Interleukin-17A mediates tobacco smoke-induced lung cancer epithelial-mesenchymal transition through transcriptional regulation of Delta Np63 alpha on miR-19
Interleukin-17A mediates tobacco smoke-induced lung cancer epithelial-mesenchymal transition through transcriptional regulation of Delta Np63 alpha on miR-19
复制标题
Interleukin-17A 通过 miR-19 上 Delta Np63 α 的转录调节介导烟草烟雾诱导的肺癌上皮间质转化
DOI：
10.1007/s10565-021-09594-0
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发表时间：
2021
影响因子：
6.1
通讯作者：
Zhong Caiyun
中科院分区：
文献类型：
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作者：
Xie Chunfeng;Zhu Jianyun;Huang Cong;Yang Xue;Wang Xiaoqian;Meng Yu;Geng Shanshan;Wu Jieshu;Shen Hongbin;Hu Zhibin;Meng Zili;Li Xiaoting;Zhong Caiyun
白细胞介素-17A（IL-17 A）是肿瘤发生发展过程中必需的炎性细胞因子。烟草烟雾（TS）是影响上皮间质转化（EMT）过程的主要肺癌危险因素。然而，IL-17 A在TS诱导的EMT中介导肺癌进展的潜在机制仍然难以捉摸。在本研究中，发现IL-17 A水平在肺癌组织中升高，特别是在有吸烟经历的病例的肿瘤组织中，并且较高的IL-17 A水平与这些标本中EMT的诱导相关。IL-17 A刺激肺癌细胞后，Δ Np 63 α表达增加。Δ Np 63 α是一个关键的癌基因，与miR-17-92簇启动子结合，在肺癌细胞中转录增加miR-19的表达。miR-19过表达促进肺癌EMT，下调E-cadherin，上调N-cadherin，而抑制miR-19则抑制EMT。最后，TS暴露小鼠肺组织中IL-17 A、Δ Np 63 α和miR-19沿着上调水平以及EMT相关生物标志物的改变。综上所述，上述结果表明，IL-17 A增加Δ Np 63 α表达，转录提高miR-19表达，并促进TS诱导的肺癌EMT。这些发现可能为肺癌治疗靶点的确定提供新的见解。图形摘要
Interleukin-17A (IL-17A) is an essential inflammatory cytokine in the progress of carcinogenesis. Tobacco smoke (TS) is a major risk factor of lung cancer that influences epithelial-mesenchymal transition (EMT) process. However, the potential mechanism by which IL-17A mediates the progression of lung cancer in TS-induced EMT remains elusive. In the present study, it was revealed that the IL-17A level was elevated in lung cancer tissues, especially in tumor tissues of cases with experience of smoking, and a higher IL-17A level was correlated with induction of EMT in those specimens. Moreover, the expression of ΔNp63α was increased in IL-17A-stimulated lung cancer cells. ΔNp63α functioned as a key oncogene that bound to the miR-17-92 cluster promoter and transcriptionally increased the expression of miR-19 in lung cancer cells. Overexpression of miR-19 promoted EMT in lung cancer with downregulation of E-cadherin and upregulation of N-cadherin, while its inhibition suppressed EMT. Finally, the upregulated levels of IL-17A, ΔNp63α, and miR-19 along with the alteration of EMT-associated biomarkers were found in lung tissues of TS-exposed mice. Taken together, the abovementioned results suggest that IL-17A increases ΔNp63α expression, transcriptionally elevates miR-19 expression, and promotes TS-induced EMT in lung cancer. These findings may provide a new insight for the identification of therapeutic targets for lung cancer.Graphical abstract