title: PHLPP2 Downregulation Contributes to Lung Carcinogenesis Following B[a]P/B[a]PDE Exposure.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  We used the Western blotting, RT-PCR, [(35)S]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 TNFα 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.
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Haishan
authors.initials: H
authors.lastname: Huang
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiaofu
authors.initials: X
authors.lastname: Pan
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Honglei
authors.initials: H
authors.lastname: Jin
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Caili
authors.initials: C
authors.lastname: Yang
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
authors.forename: Xingruo
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.affiliation: Department of Pathology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. Chuanshu.huang@nyumc.org jimingao@wmu.edu.cn chengr@wzhospital.cn.
authors.forename: Guorong
authors.initials: G
authors.lastname: Chen
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. Chuanshu.huang@nyumc.org jimingao@wmu.edu.cn chengr@wzhospital.cn.
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York. Chuanshu.huang@nyumc.org jimingao@wmu.edu.cn chengr@wzhospital.cn.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity*; D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D063646:Carcinogenesis / Q000235:genetics; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D002273:Carcinogens; C576666:MIRN205 microRNA, mouse; D035683:MicroRNAs; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C541572:PHLPP2 protein, human; D010749:Phosphoprotein Phosphatases