Microenvironment. Sci Rep. 2020;10(1):9955. Published 2020 Jun 22. doi:10.1038/s41598-020-66471-2
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Funder Name |
Japan Society for the Promotion of Science
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助成番号 | 25242045
26640079
18K15243
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