DataSheet_1_miR-377-3p-Mediated EGR1 Downregulation Promotes B[a]P-Induced Lung Tumorigenesis by Wnt/Beta-Catenin Transduction.pdf

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.

多环芳烃（Polycyclic Aromatic Hydrocarbons, PAHs），尤其是苯并[a]芘（Benzo[a]Pyrene, B[a]P），广泛存在于香烟烟雾与大气污染物中，是一类重要的致癌物。然而，苯并[a]芘介导的细胞转化与肿瘤起始过程中的早期分子事件及相关调控效应仍未明确。本研究发现，在暴露于苯并[a]芘的人支气管上皮细胞转化进程，以及暴露于其活性形式BPDE的小鼠肺癌发生过程中，早期生长反应因子1（Early Growth Response 1, EGR1）的表达均显著下调。反之，过表达EGR1可抑制BPDE诱导的细胞恶性转化。此外，BPDE/苯并[a]芘暴露可显著上调miR-377-3p的表达，而该微小RNA可通过靶向结合EGR1的3'非翻译区（3'UTR）抑制其表达。miR-377-3p拮抗剂（antagomir）可逆转EGR1下调在细胞恶性转化与肿瘤起始模型中的效应。此外，本研究通过免疫组化（Immunohistochemistry, IHC）检测了临床肺癌组织中苯并[a]芘诱导的分子变化，并结合临床数据库开展了相关分析。机制层面研究显示，EGR1的抑制还参与了Wnt/β-连环蛋白（β-catenin）信号转导的调控，进而在苯并[a]芘/BPDE暴露后促进肺肿瘤发生。综上，本研究结果表明，苯并[a]芘暴露可通过miR-377-3p介导的EGR1表达下调诱导肺肿瘤发生，提示EGR1在多环芳烃诱导的肺癌发生过程中发挥重要作用。