Skip to main content
SpringerLink
Log in

Expression profiling and pathway analysis of microRNA expression in the lungs of mice exposed to long-term, low-dose benzo(a)pyrene

  • Original Paper
  • Published:
Molecular & Cellular Toxicology Aims and scope Submit manuscript

Abstract

We investigated the effect of low-dose, long-term benzo(a)pyrene exposure on the miRNA expression profile in lung tissue of mice, and the potential mechanism of miRNAs in the benzo(a)pyreneinduced damage to health. Subject mice were treated with 5 μg/kg benzo(a)pyrene twice a week for 8 weeks by intragastrical administration, while control mice were treated with the same volume of olive oil solvent. All mice were then fed for another 8 weeks without exposure to benzo(a)pyrene, after which total RNA was isolated from lung tissue. miRNA expression profiles were generated by SOLiD™3 high-throughput sequencing and the signaling pathways represented were analyzed by DIANA-mirPath. A total of 74 miRNAs were dysregulated in mice lung tissues exposed to benzo(a)pyrene. Signaling pathways regulated by benzo(a)pyrene exposure included those involved in the environmental information process and human tumorigenesis. We conclude that low-dose, long-term benzo(a)pyrene exposure alters specific miRNA expression profiles.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Wogan, G. N., Hecht, S. S., Felton, J. S., Conney, A. H. & Loeb, L. A. Environmental and chemical carcinogenesis. Seminars in Cancer Biology 14:473–486 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Halappanavar, S. et al. Pulmonary gene and microRNA expression changes in mice exposed to benzo(a)pyrene by oral gavage. Toxicology 285:133–141 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Croce, C. M. & Calin, G. A. miRNAs, cancer, and stem cell division. Cell 122:6–7 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Du, T. & Zamore, P. D. MicroPrimer: the biogenesis and function of microRNA. Development 132:4645–4652 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Skaftnesmo, K. O., Prestegarden, L., Micklem, D. R. & Lorens, J. B. MicroRNAs in tumorigenesis. Curr Pharm Biotechnol 8:320–325 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Hernando, E. microRNAs and cancer: role in tumorigenesis, patient classification and therapy. Clinical Translational Oncology 9:55–160 (2007).

    Article  Google Scholar 

  7. Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435:834–838 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Zhang, B. & Pan, X. RDX induces aberrant expression of microRNAs in mouse brain and liver. Environment Health Perspect 117:231–240 (2009).

    Article  CAS  Google Scholar 

  9. Pogribny, I. P. et al. Induction of microRNAome deregulation in rat liver by long-term tamoxifen exposure. Mutat Res 619:30–37 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Izzotti, A. et al. Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke. FASEB J 23:806–812 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Chen, T., Mally, A., Ozden, S. & Chipman, J. K. Low doses of the carcinogen furan alter cell cycle and apoptosis gene expression in rat liver independent of DNA methylation. Environ Health Perspect 118:1597–1602 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Jardim, M. J., Fry, R. C., Jaspers, I., Dailey, L. & Diaz-Sanchez, D. Disruption of microRNA expression in human airway cells by diesel exhaust particles is linked to tumorigenesis-associated pathways. Environ Health Perspect 117:1745–1751 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Gaidatzis, D., Van Nimwegen, E., Hausser, J. & Zavolan, M. Inference of miRNA targets using evolutionary conservation and pathway analysis. BMC Bioinformatics 8:69 (2007).

    Article  PubMed Central  PubMed  Google Scholar 

  14. Gusev, Y., Schmittgen, T. D., Lerner, M., Postier, R. & Brackett, D. Computational analysis of biological functions and pathways collectively targeted by COexpressed microRNAs in cancer. BMC Bioinformatics 8:(Suppl7)S16 (2007).

  15. Jemal, A. et al. Cancer statistics. CA Cancer J Clin 59:225–249 (2009).

    Article  PubMed  Google Scholar 

  16. Johnson, C. D. et al. The let-7 miRNAs represses cell proliferation pathways in human cells. Cancer Res 67: 7713–7722 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Büssing, I., Slack, F. J. & Grosshans, H. Let-7 micro RNAs in development, stem cells and cancer. Trends Mol Med 14:400–409 (2008).

