Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan.
Int J Biol Sci. 2024 Jun 3;20(9):3257-3268. doi: 10.7150/ijbs.94339. eCollection 2024.
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 . 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.
肺癌是导致全球癌症相关死亡的主要原因之一，而香烟烟雾在其发展和转移中起着关键作用。香烟烟雾也被认为是骨质疏松等骨丢失疾病的一个危险因素。然而，香烟烟雾与另一种骨丢失疾病——肺癌溶骨性骨转移之间的关联在很大程度上仍不确定。我们的基因集富集分析（GSEA）表明，肺癌患者中的吸烟者表现出更高水平的骨转换基因集表达。癌症基因组图谱（TCGA）数据库和我们的临床样本都表明，肺癌伴骨转移的曾吸烟者中，溶骨性因子 IL-6 的表达水平升高。我们的细胞实验表明，苯并[α]芘（B[α]P）和香烟烟雾提取物（CSE）促进了肺癌细胞中 IL-6 的产生和细胞迁移。PI3K、Akt 和 NF-κB 信号通路的激活参与了香烟烟雾增强的 IL-6 依赖性迁移。此外，香烟烟雾肺癌分泌的 IL-6 促进了破骨细胞的形成。重要的是，阻断 IL-6 消除了香烟烟雾促进肺癌溶骨性骨转移的作用。我们的研究结果提供了证据表明，香烟烟雾是溶骨性骨转移的一个危险因素。因此，抑制 IL-6 可能是治疗吸烟肺癌患者溶骨性骨转移的一种有价值的治疗策略。
