Abstract

Exposure to environmental and occupational contaminants leads to lung cancer. 3-Nitrobenzanthrone (3-nitro-7H-benz[de]anthracen-7-one, 3-NBA) is a potential carcinogen in ambient air or diesel particulate matter. Studies have revealed that short-term exposure to 3-NBA induces cell death, reactive oxygen species activation, and DNA adduct formation and damage. However, details of the mechanism by which chronic exposure to 3-NBA influences lung carcinogenesis remain largely unknown. In this study, human lung epithelial BEAS-2B cells were continuously exposed to 0–10-μM 3-NBA for 6 months. NanoString analysis was conducted to evaluate gene expression in the cells, revealing that 3-NBA–mediated transformation results in a distinct gene expression signature including carbon cancer metabolism, metastasis, and angiogenesis. Alterations in tumor-promoting genes such as EREG (epiregulin), SOX9, E-cadherin, TWIST, and IL-6 were involved in epithelial cell aggressiveness. Kaplan–Meier plotter analyses indicated that increased EREG and IL-6 expressions in early-stage lung cancer cells are correlated with poor survival. In vivo xenografts on 3-NBA–transformed cells exhibited prominent tumor formation and metastasis. EREG knockout cells exposed to 3-NBA for a short period exhibited high apoptosis and low colony formation. By contrast, overexpression of EREG in 3-NBA–transformed cells markedly activated the PI3K/AKT and MEK/ERK signaling pathways, resulting in tumorigenicity. Furthermore, elevated IL-6 and EREG expressions synergistically led to STAT3 signaling activation, resulting in clonogenic cell survival and migration. Taken together, chronic exposure of human lung epithelial cells to 3-NBA leads to malignant transformation, in which the EREG signaling pathway plays a pivotal mediating role.

Graphical abstract

中文翻译：

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3-硝基苯并蒽酮通过上皮调节蛋白信号通路促进人肺上皮细胞的恶性转化

摘要

接触环境和职业污染物会导致肺癌。3-Nitrobenzanthrone (3-nitro-7H-benz[de]anthracen-7-one, 3-NBA) 是环境空气或柴油颗粒​​物中的潜在致癌物。研究表明，短期暴露于 3-NBA 会导致细胞死亡、活性氧激活以及 DNA 加合物的形成和损伤。然而，长期暴露于 3-NBA 影响肺癌发生的机制的细节仍然很大程度上未知。在这项研究中，人肺上皮 BEAS-2B 细胞连续暴露于 0-10-μM 3-NBA 6 个月。进行 NanoString 分析以评估细胞中的基因表达，揭示 3-NBA 介导的转化导致不同的基因表达特征，包括碳癌代谢、转移和血管生成。EREG（上皮调节蛋白）、SOX9、E-cadherin、TWIST和IL-6与上皮细胞侵袭性有关。Kaplan-Meier 绘图仪分析表明，早期肺癌细胞中EREG和IL-6表达增加与存活率低相关。3-NBA 转化细胞上的体内异种移植物表现出显着的肿瘤形成和转移。短时间暴露于 3-NBA 的EREG敲除细胞表现出高凋亡和低集落形成。相比之下，EREG的过表达在 3-NBA 转化细胞中显着激活 PI3K/AKT 和 MEK/ERK 信号通路，导致致瘤性。此外，升高的 IL-6 和 EREG 表达协同导致 STAT3 信号激活，导致克隆细胞存活和迁移。总之，人肺上皮细胞长期暴露于 3-NBA 会导致恶性转化，其中 EREG 信号通路起着关键的介导作用。

图形概要