Upregulation of Circ_0035266 Contributes to the Malignant Progression of Inflammation-Associated Malignant Transformed Cells Induced by Tobacco-Specific Carcinogen NNK
Upregulation of Circ_0035266 Contributes to the Malignant Progression of Inflammation-Associated Malignant Transformed Cells Induced by Tobacco-Specific Carcinogen NNK
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Circ_0035266 的上调有助于烟草特异性致癌物 NNK 诱导的炎症相关恶性转化细胞的恶性进展
DOI：
10.1093/toxsci/kfac072
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发表时间：
2022-07-22
影响因子：
3.8
通讯作者：
Jiang, Yiguo
中科院分区：
文献类型：
--
作者：
Hua, Qiuhan;Liu, Yufei;Jiang, Yiguo
吸烟引起的慢性炎症被认为是肺部肿瘤发生的重要驱动因素。化合物 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 是一种烟草特有的致癌物质，而脂多糖 (LPS) 是一种炎症诱导剂，它们是烟草烟雾的重要成分，与炎症驱动的致癌作用有关。然而，LPS介导的炎症对NNK诱导的肿瘤发生的生物学效应和潜在机制仍不清楚。在这项研究中，BEAS-2B 人支气管上皮细胞短期或长期暴露于 NNK、LPS 或两者。我们发现，急性 LPS 暴露促进 NNK 处理的 BEAS-2B 细胞中粒细胞巨噬细胞集落刺激因子 (GM-CSF) 和白细胞介素 (IL)-6 的分泌。此外，长期接触 LPS 通过促进细胞增殖、细胞周期改变、迁移和克隆形成，促进了 NNK 诱导的恶性转化过程。此前，我们确定环状RNA circ_0035266通过海绵miR-181d-5p并调节其下游靶DEAD-Box解旋酶3 X-Linked (DDX3X)的表达来增强对NNK + LPS的细胞炎症反应。在这里，我们发现circ_0035266或DDX3X的敲除导致NNK + LPS转化的BEAS-2B细胞的增殖、细胞周期进程和迁移的显着抑制，而这些基因的过度表达产生相反的效果，表明circ_0035266和DDX3X在慢性炎症驱动的恶性转化细胞的恶性进展中的致癌作用。此外，利用一组肺癌组织进一步证实了circ_0035266、miR-181d-5p和DDX3X之间的调控关系。总之，我们的研究结果为我们使用细胞恶性转化模型理解炎症驱动的肿瘤发生提供了新的见解，并表明 circ_0035266 在化学致癌作用中具有新的肿瘤促进作用。
Cigarette smoking-induced chronic inflammation has been considered a vital driver of lung tumorigenesis. The compounds 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific carcinogen, and lipopolysaccharide (LPS), an inflammatory inducer, are important components of tobacco smoke which have been implicated in inflammation-driven carcinogenesis. However, the biological effects and underlying mechanisms of LPS-mediated inflammation on NNK-induced tumorigenesis are still unclear. In this study, BEAS-2B human bronchial epithelial cells were exposed to NNK, LPS or both, for short- or long-term periods. We found that acute LPS exposure promoted the secretion of granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-6 in NNK-treated BEAS-2B cells. In addition, chronic LPS exposure facilitated the NNK-induced malignant transformation process by promoting cell proliferation, cell cycle alteration, migration, and clonal formation. Previously, we determined that circular RNA circ_0035266 enhanced cellular inflammation in response to NNK + LPS by sponging miR-181d-5p and regulating expression of its downstream target DEAD-Box Helicase 3 X-Linked (DDX3X). Here, we found that knockdown of circ_0035266 or DDX3X led to a remarkable inhibition of the proliferation, cell cycle progression, and migration of NNK + LPS-transformed BEAS-2B cells, whereas overexpression of these genes produced the opposite effects, indicating the oncogenic roles of circ_0035266 and DDX3X in the malignant progression of chronic inflammation-driven malignant transformed cells. Moreover, the regulatory relationships among circ_0035266, miR-181d-5p, and DDX3X were further confirmed using a group of lung cancer tissues. Conclusively, our findings provide novel insights into our understanding of inflammation-driven tumorigenesis using a cellular malignant transformation model, and indicate a novel tumor-promoting role for circ_0035266 in chemical carcinogenesis.