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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.
摘要：
吸烟（TS）通过代谢综合征的发展与肺癌（LC）的进展有关。然而,将代谢综合征与TS介导的LC进展联系起来的直接证据仍有待确定.我们的研究结果表明，4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮和苯并[a]芘（NNK和BaP;NB），烟草烟雾的成分，诱导代谢综合征的特点，特别是高血糖症，促进雄性C57BL/6J小鼠肺癌进展。NB通过增加葡萄糖转运蛋白（GLUT）1和3的表达和表面定位来增强肿瘤相关巨噬细胞的葡萄糖摄取，从而导致胰岛素样生长因子2（IGF2）的转录上调，随后以旁分泌方式激活LC细胞中的胰岛素受体（IR），促进其核进口。核IR与核磷蛋白（NPM1）结合，导致IR/NPM1介导的CD274启动子激活和程序性死亡配体-1（PD-L1）的表达。限制糖酵解，消耗巨噬细胞，或阻断PD-L1抑制NB介导的LC进展。对患者组织和公共数据库的分析显示，肿瘤相关巨噬细胞中IGF2和GLUT1的水平升高，以及肿瘤PD-L1和磷酸化胰岛素样生长因子1受体/胰岛素受体（pIGF-1R/IR）的表达，提示LC患者预后不良的潜在生物标志物。我们的数据表明，旁分泌IGF2/IR/NPM1/PD-L1信号，由NB诱导的葡萄糖水平失调和巨噬细胞的代谢重编程促进，有助于TS介导的LC进展。
