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Carcinogenesis
Year: 2010 | Volume: 31 | Issue: 10 | Page No.: 1897 - 1902
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Enhancement of ultraviolet B-induced skin tumor development in phospholipase C{varepsilon}-knockout mice is associated with decreased cell death
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M Oka,
H Edamatsu,
M Kunisada,
L Hu,
N Takenaka,
S Dien,
M Sakaguchi,
R Kitazawa,
K Norose,
T Kataoka
and
C. Nishigori
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Abstract: Phospholipase C (PLC) is a phosphoinositide-specific PLC regulated by small guanosine triphosphatases including Ras and Rap. Our previous studies revealed that PLC gene-knockout (PLC–/–) mice exhibit marked resistance to tumor formation in two-stage skin chemical carcinogenesis using 7,12-dimethylbenz(a)anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate as a promoter. In this model, PLC functions in tumor promotion through augmentation of 12-O-tetradecanoylphorbol-13-acetate-induced inflammation. In this study, we have further assessed the role of PLC in tumorigenesis using a mouse model of ultraviolet (UV) B-induced skin tumor development. We irradiated PLC+/+, PLC+/– or PLC–/– mice with doses of UVB increasing from 1 to 10 kJ/m2 three times a week for a total of 25 weeks and observed tumor formation for up to 50 weeks. In sharp contrast to the results from the two-stage chemical carcinogenesis study, PLC–/– mice developed a large number of neoplasms including malignant tumors, whereas PLC+/+ and PLC+/– mice developed a relatively small number of benign tumors. However, UVB-induced skin inflammation was greatly suppressed in PLC–/– mice, as observed with 12-O-tetradecanoylphorbol-13-acetate-induced inflammation, implying that PLC’s role in the suppression of UVB-induced tumorigenesis is not mediated by inflammation. Studies of the tumor initiation stage revealed that UVB-induced cell death in the skin was markedly suppressed in PLC–/–mice. Our findings identify a novel function for PLC as a critical molecule regulating UVB-induced cell death and suggest that resistance to UVB-induced cell death conferred by the absence of PLC is closely related to the higher incidence of skin tumor formation. |
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