title: Pulmonary preconditioning, injury, and inflammation modulate expression of the candidate tumor suppressor gene ECRG4 in lung.
abstract: OBJECTIVE
  The human c2orf40 gene encodes a candidate tumor suppressor called Esophageal Cancer-Related Gene-4 (ECRG4) that is a cytokine-like epigenetically-regulated protein that is characteristically downregulated in cancer, injury, inflammation, and infection. Here, we asked whether ECRG4 gene expression is detectable in lung epithelial cells and if its expression changes with inflammation, infection, and/or protective preconditioning.
  
  
  METHODS
  We used immunoblotting, PCR, and quantitative PCR to measure ECRG4 and either inhalation anesthesia preconditioning, lipopolysaccharide injection, or laparotomy to modulate lung inflammation.
  
  
  RESULTS
  Immunoblotting establishes the presence of the full-length 14 kDa ECRG4 peptide in mouse lung. Immunohistochemistry localizes ECRG4 to type l alveolar epithelial cells. Basal ECRG4 mRNA is greater than TNF-α, IL-1β, and IL-6 but following inflammatory lung injury, TNF-α, IL-1β, IL-6, and IL-10 are upregulated while ECRG4 gene expression is decreased. Similar findings are observed after an intravenous administration of lipopolysaccharide. In contrast, lung preconditioning with isoflurane anesthesia increases lung ECRG4 gene expression. Over-expression of ECRG4 in human lung epithelial cells in vitro decreases cell proliferation implying that a loss of ECRG4 in vivo would be permissive to cell growth.
  
  
  CONCLUSIONS
  This study supports the hypothesis that ECRG4 acts as a sentinel growth inhibitor in lung alveolar epithelial cells. Its downregulation by injury, infection, and inflammation and upregulation by preconditioning supports a role for ECRG4 in regulating the alveolar epithelium response to injury and inflammation. By extension, the findings support a functional consequence to its inhibition by promoter hypermethylation (i.e. lung cancer) and suggest potential benefits to its upregulation.
authors.affiliation: Department of Surgery Division of Trauma, Surgical Critical Care, Burn and Acute Care Surgery, School of Medicine, University of California in San Diego, La Jolla, California, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Kao
authors.forename: Ashkaun
authors.initials: A
authors.lastname: Shaterian
authors.forename: David M
authors.initials: DM
authors.lastname: Cauvi
authors.forename: Xitong
authors.initials: X
authors.lastname: Dang
authors.forename: Hyun Bae
authors.initials: HB
authors.lastname: Chun
authors.forename: Antonio
authors.initials: A
authors.lastname: De Maio
authors.forename: Todd W
authors.initials: TW
authors.lastname: Costantini
authors.forename: Raul
authors.initials: R
authors.lastname: Coimbra
authors.forename: Brian P
authors.initials: BP
authors.lastname: Eliceiri
authors.forename: Andrew
authors.initials: A
authors.lastname: Baird
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D055370:Lung Injury / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011014:Pneumonia / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D007378:Interleukins; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha
keywords: c20rf40; epithelial to mesenchymal transition; infection; inflammation; precondtitioning; tumor suppressor gene