miR-377-3p-Mediated EGR1 Downregulation Promotes B[a]P-Induced Lung Tumorigenesis by Wnt/Beta-Catenin Transduction.
miR-377-3p-Mediated EGR1 Downregulation Promotes B[a]P-Induced Lung Tumorigenesis by Wnt/Beta-Catenin Transduction.
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miR-377-3p 介导的 EGR1 下调通过 Wnt/β-Catenin 转导促进 B[a]P 诱导的肺肿瘤发生。
DOI：
10.3389/fonc.2021.699004
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发表时间：
2021
影响因子：
4.7
通讯作者：
Qi H
中科院分区：
文献类型：
--
作者：
Ke X;He L;Wang R;Shen J;Wang Z;Shen Y;Fan L;Shao J;Qi H
多环芳烃(PAHs)，尤其是苯并[a]芘(B[a]P)，存在于香烟烟雾和空气污染中，是一种重要的致癌物质。然而，B[a]P介导的细胞转化和肿瘤启动的早期分子事件和相关调控作用仍不清楚。本研究发现，苯并[a]P及其活性形式BPDE分别作用于人支气管上皮细胞转化和小鼠肺癌过程中，Egr1的表达显著下调。反之，Egr1过表达可抑制BPDE诱导的细胞恶性转化。此外，BPDE/B[a]P可显著增强miR-377-3p的表达，并通过靶向Egr1的3‘非编码区，对抑制Egr1的表达起关键作用。MIR-377-3P Anagomir逆转了Egr1在细胞恶性转化和肿瘤起始模型中的下调作用。此外，用免疫组织化学方法评价了苯并[a]P所致的临床肺癌组织中的分子变化，并与临床数据库进行了验证。从机制上讲，EGR1抑制也参与了Wnt/β-catenin信号转导的调节，从而促进了苯并[a]P/BPDE暴露后肺肿瘤的发生。综上所述，本研究结果表明，苯并[a]芘暴露可能通过miR-377-3P介导的Egr1表达下调而诱导肺肿瘤的发生，提示Egr1在多环芳烃诱导的肺癌发生中起重要作用。
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.
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作者：
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