Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Thoracic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Sci Total Environ. 2024 Jan 1;906:167824. doi: 10.1016/j.scitotenv.2023.167824. Epub 2023 Oct 13.
Benzo[a]pyrene (BaP) is commonly found in the environment as a result of incomplete combustion of organic materials and cigarette smoke. Epidemiological studies have consistently suggested that elderly smokers are at higher risk for small cell lung cancer (SCLC), with risks and clinical stages increasing with the intensity and duration of smoking. However, the underlying mechanism remains insufficiently investigated. Here, we established a positive correlation between smoking and BaP metabolite 3-hydroxybenzo[a]pyrene (3OH-BaP) in urine. The pooled standardized mean difference of urinary 3OH-BaP concentration for smokers versus nonsmokers was 5.18 (95 % CI 2.86-7.50). Clinical data suggested that smoking led to more lymph node metastasis, higher pathological N-stage, and worse overall survival in SCLC patients. We identified 75 genes that participate in BaP-associated cancer stemness of SCLC from Comparative Toxicogenomics Database and validated the expression of these candidate genes in SCLC patient samples. Protein kinase cAMP-activated catalytic subunit alpha (PRKACA) was found to be most upregulated in SCLC patients and in vitro experiments indicated that long-term exposure of SCLC cells to BaP, at the concentration equivalent to those detected in blood, increased PKA protein level. Further investigation revealed that PKA could directly interact with SOX2 and protect SOX2 from COP1-mediated ubiquitination and degradation. Upregulated SOX2 then contributed to the stemness and metastasis of SCLC cells while inhibition of aryl hydrocarbon receptor (AhR) signaling pathway abolished BaP induced PKA expression and downstream PKA/SOX2 axis. Our findings firstly pinpoint BaP exposure as a high-risk factor for SCLC and worse outcomes in patients, with the underlying mechanism being the activation of cancer stemness of SCLC via the AhR/PKA/SOX2 axis.
苯并[a]芘（BaP）是有机物质不完全燃烧和香烟烟雾的常见产物，存在于环境中。流行病学研究一直表明，老年吸烟者患小细胞肺癌（SCLC）的风险更高，风险和临床阶段随着吸烟强度和持续时间的增加而增加。然而，其潜在机制仍未得到充分研究。在这里，我们在尿液中建立了吸烟与 BaP 代谢物 3-羟基苯并[a]芘（3OH-BaP）之间的正相关。吸烟者与不吸烟者尿液中 3OH-BaP 浓度的汇总标准化均数差值为 5.18（95%置信区间 2.86-7.50）。临床数据表明，吸烟导致 SCLC 患者的淋巴结转移更多，病理 N 期更高，总生存期更差。我们从比较毒理学基因组数据库中确定了 75 个参与 SCLC 中 BaP 相关癌症干性的基因，并在 SCLC 患者样本中验证了这些候选基因的表达。蛋白激酶 cAMP 激活催化亚单位 α（PRKACA）在 SCLC 患者中表达上调最为明显，体外实验表明，SCLC 细胞长期暴露于浓度相当于血液中检测到的 BaP 会增加 PKA 蛋白水平。进一步的研究表明，PKA 可以直接与 SOX2 相互作用，并保护 SOX2 免受 COP1 介导的泛素化和降解。上调的 SOX2 随后促进了 SCLC 细胞的干性和转移，而抑制芳香烃受体（AhR）信号通路则消除了 BaP 诱导的 PKA 表达和下游 PKA/SOX2 轴。我们的研究结果首次指出 BaP 暴露是 SCLC 的高危因素，并且会导致患者预后更差，其潜在机制是通过 AhR/PKA/SOX2 轴激活 SCLC 的癌症干性。
