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Role and mechanism of benzo[a]pyrene in the transformation of chronic obstructive pulmonary disease into lung adenocarcinoma

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Abstract

Objective

This experiment is explores the genes that play a key role, their expression changes and the biological processes in the transformation of chronic obstructive pulmonary disease (COPD) into lung adenocarcinoma (LAC). Meanwhile, identify the effects of Benzo[a]pyrene (BaP) in the conversion of COPD into LAC.

Methods

1. Differential expression genes of COPD and LAC were screened and analyzed by high-throughput microarray data between the two diseases and their respective control groups. 2. The screened genes were used for routine bioinformatics analysis such as functional analysis, expression verification, protein interaction analysis and functional enrichment. 3. Cigarette smoke extract (CSE) combined with lipopolysaccharide (LPS) was used to establish an in vitro COPD model. 4. MTT assay was used to detect the influence of B(a)P in effect on A549 cell proliferation. CCK-8, Transwell invasion test and scratch test were used to detect the cell proliferation, invasion and migration ability, while qPCR and Western Blot tests were used to observe the cell proliferation, apoptosis and changes in related indicators such as EMT. 5. Experimental method of separately adding agonists (tBHQ) and inhibitors (DIC) of NQO1 was used to confirm the effect of NQO1 on A549 cell proliferation, apoptosis, migration and invasion. 6. To further clarify whether BaP exerted effect on cell proliferation, apoptosis, migration and invasion through NQO1, we knocked down NQO1 gene and then infecting cells with BaP.

Results

1. We screened genes of COPD and LAC using datasets from GSE151052, GSE118370, and GSE140797. After screening, the genes upregulated in COPD and downregulated in LAC were RTKN2, SLC6A4, and HBB, the gene downregulated in COPD and upregulated in LAC was NQO1, the genes downregulated in both COPD and LAC were FPR1, LYVE1 and PKHD1L1. 2. The main signaling pathways in which the target genes were enriched are cell cycle, EMT, PI3K/AKT, and apoptosis. In the data included GEPIA, PKHD1L1, FPR1, LYVE1, RTKN2, HBB, and SLC6A4 were significantly downregulated and NQO1 was upregulated in LAC relative to controls. In addition, there were 46 interaction proteins in the target genes, and the functions they enriched included hydrogen peroxide catabolism, etc. 3. When A549 cell was stimulated with 100 ng/mL LPS+ 10% CSE, the COX-2 expression indicated that COPD model in vitro was successfully established. 4. The optimal dose and action time were screened which were 1 μM and 24 h. Compared to the control group, COPD and BaP group increased cell proliferation and invasion capabilities. On the basis of COPD, adding BaP could further increase the proliferation and migration capabilities. Interestingly, the levels of NQO1 decreased in COPD models, while increased by BaP. 5. tBHQ can increase the proliferation and migration capacity of A549 cells, which is inhibited by the addition of DIC. 6. The enhanced proliferation, migration and invasion of A549 cells by BaP were attenuated after knockdown of NQO1.

Conclusion

Our study reveals that PKHD1L1, FPR1, LYVE1, RTKN2, HBB, SLC6A4 and NQO1 may play an important role in the conversion of COPD to LAC. High NQO1 expression may increase the proliferation and migration ability of A549 cells, and BaP may promote the EMT state by increasing the expression of NQO1, thereby making the COPD model in vitro expose the tumor characteristics.

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Funding

National Natural Science Foundation of China (81760676, 82260733); National Natural Science Foundation of Inner Mongolia Auton (2019LH08017).

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Author notes

  1. Lei Wang and Qi Chen have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. School of Pharmacy, Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010000, China

    Lei Wang, Qi Chen, Tingting Liu, Tuya Bai, Mengdi Zhang, Yuxia Hu, Jun Li & Fuhou Chang

  2. New Drug Screening Engineering Research Center of Inner Mongolia Autonomous Region, Inner Mongolia Autonomous Region, Hohhot, China

    Tuya Bai, Mengdi Zhang, Yuxia Hu, Jun Li & Fuhou Chang

  3. New Drug Safety Evaluation Research Center, Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, China

    Yuxia Hu & Jun Li

  4. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China

    Qi Chen

  5. School of Life Sciences, Henan University, Kaifeng, Henan, China

    Tingting Liu

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  1. Lei Wang
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Contributions

Lei Wang and Qi Chen wrote the main manuscript text. Lei Wang prepared figures 5-8. Qi Chen prepared figures 1-3. Tingting Liu prepared figures 4, Supplementary Figure 1 and 2. Tuya Bai prepared Supplementary Figure 4 and 5 Mengdi Zhang prepared Supplementary Figure 3 and Table 1. Yuxia Hu prepared Supplementary Table 2-3. Jun Li and Fuhou Chang oversight and leadership responsibility for the research activity planning and execution. All authors reviewed the manuscript. We have two corresponding authors, Jun Li and Fuhou Chang. This authors, Lei Wang and Qi Chen, have contributed equally to this work and share first authorship.

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Correspondence to Yuxia Hu, Jun Li or Fuhou Chang.

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Wang, L., Chen, Q., Liu, T. et al. Role and mechanism of benzo[a]pyrene in the transformation of chronic obstructive pulmonary disease into lung adenocarcinoma. J Cancer Res Clin Oncol 149, 4741–4760 (2023). https://doi.org/10.1007/s00432-022-04353-y

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