Nicotine enhances the stemness and tumorigenicity in intestinal stem cells via Hippo-YAP/TAZ and Notch signal pathway
Cigarette smoking is a well-known risk factor inducing the development and progression of various diseases. Nicotine (NIC) is the major constituent of cigarette smoke. However, knowledge of the mechanism underlying the NIC-regulated stem cell functions is limited. In this study, we demonstrate that...
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| Format: | Article |
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eLife Sciences Publications Ltd
2025-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/95267 |
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| author | Ryosuke Isotani Masaki Igarashi Masaomi Miura Kyoko Naruse Satoshi Kuranami Manami Katoh Seitaro Nomura Toshimasa Yamauchi |
| author_facet | Ryosuke Isotani Masaki Igarashi Masaomi Miura Kyoko Naruse Satoshi Kuranami Manami Katoh Seitaro Nomura Toshimasa Yamauchi |
| author_sort | Ryosuke Isotani |
| collection | DOAJ |
| description | Cigarette smoking is a well-known risk factor inducing the development and progression of various diseases. Nicotine (NIC) is the major constituent of cigarette smoke. However, knowledge of the mechanism underlying the NIC-regulated stem cell functions is limited. In this study, we demonstrate that NIC increases the abundance and proliferative activity of murine intestinal stem cells (ISCs) in vivo and ex vivo. Moreover, NIC induces Yes-associated protein (YAP) /Transcriptional coactivator with PDZ-binding motif (TAZ) and Notch signaling in ISCs via α7-nicotinic acetylcholine receptor (nAchR) and protein kinase C (PKC) activation; this effect was not detected in Paneth cells. The inhibition of Notch signaling by dibenzazepine (DBZ) nullified the effects of NIC on ISCs. NIC enhances in vivo tumor formation from ISCs after loss of the tumor suppressor gene Apc, DBZ inhibited NIC-induced tumor growth. Hence, this study identifies a NIC-triggered pathway regulating the stemness and tumorigenicity of ISCs and suggests the use of DBZ as a potential therapeutic strategy for treating intestinal tumors. |
| format | Article |
| id | doaj-art-a612913476aa4cf195a0daa61a7f2e3b |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-a612913476aa4cf195a0daa61a7f2e3b2025-01-03T16:26:16ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011310.7554/eLife.95267Nicotine enhances the stemness and tumorigenicity in intestinal stem cells via Hippo-YAP/TAZ and Notch signal pathwayRyosuke Isotani0Masaki Igarashi1https://orcid.org/0000-0002-3331-3877Masaomi Miura2Kyoko Naruse3Satoshi Kuranami4Manami Katoh5Seitaro Nomura6Toshimasa Yamauchi7Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Cardiovascular Medicine, The University of Tokyo Graduate, School of Medicine, Tokyo, Japan; Department of Frontier Cardiovascular Science, The University of Tokyo, Graduate School of Medicine, Tokyo, JapanDepartment of Cardiovascular Medicine, The University of Tokyo Graduate, School of Medicine, Tokyo, Japan; Department of Frontier Cardiovascular Science, The University of Tokyo, Graduate School of Medicine, Tokyo, JapanDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanCigarette smoking is a well-known risk factor inducing the development and progression of various diseases. Nicotine (NIC) is the major constituent of cigarette smoke. However, knowledge of the mechanism underlying the NIC-regulated stem cell functions is limited. In this study, we demonstrate that NIC increases the abundance and proliferative activity of murine intestinal stem cells (ISCs) in vivo and ex vivo. Moreover, NIC induces Yes-associated protein (YAP) /Transcriptional coactivator with PDZ-binding motif (TAZ) and Notch signaling in ISCs via α7-nicotinic acetylcholine receptor (nAchR) and protein kinase C (PKC) activation; this effect was not detected in Paneth cells. The inhibition of Notch signaling by dibenzazepine (DBZ) nullified the effects of NIC on ISCs. NIC enhances in vivo tumor formation from ISCs after loss of the tumor suppressor gene Apc, DBZ inhibited NIC-induced tumor growth. Hence, this study identifies a NIC-triggered pathway regulating the stemness and tumorigenicity of ISCs and suggests the use of DBZ as a potential therapeutic strategy for treating intestinal tumors.https://elifesciences.org/articles/95267intestinal stem cellpaneth cellnicotinenAChRNotchYAP/TAZ |
| spellingShingle | Ryosuke Isotani Masaki Igarashi Masaomi Miura Kyoko Naruse Satoshi Kuranami Manami Katoh Seitaro Nomura Toshimasa Yamauchi Nicotine enhances the stemness and tumorigenicity in intestinal stem cells via Hippo-YAP/TAZ and Notch signal pathway eLife intestinal stem cell paneth cell nicotine nAChR Notch YAP/TAZ |
| title | Nicotine enhances the stemness and tumorigenicity in intestinal stem cells via Hippo-YAP/TAZ and Notch signal pathway |
| title_full | Nicotine enhances the stemness and tumorigenicity in intestinal stem cells via Hippo-YAP/TAZ and Notch signal pathway |
| title_fullStr | Nicotine enhances the stemness and tumorigenicity in intestinal stem cells via Hippo-YAP/TAZ and Notch signal pathway |
| title_full_unstemmed | Nicotine enhances the stemness and tumorigenicity in intestinal stem cells via Hippo-YAP/TAZ and Notch signal pathway |
| title_short | Nicotine enhances the stemness and tumorigenicity in intestinal stem cells via Hippo-YAP/TAZ and Notch signal pathway |
| title_sort | nicotine enhances the stemness and tumorigenicity in intestinal stem cells via hippo yap taz and notch signal pathway |
| topic | intestinal stem cell paneth cell nicotine nAChR Notch YAP/TAZ |
| url | https://elifesciences.org/articles/95267 |
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