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장현지Hyun-Ji Jang

서울대학교

Nat. Commun., Jun 08 2024, 15 (1) | https://doi.org/10.1038/s41467-024-49199-9 Tobacco-induced hyperglycemia promotes lung cancer progression via cancer cell-macrophage interaction through paracrine IGF2/IR/NPM1-driven PD-L1 expression

Hyun-Ji Jang^1,9, Hye-Young Min^1,2,9, Yun Pyo Kang³, Hye-Jin Boo^1,4, Jisung Kim¹, Jee Hwan Ahn^1,5, Seung Ho Oh³, Jin Hwa Jung⁶, Choon-Sik Park⁷, Jong-Sook Park⁷, Seog-Young Kim^6,8 & Ho-Young Lee^1,2,3

¹Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

²Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

³College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.

⁴Department of Histology, College of Medicine, Jeju National University, Jeju 63243, Republic of Korea.

⁵Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

⁶PET core, Convergence Medicine Research Center, Asan Medical Center, Seoul 05505, Republic of Korea.

⁷Soonchunhyang University Bucheon Hospital, Bucheon-si, Gyeonggido 14584, Republic of Korea.

⁸Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.

⁹These authors contributed equally: Hyun-Ji Jang, Hye-Young Min.

Corresponding author

Correspondence to Ho-Young Lee.

Abstract

Tobacco smoking (TS) is implicated in lung cancer (LC) progression through the development of metabolic syndrome. However, direct evidence linking metabolic syndrome to TS-mediated LC progression remains to be established. Our findings demonstrate that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (NNK and BaP; NB), components of tobacco smoke, induce metabolic syndrome characteristics, particularly hyperglycemia, promoting lung cancer progression in male C57BL/6 J mice. NB enhances glucose uptake in tumor-associated macrophages by increasing the expression and surface localization of glucose transporter (GLUT) 1 and 3, thereby leading to transcriptional upregulation of insulin-like growth factor 2 (IGF2), which subsequently activates insulin receptor (IR) in LC cells in a paracrine manner, promoting its nuclear import. Nuclear IR binds to nucleophosmin (NPM1), resulting in IR/NPM1-mediated activation of the CD274 promoter and expression of programmed death ligand-1 (PD-L1). Restricting glycolysis, depleting macrophages, or blocking PD-L1 inhibits NB-mediated LC progression. Analysis of patient tissues and public databases reveals elevated levels of IGF2 and GLUT1 in tumor-associated macrophages, as well as tumoral PD-L1 and phosphorylated insulin-like growth factor 1 receptor/insulin receptor (pIGF-1R/IR) expression, suggesting potential poor prognostic biomarkers for LC patients. Our data indicate that paracrine IGF2/IR/NPM1/PD-L1 signaling, facilitated by NB-induced dysregulation of glucose levels and metabolic reprogramming of macrophages, contributes to TS-mediated LC progression.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-10)
연구진국내 연구진
분야 생명과학 > 노화/암생물학

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