Enhancement of ultraviolet B-induced skin tumor development in phospholipase Cε-knockout mice is associated with decreased cell death.
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/m(2) 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.
Oka
Masahiro
M
Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. oka@med.kobe-u.ac.jp
Edamatsu
Hironori
H
Kunisada
Makoto
M
Hu
Lizhi
L
Takenaka
Nobuyuki
N
Dien
Siphora
S
Sakaguchi
Masanobu
M
Kitazawa
Riko
R
Norose
Kazumi
K
Kataoka
Tohru
T
Nishigori
Chikako
C
D000818:Animals; D017209:Apoptosis; D016753:Interleukin-10 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000473:pathology; D054801:Phosphoinositide Phospholipase C / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D012878:Skin Neoplasms / Q000209:etiology* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate; D014466:Ultraviolet Rays / Q000009:adverse effects*; D051028:bcl-2-Associated X Protein / Q000502:physiology
C494827:Bax protein, mouse; D053583:Interleukin-1beta; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D016753:Interleukin-10; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; D013755:Tetradecanoylphorbol Acetate