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Supplementary Table S3 from Smoking-Associated Carcinogen–Induced Inflammation Promotes Lung Carcinogenesis via IRAK4 Activation

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posted on 2025-02-17, 08:22 authored by Ritesh K. Aggarwal, Simone Sidoli, Jingli Wang, Srabani Sahu, Rahul Sanawar, Varun Gupta, Srinivas Aluri, Vineeth Sukrithan, Charan T.R. Vegivinti, Phaedon D. Zavras, Divij Verma, Shanisha Gordon-Mitchell, Beamon Agarwal, Tanya Verma, Daniel T. Starczynowski, Ulrich G. Steidl, Aditi Shastri, Balazs Halmos, Lindsay M. LaFave, Haiying Cheng, Amit Verma, Yiyu Zou

Supplementary Table S3. Manuscript Figure 3 data - The Excel file has data points for easy access to infer numerical values for data presented in the manuscript. Also see Data Availability Statement.

Funding

Division of Cancer Prevention, National Cancer Institute (DCP, NCI)

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ARTICLE ABSTRACT

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.