title: Involvement of retrotransposition of long interspersed nucleotide element-1 in skin tumorigenesis induced by 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate.
abstract: Tumor development induced by 7,12-dimethylbenz[a]anthracene (DMBA) plus 12-O-tetradecanoylphorbol-13-acetate (TPA) is a well-characterized model of multistep carcinogenesis. DMBA mutates the Ha-ras gene, whereas TPA promotes the growth of transformed cells by activating cellular signaling molecules. It remains to be clarified how repeated TPA treatment endows transformed cells with autonomous cell growth. Long interspersed nucleotide element-1 (L1) is an endogenous retroelement, and 80-100 copies of L1 function as autonomous mobile elements. Although the L1 retrotransposition (RTP) has been found in various human tumors, implying the possible mobility of L1 during carcinogenesis, little is known about how L1-RTP arises in tumor cells, owing to a lack of experimental models. To dissect the mechanism of L1-RTP during carcinogenesis, we established a line of transgenic mice carrying human L1 and enhanced green fluorescent protein (hL1-EGFP mice) and subjected them to DMBA/TPA-induced skin tumorigenesis. Of 15 skin tumors examined, 13 were positive for L1-RTP; L1-RTP was not detected in normal skin tissues adjacent to the tumors. Moreover, nine L1-RTP-positive tumors were positive for activated Ha-ras, and immunohistochemical analysis revealed cells positive for both L1-RTP and phosphorylated Stat3, a marker of tumor cells. Additional in vivo experiments suggested that L1-RTP occurred during tumor promotion by TPA. This is the first report on the involvement of L1-RTP in chemical carcinogenesis. We propose hL1-EGFP mice as a versatile system for investigating the mode of L1-RTP in tumor development and discuss the possible role of L1-RTP in tumorigenesis.
authors.affiliation: Department of Intractable Diseases, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Okudaira
authors.forename: Motohito
authors.initials: M
authors.lastname: Goto
authors.forename: Rieko
authors.initials: R
authors.lastname: Yanobu-Takanashi
authors.forename: Masato
authors.initials: M
authors.lastname: Tamura
authors.forename: Akihiro
authors.initials: A
authors.lastname: An
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Abe
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kano
authors.forename: Shotaro
authors.initials: S
authors.lastname: Hagiwara
authors.forename: Yukihito
authors.initials: Y
authors.lastname: Ishizaka
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okamura
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D003043:Cocarcinogenesis; D004357:Drug Synergism; D011905:Genes, ras / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000502:physiology; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D014162:Transfection
chemical_list: D002273:Carcinogens; D009363:Neoplasm Proteins; D018336:Receptors, Aryl Hydrocarbon; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate