Upregulation of Circ_0035266 Contributes to the Malignant Progression of Inflammation-Associated Malignant Transformed Cells Induced by Tobacco-Specific Carcinogen NNK. (22nd July 2022)

• Record Type: Journal Article
• Authors: Hua, Qiuhan; Liu, Yufei; Li, Meizhen; Li, Xueqi; Chen, Wei; Diao, Qinqin; Ling, Yihui; Jiang, Yiguo
• Is Part Of: Toxicological sciences. Volume 189:Number 2(2022)
• Page Start: 203
• Page End: 215
• Publication Date: 2022-07-22
• Subjects: NNK -- circ_0035266 -- malignant transformation -- inflammation -- DDX3X; Toxicology -- Periodicals; Toxicology -- Periodicals; Toxicology; Periodicals; 615.9
• DOI: 10.1093/toxsci/kfac072
• Languages: English
• ISSNs: 1096-6080

Abstract

Abstract: 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.