    Article  PubMed  Google Scholar 

  18. Takamizawa, J. et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64:3753–3756 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Boyerinas, B. et al. Identification of let-7-regulated oncofetal genes. Cancer Res 68:2587–2591 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Ding, X. C., Slack, F. J. & Grosshans, H. The let-7 miRNAs interfaces extensively with the translation machinery to regulate cell differentiation. Cell Cycle 7:3083–3090 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Huang, Y. et al. Circulating microRNAs as potential biomarkers for smoking-related interstitial fibrosis. Biomarkers 17:435–440 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Cheung, T. H. et al. Dysregulated microRNAs in the pathogenesis and progression of cervical neoplasm. Cell Cycle 11:2876–2884 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Wang, X. et al. Evidence that miR-133a causes recurrent spontaneous abortion by reducing HLA-G expression. Reprod Biomed Online 25:415–424 (2012).

    Article  PubMed  Google Scholar 

  24. Duan, H., Jiang, Y., Zhang, H. & Wu, Y. MiR-320 and miR-494 affect cell cycles of primary murine bronchial epithelial cells exposed to benzo(a)pyrene. Toxicol In Vitro 24:928–935 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Chen, J. Y., Wang, C. & Wang, J. MAPK signaling pathway research progress. Chinese Medical Sciences 1:32–34 (2011).

    Google Scholar 

  26. Wang, W., Ren, L. & Wang, J. N. The relationship of MAPK signaling pathway and apoptosis. Chinese Medicine 5:260–261 (2010).

    Article  Google Scholar 

  27. Assoian, R. K., Komoriya, A., Meyers, C. A., Miller, D. M. & Sporn, M. B. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem 258:7155–7160 (1983).

    CAS  PubMed  Google Scholar 

  28. Surendran, K., Schiavi, S. & Hruska, K. A. Wnt-dependent beta-catenin signaling is activated after unilateral ureteral obstruction and recombinant secreted frizzled related protein 4 alters the progression of renal fibrosis. J Am Soc Nephrol 16:2373–2784 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Howard, B. & Ashworth, A. Signaling pathways implicated in early mammary gland morphogenesis and breast cancer. PloS Genet 2:e112 (2006).

    Article  PubMed Central  PubMed  Google Scholar 

  30. Heitman, J., Movva, N. R. & Hall, M. N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Scinece 253:905–909 (1991).

    Article  CAS  Google Scholar 

  31. Zheng, P. S. & Ji, J. mTOR signaling pathway with tumor progress. Xi’an Jiaotong University (Medical Sciences) 31:1–9 (2010).

    CAS  Google Scholar 

  32. Mascaux, C. et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br. J. Cancer 92: 131–139 (2006).

    Article  Google Scholar 

  33. Ludovini, V. et al. Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. Journal of Thoracic Oncology 6:707–15 (2011).

    Article  PubMed  Google Scholar 

  34. Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129:1261–1274 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Brognard, J., Clark, A. S., Ni, Y. & Dennis, P. A. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 61:3986–3997 (2001).

    CAS  PubMed  Google Scholar 

  36. Zhou, C. et al. The cyclin D1 (CCND1) G870A polymorphism and lung cancer susceptibility: a meta-analysis. Tumour Biol 34:3831–3837 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Hsia, T. C. et al. Interaction of CCND1 genotype and smoking habit in Taiwan lung cancer patients. Anticancer Res 31:3601–3605 (2011).

    CAS  PubMed  Google Scholar 

  38. Papadopoulos, G. L., Alexiou, P., Maragkakis, M., Reczko, M. & Hatzigeorgiou, A. G. DIANA-mirPath: Integrating human and mouse microRNAs in pathways. Bioinformatic Applications Note 25:1991–1993 (2009).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Key Laboratory of Environmental Medicine Engineering Ministry of Education, School of Public Health Southeast University Nanjing, Nanjing, The people’s Republic of China

    Yanqiu Zhang, Xikai Wang, Yanyun Fu, Lihong Yin, Yuepu Pu & Geyu Liang

Authors
  1. Yanqiu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xikai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanyun Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lihong Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuepu Pu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Geyu Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Geyu Liang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Wang, X., Fu, Y. et al. Expression profiling and pathway analysis of microRNA expression in the lungs of mice exposed to long-term, low-dose benzo(a)pyrene. Mol. Cell. Toxicol. 10, 67–74 (2014). https://doi.org/10.1007/s13273-014-0008-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13273-014-0008-9

Keywords

Search

Navigation