PHLPP2 downregulation contributes to lung carcinogenesis following B[a]P/B[a]PDE exposure

Haishan Huang, Xiaofu Pan, Honglei Jin, Yang Li, Lin Zhang, Caili Yang, Pei Liu, Ya Liu, Lili Chen, Jingxia Li, Junlan Zhu, Xingruo Zeng, Kai Fu, Guorong Chen, Jimin Gao, Chuanshu Huang

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Purpose: The carcinogenic capacity of B[a]P/B[a]PDE is supported by epidemiologic studies. However, the molecular mechanisms responsible for B[a]P/B[a]PDE-caused lung cancer have not been well investigated. We evaluated here the role of novel target PHLPP2 in lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure. Experimental Design: We used the Western blotting, RT-PCR, [35S]methionine pulse and immunohistochemistry staining to determine PHLPP2 downregulation following B[a]P/B[a]PDE exposure. Both B[a]PDE-induced Beas-2B cell transformation model and B[a]P-caused mouse lung cancer model were used to elucidate the mechanisms leading to PHLPP2 downregulation and lung carcinogenesis. The important findings were also extended to in vivo human studies. Results: We found that B[a]P/B[a]PDE exposure downregulated PHLPP2 expression in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The ectopic expression of PHLPP2 dramatically inhibited cell transformation upon B[a]PDE exposure. Mechanistic studies showed that miR-205 induction was crucial for inhibition of PHLPP2 protein translation by targeting PHLPP2-3′-UTR. Interestingly, PHLPP2 expression was inversely associated with tumor necrosis factor alpha (TNFα) expression, with low PHLPP2 and high TNFa expression in lung cancer tissues compared with the paired adjacent normal lung tissues. Additional studies revealed that PHLPP2 exhibited its antitumorigenic effect of B[a]P/B[a]PDE through the repression of inflammatory TNFα transcription. Conclusions: Our studies not only first time identify PHLPP2 downregulation by lung carcinogen B[a]P/B[a]PDE, but also elucidate a novel molecular mechanisms underlying lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure.

Original languageEnglish (US)
Pages (from-to)3783-3793
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number16
DOIs
StatePublished - Aug 15 2015

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Huang, H., Pan, X., Jin, H., Li, Y., Zhang, L., Yang, C., Liu, P., Liu, Y., Chen, L., Li, J., Zhu, J., Zeng, X., Fu, K., Chen, G., Gao, J., & Huang, C. (2015). PHLPP2 downregulation contributes to lung carcinogenesis following B[a]P/B[a]PDE exposure. Clinical Cancer Research, 21(16), 3783-3793. https://doi.org/10.1158/1078-0432.CCR-14-2829