Crucial role of phospholipase Cepsilon in chemical carcinogen-induced skin tumor development.
Mutational activation of the ras proto-oncogenes is frequently found in skin cancers. However, the nature of downstream signaling pathways from Ras involved in skin carcinogenesis remains poorly understood. Recently, we and others identified phospholipase C (PLC) epsilon as an effector of Ras. Here we have examined the role of PLCepsilon in de novo skin chemical carcinogenesis by using mice whose PLCepsilon is genetically inactivated. PLCepsilon(-/-) mice exhibit delayed onset and markedly reduced incidence of skin squamous tumors induced by initiation with 7,12-dimethylbenz(a)anthracene followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, the papillomas formed in PLCepsilon(-/-) mice fail to undergo malignant progression into carcinomas, in contrast to a malignant conversion rate of approximately 20% observed with papillomas in PLCepsilon(+/+) mice. In all of the tumors analyzed, the Ha-ras gene is mutationally activated irrespective of the PLCepsilon background. The skin of PLCepsilon(-/-) mice fails to exhibit basal layer cell proliferation and epidermal hyperplasia in response to TPA treatment. These results indicate a crucial role of PLCepsilon in ras oncogene-induced de novo carcinogenesis and downstream signaling from TPA, introducing PLCepsilon as a candidate molecular target for the development of anticancer drugs.
Bai
Yunfeng
Y
Division of Molecular Biology, Department of Molecular and Cellular Biology and Division of Molecular Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
Edamatsu
Hironori
H
Maeda
Sakan
S
Saito
Hiromitsu
H
Suzuki
Noboru
N
Satoh
Takaya
T
Kataoka
Tohru
T
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D054801:Phosphoinositide Phospholipase C; D012313:RNA / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000201:enzymology*; D013755:Tetradecanoylphorbol Acetate; D010738:Type C Phospholipases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics
D002273:Carcinogens; D012333:RNA, Messenger; D015127:9,10-Dimethyl-1,2-benzanthracene; D012313:RNA; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate