lncRNA NONHSAT021963, which upregulates VEGF in A549 cells, mediates PM2.5 exposure-induced angiogenesis in Shenyang, China

Abstract

Background

PM2.5 is airborne particulate matter that is involved in air pollution and has become an important problem endangering human health. LncRNAs play important roles in malignant tumors. However, few studies have reported the mechanisms by which PM2.5 affects lung cancer.

Objective

To investigate the functional changes in PM2.5-exposed cells, we conducted tubule formation assays to determine angiogenesis and sequenced RNA to elucidate the key molecular effects of PM2.5 in Shenyang, China.

Results

RNA sequencing showed that the overall exposure values were very similar to the QPCR values. We found that 1379 lncRNA signatures and 162 mRNAs were differentially expressed between PM2.5-exposed and neutral saline-exposed cells. We further validated these changes via quantitative PCR in A549 human non-small-cell lung cancer (NSCLC) cell lines. PM2.5-exposed A549 cells presented carcinogenic transformation via lncRNA NONHSAT021963, which upregulates VEGF levels. The tubule formation assays showed that PM2.5-exposed cells were more angiogenic.

Conclusion

These results may help to clarify the proteins and signaling pathways affected by PM2.5 and lead to new diagnostic and therapeutic approaches in treating NSCLC.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Abbreviations

PM2.5:

Fine particulate matter

ROS:

Reactive oxygen species

HIF-1:

Hypoxia inducible factor-1

VEGF-β:

Vascular endothelial growth factor-β

PTGS2:

Prostaglandin endoperoxide synthase 2

HSPA1B:

Heat shock 70 kDa protein 1B

bFGF:

Basic fibroblast growth factor

MMPs:

Matrix metalloproteinases

IL24:

Interleukin24

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

KEGG:

Kyoto Encyclopedia of Genes and Genomes

NSCLC:

Non-small-cell lung cancer

ECM:

Extracellular matrix

References

  1. Akamatsu H et al (2014) Progression-free survival at 2 years is a reliable surrogate marker for the 5-year survival rate in patients with locally advanced non-small cell lung cancer treated with chemoradiotherapy. BMC Cancer 14:18. https://doi.org/10.1186/1471-2407-14-18

    Article  PubMed  PubMed Central  Google Scholar 

  2. Deng X et al (2017) PM2.5 exposure-induced autophagy is mediated by lncRNA loc146880 which also promotes the migration and invasion of lung cancer cells. Biochim Biophys Acta 1861:112–125. https://doi.org/10.1016/j.bbagen.2016.11.009

    CAS  Article  Google Scholar 

  3. Eckel SP et al (2016) Air pollution affects lung cancer survival. Thorax 71:891–898. https://doi.org/10.1136/thoraxjnl-2015-207927

    Article  PubMed  PubMed Central  Google Scholar 

  4. Fu J, Jiang D, Lin G, Liu K, Wang Q (2015) An ecological analysis of PM2.5 concentrations and lung cancer mortality rates in China. BMJ 5:e009452. DOI:10.1136/bmjopen-2015–009452

  5. Giatromanolaki A et al (2001) Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer 85:881–890. https://doi.org/10.1054/bjoc.2001.2018

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Goodman RB, Pugin J, Lee JS, Matthay MA (2003) Cytokine-mediated inflammation in acute lung injury. Cytokine Growth Factor Rev 14:523–535. https://doi.org/10.1016/s1359-6101(03)00059-5

    CAS  Article  PubMed  Google Scholar 

  7. Grommes J, Soehnlein O (2011) Contribution of neutrophils to acute lung injury. Mol Med 17:293–307. https://doi.org/10.2119/molmed.2010.00138

    CAS  Article  PubMed  Google Scholar 

  8. Hainaud P et al (2006) The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-ephrin B2 cascade in tumor vessel remodeling and endothelial cell functions. Cancer Res 66:8501–8510. https://doi.org/10.1158/0008-5472.CAN-05-4226

    CAS  Article  PubMed  Google Scholar 

  9. Hamad SH, Schauer JJ, AntkiewiczDS SMM, Kadhim AK (2016) Ros production and gene expression in alveolar macrophages exposed to pm2.5 from baghdad, iraq: seasonal trends and impact of chemical composition. Sci Total Environ 543:739–745. https://doi.org/10.1016/j.scitotenv.2015.11.065

    CAS  Article  PubMed  Google Scholar 

  10. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Herrera-Solorio AM et al (2017) Histone code and long non-coding RNAs (lncRNAs) aberrations in lung cancer: implications in the therapy response. Clin Epigenetics 9:98. https://doi.org/10.1186/s13148-017-0398-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Kaya A et al (2004) The prognostic significance of vascular endothelial growth factor levels in sera of non-small cell lung cancer patients. Respir Med 98:632–636. https://doi.org/10.1016/j.rmed.2003.12.017

    Article  PubMed  Google Scholar 

  13. Keeratichamroen S, Lirdprapamongkol K, Svasti J (2018) Mechanism of ECM-induced dormancy and chemoresistance in A549 human lung carcinoma cells. Oncol Rep 39:1765–1774. https://doi.org/10.3892/or.2018.6258

    CAS  Article  PubMed  Google Scholar 

  14. Kim HJ, Choi MG, Park MK, Seo YR (2017) Predictive and Prognostic Biomarkers of Respiratory Diseases due to Particulate Matter Exposure. J Cancer Prev 22:6–15. https://doi.org/10.15430/JCP.2017.22.1.6

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kopp F, Mendell JT (2018) Functional Classification and Experimental Dissection of Long Noncoding RNAs. Cell 172:393–407. https://doi.org/10.1016/j.cell.2018.01.011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Ku T et al (2017) NF-κB-regulated microRNA-574–5p underlies synaptic and cognitive impairment in response to atmospheric PM2.5 aspiration. Part Fibre Toxicol 14:34 DOI:10.1186/s12989–017–0215–3

  17. Liang Y et al (2020) A novel long non-coding RNA LINC00355 promotes proliferation of lung adenocarcinoma cells by down-regulating miR-195 and up-regulating the expression of CCNE1. Cell Signal 66:109462. https://doi.org/10.1016/j.cellsig.2019.109462

    CAS  Article  PubMed  Google Scholar 

  18. Liu Y et al (2017) Autophagy associated cytotoxicity and cellular uptake mechanisms of bismuth nanoparticles in human kidney cells. Toxicol Lett 275:39–48. https://doi.org/10.1016/j.toxlet.2017.04.014

    CAS  Article  PubMed  Google Scholar 

  19. Liu JQ, Feng YH, Zeng S, Zhong MZ (2020) linc01088 promotes cell proliferation by scaffolding EZH2 and repressing p21 in human non-small cell lung cancer. Life Sci 241:117134. https://doi.org/10.1016/j.lfs.2019.117134

    CAS  Article  PubMed  Google Scholar 

  20. Lu F et al (2015) Systematic review and meta-analysis of the adverse health effects of ambient PM2.5 and PM10 pollution in the Chinese population. Environ Res 136:196–204. https://doi.org/10.1016/j.envres.2014.06.029

    CAS  Article  PubMed  Google Scholar 

  21. Ma M et al (2015) Characteristics and oxidative stress on rats and traffic policemen of ambient fine particulate matter from Shenyang. Sci Total Environ 526:110–115. https://doi.org/10.1016/j.scitotenv.2015.04.075

    CAS  Article  PubMed  Google Scholar 

  22. Oskarsson T, Batlle E, Massagué J (2014) Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14:306–321. https://doi.org/10.1016/j.stem.2014.02.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Pope CA 3rd et al (2002) Lung cancer, cardipulmonary mortality, and long-term exposure to fine particulate air pollution. JAMA 287:1132–1141. https://doi.org/10.1001/jama.287.9.1132

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Pope CA 3rd, Ezzati M, Dockery DW (2009) Fine-particulate air pollution and life expectancy in the United States. N Engl J Med 360:376–386. https://doi.org/10.1056/NEJMsa0805646

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Pothirat C et al (2019) Acute effects of air pollutants on daily mortality and hospitalizations due to cardiovascular and respiratory diseases.J Thorac Dis 11:3070–3083. DOI:10.21037/jtd.2019.07.37

  26. Singh SK, Mishra MK, Singh R (2019) Hypoxia-inducible factor-1α induces CX3CR1 expression and promotes the epithelial to mesenchymal transition (EMT) in ovarian cancer cells. J Ovarian Res 12:42. https://doi.org/10.1186/s13048-019-0517-1

    Article  PubMed  PubMed Central  Google Scholar 

  27. Soni S, Padwad YS (2017) HIF-1 in cancer therapy: two decade long story of a transcription factor. Acta Oncol 56:503–515. https://doi.org/10.1080/0284186X.2017.1301680

    CAS  Article  PubMed  Google Scholar 

  28. Szklarczyk D et al (2011) The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 39(Database issue):D561–8. doi: 10.1093/nar/gkq973.

  29. Tang HL, Yuen KL, Tang HM, Fung MC (2009) Reversibility of apoptosis in cancer cells. Br JCancer 100:118–122. https://doi.org/10.1038/sj.bjc.6604802

    CAS  Article  Google Scholar 

  30. White AG et al (2014) Environmental arsenic exposure and microbiota in induced sputum. Int J Environ Res Public Health 11:2299–2313. https://doi.org/10.3390/ijerph110202299

    Article  PubMed  PubMed Central  Google Scholar 

  31. Xiang J et al (2020) LINC00511 influences cellular proliferation through cyclin-dependent kinases in papillary thyroid carcinoma. J Cancer 11:450–459. https://doi.org/10.7150/jca.35364

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Xu MX, Zhu YF, Chang HF, Liang Y (2016) Nanoceria restrains PM2.5-induced metabolic disorder and hypothalamus inflammation by inhibition of astrocytes activation related NF-κB pathway in Nrf2 deficient mice. Free Radic Biol Med 99:259–272. https://doi.org/10.1016/j.freeradbiomed.2016.08.021

    CAS  Article  PubMed  Google Scholar 

  33. Yang B, Chen D, Zhao H, Xiao C (2016) The effects for PM2.5 exposure on non-small-cell lung cancer induced motility and proliferation. Springerplus 5:2059. DOI:10.1186/s40064–016–3734–8

  34. Yao C et al (2019) The association between high particulate matter pollution and daily cause-specific hospital admissions: a time-series study in Yichang. Environ Sci Pollut Res Int, China. https://doi.org/10.1007/s11356-019-06734-2

    Google Scholar 

  35. Yao L, Lu N (2014) Particulate Matter Pollution and Population Exposure Assessment over Mainland China in 2010 with Remote Sensing. Int J Environ Res Public Health 11:5241–5250. https://doi.org/10.3390/ijerph110505241

    Article  PubMed  PubMed Central  Google Scholar 

  36. Yuan X et al (2015) Pm2.5 induces embryonic growth retardation: potential involvement of ROS-MAPKs-apoptosis and G0/G1 arrest pathways. Environ Toxicol 31:2028–2044. https://doi.org/10.1002/tox.22203

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgement

The work was supported by the research funding from the Department of Science & Technology Liaoning (grant no. 2017225076 and 20180550862), the Shenyang Bureau of Science and Technology (no. 18-400-4-09), and Shenyang Medical College Fund Project (no. 20191030).

Author information

Affiliations

Authors

Contributions

BY and CX contributed conception and design of the study; BY carried out all experimental assays. HT and BY performed the statistical analysis; BY wrote the first draft of the manuscript; BY and HT wrote sections of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Corresponding author

Correspondence to Chunling Xiao.

Ethics declarations

Conflict of interest

The authors declare that no potential competing interests exist.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (TXT 0 kb)

Supplementary file2 (TXT 148 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yang, B., Tian, H. & Xiao, C. lncRNA NONHSAT021963, which upregulates VEGF in A549 cells, mediates PM2.5 exposure-induced angiogenesis in Shenyang, China. Mol. Cell. Toxicol. (2020). https://doi.org/10.1007/s13273-020-00095-5

Download citation

Keyword

  • PM2.5
  • A549
  • lncRNA
  • angiogenesis
  • VEGF