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Interleukin-17A mediates tobacco smoke–induced lung cancer epithelial-mesenchymal transition through transcriptional regulation of ΔNp63α on miR-19
Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2021-04-03 , DOI: 10.1007/s10565-021-09594-0
Chunfeng Xie 1 , Jianyun Zhu 1, 2 , Cong Huang 3 , Xue Yang 4 , Xiaoqian Wang 4 , Yu Meng 5 , Shanshan Geng 1 , Jieshu Wu 1 , Hongbin Shen 6, 7 , Zhibin Hu 6, 7 , Zili Meng 8 , Xiaoting Li 1 , Caiyun Zhong 1, 9
Affiliation  

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



中文翻译:


Interleukin-17A 通过 miR-19 上 ΔNp63α 的转录调节介导烟草烟雾诱导的肺癌上皮间质转化



白细胞介素-17A (IL-17A) 是癌发生过程中重要的炎症细胞因子。烟草烟雾(TS)是影响上皮间质转化(EMT)过程的肺癌的主要危险因素。然而,IL-17A 在 TS 诱导的 EMT 中介导肺癌进展的潜在机制仍不清楚。本研究发现,肺癌组织中,尤其是有吸烟史的肿瘤组织中,IL-17A水平升高,且较高的IL-17A水平与这些标本中EMT的诱导相关。此外,IL-17A刺激的肺癌细胞中ΔNp63α的表达增加。 ΔNp63α 作为关键癌基因,与 miR-17-92 簇启动子结合,并在转录上增加肺癌细胞中 miR-19 的表达。 miR-19的过表达通过E-钙粘蛋白的下调和N-钙粘蛋白的上调促进肺癌中的EMT,而其抑制则抑制EMT。最后,在 TS 暴露小鼠的肺组织中发现 IL-17A、ΔNp63α 和 miR-19 水平上调以及 EMT 相关生物标志物的改变。综上所述,上述结果表明,IL-17A 增加 ΔNp63α 表达,转录升高 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。

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更新日期:2021-04-04
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