Abstract
Polycyclic aromatic hydrocarbons (PAHs), particularly benzo[a]pyrene (B[a]P), found in cigarette smoke and air pollution, is an important carcinogen. Nevertheless, early molecular events and related regulatory effects of B[a]P-mediated cell transformation and tumor initiation remain unclear. This study found that EGR1 was significantly downregulated during human bronchial epithelial cell transformation and mice lung carcinogenesis upon exposure to B[a]P and its active form BPDE, respectively. In contrast, overexpression of EGR1 inhibited the BPDE-induced cell malignant transformation. Moreover, miR-377-3p was strongly enhanced by BPDE/B[a]P exposure and crucial for the inhibition of EGR1 expression by targeting the 3’UTR of EGR1. MiR-377-3p antagomir reversed the effect of EGR1 downregulation in cell malignant transformation and tumor initiation models. Furthermore, the B[a]P-induced molecular changes were evaluated by IHC in clinical lung cancer tissues and examined with a clinic database. Mechanistically, EGR1 inhibition was also involved in the regulation of Wnt/β-catenin transduction, promoting lung tumorigenesis following B[a]P/BPDE exposure. Taken together, the results demonstrated that bBenzo[a]pyrene exposure might induce lung tumorigenesis through miR-377-3p-mediated reduction of EGR1 expression, suggesting an important role of EGR1 in PAHs-induced lung carcinogenesis.
Highlights
Lung cancer has the highest morbidity and mortality worldwide
Our results suggest that the upregulation of miR-3773p inhibits Early growth response 1 (EGR1) transcription, which is implicated in BPDE/B[a] P-induced cell malignant transformation and lung tumorigenesis
This study further investigated early events and the molecular mechanisms of gene dysregulation that lead to cell malignant transformation and lung tumorigenesis following B[a]P/BPDE exposure
Summary
Lung cancer has the highest morbidity and mortality worldwide. Late diagnosis and poor prognosis are the main causes of cancerrelated death [1, 2], and smoking is a common risk factor. Over the years, the increased non-smoking-related risk associated with ambient air pollution has been frequently reported [3]. The most widely studied PAH is Benzo[a]pyrene (B[a]P), which is frequently chosen as a substitute for evaluating the carcinogenic PAHs [5]. B[a]P is a human group 1 carcinogen capable of initiating and promoting lung tumorigenesis [6]. BPDE is the main biologically active metabolite of B[a]P that can form DNA adducts of guanine N2, exerting its carcinogenic effect [7]. In cell-based models, B [a]P or its metabolite BPDE induce cell malignant transformation, while in mice models, it can reduce lung tumors. Recent studies have shown that B[a]P-induced tumorigenesis involves DNA methylation, oxidative stress, cell cycle, inflammation, apoptosis, and other biological processes [7,8,9].
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