Isotani Ryosuke, Igarashi Masaki, Miura Masaomi, Naruse Kyoko, Kuranami Satoshi, Katoh Manami, Nomura Seitaro, Yamauchi Toshimasa
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Cardiovascular Medicine, The University of Tokyo Graduate, School of Medicine, Tokyo, Japan.
Elife. 2025 Jan 3;13:RP95267. doi: 10.7554/eLife.95267.
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.
吸烟是诱发多种疾病发生和发展的一个众所周知的风险因素。尼古丁（NIC）是香烟烟雾的主要成分。然而，关于NIC调节干细胞功能的潜在机制的了解有限。在本研究中，我们证明NIC在体内和体外均可增加小鼠肠道干细胞（ISC）的丰度和增殖活性。此外，NIC通过α7-烟碱型乙酰胆碱受体（nAchR）和蛋白激酶C（PKC）的激活，在ISC中诱导Yes相关蛋白（YAP）/具有PDZ结合基序的转录共激活因子（TAZ）和Notch信号；在潘氏细胞中未检测到这种效应。二苯并氮䓬（DBZ）对Notch信号的抑制消除了NIC对ISC的影响。在肿瘤抑制基因Apc缺失后，NIC增强了ISC在体内的肿瘤形成，DBZ抑制了NIC诱导的肿瘤生长。因此，本研究确定了一条由NIC触发的调节ISC干性和致瘤性的途径，并提出将DBZ用作治疗肠道肿瘤的潜在治疗策略。
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