Wnt信号通路
自分泌信号
癌症研究
肺癌
表观遗传学
轴2
医学
病理
免疫学
生物
细胞生物学
信号转导
内科学
遗传学
基因
受体
作者
Hye‐Jin Boo,Hye‐Young Min,Choon-Sik Park,Jong‐Sook Park,Ji Yun Jeong,Shin Yup Lee,Woo-Young Kim,Jae-Won Lee,Sei‐Ryang Oh,Rang‐Woon Park,Ho‐Young Lee
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2023-03-27
卷期号:83 (11): 1782-1799
被引量:1
标识
DOI:10.1158/0008-5472.can-22-3543
摘要
Pulmonary emphysema is a destructive inflammatory disease primarily caused by cigarette smoking (CS). Recovery from CS-induced injury requires proper stem cell (SC) activities with a tightly controlled balance of proliferation and differentiation. Here we show that acute alveolar injury induced by two representative tobacco carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (N/B), increased IGF2 expression in alveolar type 2 (AT2) cells to promote their SC function and facilitate alveolar regeneration. Autocrine IGF2 signaling upregulated Wnt genes, particularly Wnt3, to stimulate AT2 proliferation and alveolar barrier regeneration after N/B-induced acute injury. In contrast, repetitive N/B exposure provoked sustained IGF2-Wnt signaling through DNMT3A-mediated epigenetic control of IGF2 expression, causing a proliferation/differentiation imbalance in AT2s and development of emphysema and cancer. Hypermethylation of the IGF2 promoter and overexpression of DNMT3A, IGF2, and the Wnt target gene AXIN2 were seen in the lungs of patients with CS-associated emphysema and cancer. Pharmacologic or genetic approaches targeting IGF2-Wnt signaling or DNMT prevented the development of N/B-induced pulmonary diseases. These findings support dual roles of AT2 cells, which can either stimulate alveolar repair or promote emphysema and cancer depending on IGF2 expression levels.IGF2-Wnt signaling plays a key role in AT2-mediated alveolar repair after cigarette smoking-induced injury but also drives pathogenesis of pulmonary emphysema and cancer when hyperactivated.
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