title: Ethanol promotes chemically induced oral cancer in mice through activation of the 5-lipoxygenase pathway of arachidonic acid metabolism.
abstract: Alcohol drinking is a known risk factor for oral cancer in humans. However, previous animal studies on the promoting effect of ethanol on oral carcinogenesis were inconclusive. It is necessary to develop an animal model with which the molecular mechanism of ethanol-related oral carcinogenesis may be elucidated to develop effective prevention strategies. In this study, mice were first treated with 4-nitroquinoline-1-oxide (4NQO, 100 μg/mL in drinking water) for 8 weeks and then given water or ethanol (8%) as the sole drink for another 16 weeks. During the experiment, 8% ethanol was well tolerated by mice. The incidence of squamous cell carcinoma (SCC) increased from 20% (8/41) to 43% (17/40; P < 0.05). Expression of 5-lipoxygenase (5-Lox) and cyclooxygenase 2 (Cox-2) was increased in dysplasia and SCC of 4NQO-treated tongues and further enhanced by ethanol. Using this mouse model, we further showed that fewer cancers were induced in Alox5(-/-) mice, as were cell proliferation, inflammation, and angiogenesis in the tongue, as compared with Alox5(+/+) mice. Interestingly, Cox-2 expression was induced by ethanol in knockout mice, whereas 5-Lox and leukotriene A4 hydrolase (LTA4H) expression and leukotriene B4 (LTB4) biosynthesis were dramatically reduced. Moreover, ethanol enhanced expression and nuclear localization of 5-Lox and stimulated LTB4 biosynthesis in human tongue SCC cells (SCC-15 and SCC-4) in vitro. In conclusion, this study clearly showed that ethanol promoted 4NQO-induced oral carcinogenesis, at least in part, through further activation of the 5-Lox pathway of arachidonic acid metabolism.
authors: Department of Oral Medicine, Beijing Hospital for Stomatology, Capital Medical University, 4 Tian-Tan-Xi-Li, Beijing 100050, China.
authors: Yizhu
authors: Y
authors: Guo
authors: Xin
authors: X
authors: Wang
authors: Xinyan
authors: X
authors: Zhang
authors: Zheng
authors: Z
authors: Sun
authors: Xiaoxin
authors: X
authors: Chen
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity*; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000633:toxicity; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology*; D016718:Arachidonic Acid / Q000378:metabolism*; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D003043:Cocarcinogenesis; D051546:Cyclooxygenase 2 / Q000378:metabolism; D060766:Drinking Water; D004851:Epoxide Hydrolases / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D006801:Humans; D007124:Immunoenzyme Techniques; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009062:Mouth Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014062:Tongue Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology
chemical_list: D000891:Anti-Infective Agents, Local; D002273:Carcinogens; D060766:Drinking Water; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000431:Ethanol; D015112:4-Nitroquinoline-1-oxide; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase