Abstract 4002: EGR1 downregulation by miR-377-3p mediated lung tumorgenesis following benzo[a]pyrene exposure

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Abstract Polycyclic aromatic hydrocarbons (PAHs), especially Benzo[a]pyrene (B[a]P), contained in cigarette smoke and air pollution, belong to a category of important carcinogens for lung cancer. B[a]p exerts its carcinogenic function by causing mutations, cytotoxicity and inhibiting DNA synthesis. However, the early molecular events and related mechanisms of B[a]P-induced cell transformation and tumor initiation remains unclear. In this study, we showed that EGR1 was significantly downregulated during human bronchial epithelial BEAS-2B cell transformation and mice lung carcinogenesis after B[a]P and its active form B[a]PDE exposures, respectively. Using RNA-seq to screening and using qRT-PCR, western-blot and immunohistochemistry for validation. In contrast, overexpression of EGR1 inhibited the cell malignant transformation upon B[a]PDE exposure. Furthermore, miR377-3p was strongly increased by B[a]PDE/B[a]P in vitro and in vivo. And luciferase reporter assays showed that the exposure-induced miR377-3p was crucial for inhibition of EGR1 by targeting its 3'-UTR. Importantly, miR-377-3p antagomir reversed the effect of EGR1 downregulation in the cell malignant transformation and tumor initiation models. The target genes of EGR1, ANKRD1 and ATF3, which could be involved in B[a]P-induced lung tumorgenesis, were also analyzed in cell and mice model, respectively. Finally, the B[a]P exposure-induced molecular changes were examined by immunohistochemistry in clinical lung cancer tissues and evaluated with TCGA data. Taken together, the results demonstrated that Benzo[a]pyrene exposure may induce lung tumorgenesis through miR-377-3p mediated reduction of EGR1 expression, suggesting an important role of the tumor suppressor EGR1 in PAH-induced lung carcinogenesis. Keywords: EGR1, miR-377-3p, malignant transformation, lung tumorgenesis, gene regulation Citation Format: Xinxin Ke, Jing Shen, Jimin Shao, Hongyan Qi. EGR1 downregulation by miR-377-3p mediated lung tumorgenesis following benzo[a]pyrene exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4002.