한빛사논문
- 조회380
Hye-Jin Boo1,2,7, Hye-Young Min1,7, Su Jung Hwang3, Hyo-Jong Lee3, Jae-Won Lee4, Sei-Ryang Oh4, Choon-Sik Park5, Jong-Sook Park5, You Mie Lee6 and Ho-Young Lee1
1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
2Department of Histology, College of Medicine, Jeju National University, Jeju 63243, Republic of Korea.
3School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
4Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si, Chungcheongbuk-do 28116, Republic of Korea.
5Soonchunhyang University Bucheon Hospital, Bucheon, Gyeonggi-do 14584, Republic of Korea.
6Vessel-Organ Interaction Research Center (VOICE, MRC), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea.
7These authors contributed equally: Hye-Jin Boo, Hye-Young Min
Corresponding author : Correspondence to Ho-Young Lee.
Abstract
The renin-angiotensin (RA) system has been implicated in lung tumorigenesis without detailed mechanistic elucidation. Here, we demonstrate that exposure to the representative tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) promotes lung tumorigenesis through deregulation of the pulmonary RA system. Mechanistically, NNK binding to the nicotinic acetylcholine receptor (nAChR) induces Src-mediated signal transducer and activator of transcription 3 (STAT3) activation, resulting in transcriptional upregulation of angiotensinogen (AGT) and subsequent induction of the angiotensin II (AngII) receptor type 1 (AGTR1) signaling pathway. In parallel, NNK concurrently increases insulin-like growth factor 2 (IGF2) production and activation of IGF-1R/insulin receptor (IR) signaling via a two-step pathway involving transcriptional upregulation of IGF2 through STAT3 activation and enhanced secretion from intracellular storage through AngII/AGTR1/PLC-intervened calcium release. NNK-mediated crosstalk between IGF-1R/IR and AGTR1 signaling promoted tumorigenic activity in lung epithelial and stromal cells. Lung tumorigenesis caused by NNK exposure or alveolar type 2 cell-specific Src activation was suppressed by heterozygous Agt knockout or clinically available inhibitors of the nAChR/Src or AngII/AGTR1 pathways. These results demonstrate that NNK-induced stimulation of the lung RA system leads to IGF2-mediated IGF-1R/IR signaling activation in lung epithelial and stromal cells, resulting in lung tumorigenesis in smokers.
논문정보
- Research article
- 2023년 06월 (BRIC 등록일 2023-06-20)
- 국내 연구진
- 생명과학 > 노화/암생물학
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