title: Angiopoietin-like protein 2 accelerates carcinogenesis by activating chronic inflammation and oxidative stress.
abstract: Chronic inflammation has received much attention as a risk factor for carcinogenesis. We recently reported that Angiopoietin-like protein 2 (Angptl2) facilitates inflammatory carcinogenesis and metastasis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model. In particular, we demonstrated that Angptl2-induced inflammation enhanced susceptibility of skin tissues to "preneoplastic change" and "malignant conversion" in SCC development; however, mechanisms underlying this activity remain unclear. Using this model, we now report that transgenic mice overexpressing Angptl2 in skin epithelial cells (K14-Angptl2 Tg mice) show enhanced oxidative stress in these tissues. Conversely, in the context of this model, Angptl2 knockout (KO) mice show significantly decreased oxidative stress in skin tissue as well as a lower incidence of SCC compared with wild-type mice. In the chemically induced SCC model, treatment of K14-Angptl2 Tg mice with the antioxidant N-acetyl cysteine (NAC) significantly reduced oxidative stress in skin tissue and the frequency of SCC development. Interestingly, K14-Angptl2 Tg mice in the model also showed significantly decreased expression of mRNA encoding the DNA mismatch repair enzyme Msh2 compared with wild-type mice and increased methylation of the Msh2 promoter in skin tissues. Msh2 expression in skin tissues of Tg mice was significantly increased by NAC treatment, as was Msh2 promoter demethylation. Overall, this study strongly suggests that the inflammatory mediator Angptl2 accelerates chemically induced carcinogenesis through increased oxidative stress and decreased Msh2 expression in skin tissue.
  
  
  CONCLUSIONS
  Angptl2-induced inflammation increases susceptibility to microenvironmental changes, allowing increased oxidative stress and decreased Msh2 expression; therefore, Angptl2 might be a target to develop new strategies to antagonize these activities in premalignant tissue.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. oike@gpo.kumamoto-u.ac.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Aoi
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Endo
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kadomatsu
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.forename: Aki
authors.initials: A
authors.lastname: Ogata
authors.forename: Haruki
authors.initials: H
authors.lastname: Horiguchi
authors.forename: Haruki
authors.initials: H
authors.lastname: Odagiri
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Masuda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukushima
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Jinnin
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirakawa
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sawa
authors.forename: Takaaki
authors.initials: T
authors.lastname: Akaike
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ihn
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D042682:Angiopoietins / Q000378:metabolism*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D009374:Neoplasms, Experimental; D018384:Oxidative Stress / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism
chemical_list: D042682:Angiopoietins; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D000111:Acetylcysteine