An antitumorigenic role for murine 8S-lipoxygenase in skin carcinogenesis.
The levels of 8S-lipoxygenase (8S-LOX) expression and of its arachidonic acid metabolite, 8-hydroxyeicosatetraenoic acid (8-HETE), are highly elevated in the early stages of mouse skin carcinogenesis. On the other hand, several reports showing that 8-HETE is also closely associated with keratinocyte differentiation raise a question concerning the role of 8S-LOX/8-HETE in skin carcinogenesis. To address that question, here we conducted a series of gain-of-function studies. Skin targeted loricrin 8S-LOX/C57BL/6J transgenic mice showed a more differentiated epidermal phenotype as well as a 64% reduced papilloma development in a two-stage skin carcinogenesis protocol. Forced expression of 8S-LOX in MT1/2 cells, a murine papilloma cell line, also caused a more differentiated appearance as well as keratin 1 expression. Overexpression of 8S-LOX in CH72 cells, a murine carcinoma cell line, inhibited cell proliferation by 30% in vitro and by 86% in in vivo xenografts. Exogenous addition of 5 muM 8-HETE to CH72 cells caused cell cycle arrest at the G1 phase. Finally, immunohistochemical analyses showed 8S-LOX protein expression was strictly confined to the differentiated compartment of mouse skin and throughout tumorigenesis. Collectively, these data suggest that 8S-LOX plays a role as a prodifferentiating, antitumorigenic, and tumor suppressing gene in mouse skin carcinogenesis.
Kim
Eunjung
E
Science Park-Research Division, University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, PO Box 389, Smithville, TX 78957, USA.
Rundhaug
Joyce E
JE
Benavides
Fernando
F
Yang
Peiying
P
Newman
Robert A
RA
Fischer
Susan M
SM
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D002277:Carcinoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis / Q000494:pharmacology; D044243:Linoleic Acids, Conjugated / Q000096:biosynthesis / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019076:Transgenes / Q000235:genetics
D006893:Hydroxyeicosatetraenoic Acids; D044243:Linoleic Acids, Conjugated; D008565:Membrane Proteins; D012333:RNA, Messenger; C064554:loricrin; C024347:9-hydroxy-10,12-octadecadienoic acid; C047628:8-hydroxyeicosatetraenoic acid; D001091:Arachidonate Lipoxygenases; C054192:arachidonate 8-lipoxygenase; D013755:Tetradecanoylphorbol Acetate