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

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Abstract

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.

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Data Availability

Data and materials are available and transparent.

Abbreviations

ChIP:

chromatin immunoprecipitation

CSE:

cigarette smoke extract

ELISA:

enzyme- linked immunosorbent assay

EMT:

epithelial-mesenchymal transition

FA:

filtered air

H&E:

hematoxylin & eosin

HBE:

human bronchial epithelial

IHC:

immunohistochemical

IL-17A:

interleukin-17A

IL-17RA:

IL-17 receptor A

IL-17RC:

IL-17 receptor C

LC:

lung cancer

miR:

microRNA

NSCLC:

non-small cell lung cancer

TP63:

the human p63 gene

TP63αRE:

TP63α the response element

TS:

tobacco smoke

WB:

Western blot

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Funding

This work was supported by grants from the National Basic Research Program of China (973 Program) (No. 2013CB910303), the National Natural Science Foundation of China (Nos. 81803210, 81773431, 81973026), the Natural Science Foundation of Jiangsu Province (BK20180217), the China Postdoctoral Science Foundation Funded Project (2018M642280, 2020T130312), and Suzhou Talent Training Program (GSWS2020075).

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Author notes

  1. Chunfeng Xie, Jianyun Zhu and Cong Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China

    Chunfeng Xie, Jianyun Zhu, Shanshan Geng, Jieshu Wu, Xiaoting Li & Caiyun Zhong

  2. Department of Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215008, Jiangsu, China

    Jianyun Zhu

  3. Guangde Center for Diseases Prevention and Control, Guangde, 242200, Anhui, China

    Cong Huang

  4. Department of Clinical Nutrition, Nanjing Drum Tower Hospital, Nanjing, 211166, Jiangsu, China

    Xue Yang & Xiaoqian Wang

  5. Wuxi Center for Disease Control and Prevention, The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi, 214023, Jiangsu, China

    Yu Meng

  6. Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211126, China

    Hongbin Shen & Zhibin Hu

  7. Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, Nanjing Medical University, Nanjing, 211126, China

    Hongbin Shen & Zhibin Hu

  8. Department of Respiratory Medicine, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, 223300, Jiangsu, China

    Zili Meng

  9. Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China

    Caiyun Zhong

Authors
  1. Chunfeng Xie
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  2. Jianyun Zhu
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  11. Zili Meng
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  12. Xiaoting Li
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Contributions

Chunfeng Xie and Jianyun Zhu were responsible for in vivo experiments. Xiaoting Li, Cong Huang, Xue Yang, Xiaoqian Wang, Yu Meng, Shanshan Geng, and Jieshu Wu performed most of the in vitro experiments. Hongbin Shen and Zhibin Hu participated in the study design. Zili Meng contributed to the tissue preparation and study design. Xiaoting Li performed study design and data analysis and wrote the manuscript draft. Caiyun Zhong conceived, designed, and supervised the study and wrote the manuscript. All authors were involved in the revision of the manuscript and approved the submitted version.

Corresponding authors

Correspondence to Zili Meng, Xiaoting Li or Caiyun Zhong.

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All procedures involving human tumors were approved by the Ethics Committee of Nanjing Medical University with ethical clearance application number (2016-318). Mice were handled under the recommendations in the guidelines of the Animal Care and Welfare Committee of Nanjing Medical University (IACUC-14030181).

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Highlights

1. Tobacco smoke–induced upregulation of IL-17A promoted lung cancer EMT.

2. IL-17A increased ΔNp63α expression in tobacco smoke–transformed HBE cells.

3. ΔNp63α exerted tobacco smoke–triggered lung cancer EMT by transcriptional activation of miR-19.

4. IL-17A/ΔNp63α/miR-19 axis was involved in tobacco smoke–induced lung cell EMT process in vivo.

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Xie, C., Zhu, J., Huang, C. et al. Interleukin-17A mediates tobacco smoke–induced lung cancer epithelial-mesenchymal transition through transcriptional regulation of ΔNp63α on miR-19. Cell Biol Toxicol 38, 273–289 (2022). https://doi.org/10.1007/s10565-021-09594-0

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