Journal Article

Enhancement of ultraviolet B-induced skin tumor development in <i>phospholipase Cε</i>-knockout mice is associated with decreased cell death

Masahiro Oka, Hironori Edamatsu, Makoto Kunisada, Lizhi Hu, Nobuyuki Takenaka, Siphora Dien, Masanobu Sakaguchi, Riko Kitazawa, Kazumi Norose, Tohru Kataoka and Chikako Nishigori

in Carcinogenesis

Volume 31, issue 10, pages 1897-1902
Published in print October 2010 | ISSN: 0143-3334
Published online August 2010 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgq164
Enhancement of ultraviolet B-induced skin tumor development in phospholipase Cε-knockout mice is associated with decreased cell death

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Phospholipase C (PLC) ε is a phosphoinositide-specific PLC regulated by small guanosine triphosphatases including Ras and Rap. Our previous studies revealed that PLCε gene-knockout (PLCε−/−) 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, PLCε functions in tumor promotion through augmentation of 12-O-tetradecanoylphorbol-13-acetate-induced inflammation. In this study, we have further assessed the role of PLCε in tumorigenesis using a mouse model of ultraviolet (UV) B-induced skin tumor development. We irradiated PLCε+/+, PLCε+/− or PLCε−/− 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, PLCε−/− mice developed a large number of neoplasms including malignant tumors, whereas PLCε+/+ and PLCε+/− mice developed a relatively small number of benign tumors. However, UVB-induced skin inflammation was greatly suppressed in PLCε−/− mice, as observed with 12-O-tetradecanoylphorbol-13-acetate-induced inflammation, implying that PLCε’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 PLCε−/−mice. Our findings identify a novel function for PLCε as a critical molecule regulating UVB-induced cell death and suggest that resistance to UVB-induced cell death conferred by the absence of PLCε is closely related to the higher incidence of skin tumor formation.

Journal Article.  4010 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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