Interleukin-17A mediates tobacco smoke–induced lung cancer epithelial-mesenchymal transition through transcriptional regulation of ΔNp63α on miR-19,Cell Biology and Toxicology

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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

Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
Department of Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215008, Jiangsu, China.
Guangde Center for Diseases Prevention and Control, Guangde, 242200, Anhui, China.
Department of Clinical Nutrition, Nanjing Drum Tower Hospital, Nanjing, 211166, Jiangsu, China.
Wuxi Center for Disease Control and Prevention, The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi, 214023, Jiangsu, China.
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211126, China.
Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, Nanjing Medical University, Nanjing, 211126, China.
Department of Respiratory Medicine, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, 223300, Jiangsu, China.
Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.

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。

图形概要

更新日期：2021-04-04

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