title: Promotion of liver and lung tumorigenesis in DEN-treated cytoglobin-deficient mice.
abstract: Cytoglobin (Cygb) is a recently discovered vertebrate globin with molecular characteristics that are similar to myoglobin. To study the biological function of Cygb in vivo, we generated Cygb knockout mice and investigated their susceptibility to N,N-diethylnitrosamine (DEN)-induced tumorigenesis. Four-week-old male mice were administered DEN in drinking water at a dose of 25 ppm for 25 weeks or 0.05 ppm for 36 weeks. Cygb deficiency promoted the DEN-induced development of liver and lung tumors. All Cygb(+/-) and Cygb(-/-) mice treated with 25-ppm DEN exhibited liver tumors, compared with 44.4% of their wild-type counterparts. Lung tumors were present only in Cygb-deficient mice. More than 40% of Cygb(-/-) mice developed liver and lung tumors at the nontoxic dose of DEN (0.05 ppm), which did not induce tumors in wild-type mice. Cygb loss was associated with increased cancer cell proliferation, elevated extracellular signal-regulated kinase and Akt activation, overexpression of IL-1β, IL-6, Tnfα, and Tgfβ3 mRNAs, and hepatic collagen accumulation. Cygb-deficient mice also exhibited increased nitrotyrosine formation and dysregulated expression of cancer-related genes (cyclin D2, p53, Pak1, Src, Cdkn2a, and Cebpa). These results suggest that Cygb deficiency induces susceptibility to cancer development in the liver and lungs of mice exposed to DEN. Thus, globins such as Cygb will shed new light on the biological features of organ carcinogenesis.
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Le Thi Thanh
authors.initials: le TT
authors.lastname: Thuy
authors.forename: Takashi
authors.initials: T
authors.lastname: Morita
authors.forename: Kayo
authors.initials: K
authors.lastname: Yoshida
authors.forename: Kenichi
authors.initials: K
authors.lastname: Wakasa
authors.forename: Masashi
authors.initials: M
authors.lastname: Iizuka
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ogawa
authors.forename: Mami
authors.initials: M
authors.lastname: Mori
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Sekiya
authors.forename: Shinobu
authors.initials: S
authors.lastname: Momen
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Motoyama
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ikeda
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yoshizato
authors.forename: Norifumi
authors.initials: N
authors.lastname: Kawada
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation; D000078842:Cytoglobin; D004052:Diethylnitrosamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D005914:Globins / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic
chemical_list: D000477:Alkylating Agents; C000627267:Cygb protein, mouse; D000078842:Cytoglobin; D004052:Diethylnitrosamine; D005914:Globins