Aggarwal Ritesh K, Sidoli Simone, Wang Jingli, Sahu Srabani, Sanawar Rahul, Gupta Varun, Aluri Srinivas, Sukrithan Vineeth, Vegivinti Charan T R, Zavras Phaedon D, Verma Divij, Gordon-Mitchell Shanisha, Agarwal Beamon, Verma Tanya, Starczynowski Daniel T, Steidl Ulrich G, Shastri Aditi, Halmos Balazs, LaFave Lindsay M, Cheng Haiying, Verma Amit, Zou Yiyu
Department of Oncology, Montefiore Einstein Comprehensive Cancer Center, Bronx, New York.
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York.
Clin Cancer Res. 2025 Feb 17;31(4):746-755. doi: 10.1158/1078-0432.CCR-24-2182.
Even though smoking is associated with lung cancer, the exact molecular pathways that link carcinogens with inflammation and oncogenic transformation are not well elucidated. Two major carcinogens in cigarette smoke, nicotine-derived nitrosamine ketone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and benzo(α)pyrene (BaP), have not been tested in models that mimic inhaled exposure for prolonged periods of time.
Mouse models were used for intratracheal delivery of NNK and BaP (NB) for 18 months. Tissue microarrays from human lung cancers were evaluated for IL-1 receptor-associated kinase-4 (IRAK4) expression. Functional effects of IRAK4 inhibition were evaluated in cell lines and xenografts.
Smoking-associated carcinogen-treated mice developed epithelial dysplasia followed by lung cancers at increased rates relative to controls. Histology revealed myeloid inflammation in murine lung tissues. Lung macrophages showed elevated levels of proinflammatory IL-1β when exposed to cigarette smoking condensate. A key downstream mediator of IL-1β signaling, IRAK4, was overexpressed in murine lung tissues exposed to carcinogens. The majority of human lung cancer samples also exhibited overactivated IRAK4 expression. IRAK4 localized in microtubules in lung cancer cell lines. Using mass spectrometry on isolated microtubules, we observed that IRAK4 inhibition was associated with decreased phosphorylation of tubular motility proteins, including myosin heavy-chain 9. Inhibition of IRAK4 resulted in decreased invasion in lung cancer cell lines and reduced growth of lung cancer xenografts.
These data demonstrate that smoking-associated carcinogens can be linked to oncogenic transformation via inflammatory IRAK4 activation.
尽管吸烟与肺癌相关，但将致癌物与炎症及致癌转化联系起来的具体分子途径尚未完全阐明。香烟烟雾中的两种主要致癌物，尼古丁衍生的亚硝胺酮、4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）和苯并（α）芘（BaP），尚未在模拟长期吸入暴露的模型中进行测试。
使用小鼠模型经气管内给予NNK和BaP（NB），持续18个月。对人肺癌组织微阵列进行白细胞介素-1受体相关激酶4（IRAK4）表达评估。在细胞系和异种移植物中评估IRAK4抑制的功能效应。
与对照组相比，经吸烟相关致癌物处理的小鼠上皮发育异常发生率增加，随后肺癌发生率也增加。组织学检查显示小鼠肺组织中有髓系炎症。肺巨噬细胞暴露于香烟烟雾冷凝物时促炎白细胞介素-1β水平升高。白细胞介素-1β信号传导的关键下游介质IRAK4在暴露于致癌物的小鼠肺组织中过表达。大多数人肺癌样本也表现出IRAK4表达过度激活。IRAK4定位于肺癌细胞系的微管中。通过对分离的微管进行质谱分析，我们观察到IRAK4抑制与管状运动蛋白（包括肌球蛋白重链9）磷酸化减少有关。抑制IRAK4导致肺癌细胞系侵袭减少和肺癌异种移植物生长减缓。
这些数据表明，吸烟相关致癌物可通过炎症性IRAK4激活与致癌转化相关联。
