ISSN: 1449-2288International Journal of Biological Sciences
Global reach, higher impact
Int J Biol Sci 2024; 20(9):3257-3268. doi:10.7150/ijbs.94339 This issue Cite
Research Paper
Cigarette smoke promotes IL-6-dependent lung cancer migration and osteolytic bone metastasis
1. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
2. Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan.
3. Division of General Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan.
4. Department of Physical Therapy, Asia University, Taichung, Taiwan.
5. Department of General Thoracic Surgery, Asia University Hospital, Taichung, Taiwan.
6. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
7. Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.
8. Department of Medical Laboratory Science and Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
9. Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
10. Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu, Taiwan.
#These authors contributed equally to this work.
Abstract
Lung cancer stands as a major contributor to cancer-related fatalities globally, with cigarette smoke playing a pivotal role in its development and metastasis. Cigarette smoke is also recognized as a risk factor for bone loss disorders like osteoporosis. However, the association between cigarette smoke and another bone loss disorder, lung cancer osteolytic bone metastasis, remains largely uncertain. Our Gene Set Enrichment Analysis (GSEA) indicated that smokers among lung cancer patients exhibited higher expression levels of bone turnover gene sets. Both The Cancer Genome Atlas (TCGA) database and our clinic samples demonstrated elevated expression of the osteolytic factor IL-6 in ever-smokers with bone metastasis among lung cancer patients. Our cellular experiments revealed that benzo[α]pyrene (B[α]P) and cigarette smoke extract (CSE) promoted IL-6 production and cell migration in lung cancer. Activation of the PI3K, Akt, and NF-κB signaling pathways was involved in cigarette smoke-augmented IL-6-dependent migration. Additionally, cigarette smoke lung cancer-secreted IL-6 promoted osteoclast formation. Importantly, blocking IL-6 abolished cigarette smoke-facilitated lung cancer osteolytic bone metastasis in vivo. Our findings provide evidence that cigarette smoke is a risk factor for osteolytic bone metastasis. Thus, inhibiting IL-6 may be a valuable therapeutic strategy for managing osteolytic bone metastasis in lung cancer patients who smoke.
Keywords: Cigarette smoke, Lung cancer, IL-6, Bone metastasis, Osteoclast
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