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Articles by H Edamatsu
Total Records ( 2 ) for H Edamatsu
  M Li , H Edamatsu , R Kitazawa , S Kitazawa and T. Kataoka

ApcMin/+ mice, carrying an inactivated allele of the adenomatous polyposis coli gene, are widely used as an animal model for human colorectal tumorigenesis, where tumor environment, such as inflammation, is known to play a critical role in tumor progression. We previously demonstrated that phospholipase C (PLC), an effector of Ras and Rap small GTPases, plays a crucial role in two-stage skin chemical carcinogenesis using 12-O-tetradecanoyl-phorbor-13-acetate (TPA) as a promoter through augmentation of TPA-induced inflammation. Here, we show that ApcMin/+ mice lacking PLC (PLC–/–) exhibit marked resistance to spontaneous intestinal tumorigenesis compared with those with the PLC+/+ background. Time course of the development of tumors, which are histopathologically classified into low- and high-grade adenomas with increasing dysplasia and size, and adenocarcinomas indicates that not only the low-grade adenoma formation but also the progression to high-grade adenoma are suppressed in PLC–/–;ApcMin/+ mice. Low-grade adenomas of PLC–/–;ApcMin/+ mice exhibit accelerated apoptosis and reduced cellular proliferation. They also show marked attenuation of tumor angiogenesis and reduction in expression of vascular endothelial growth factor. In contrast, high-grade adenomas of PLC–/–;ApcMin/+ mice exhibit marked attenuation of tumor-associated inflammation without significant differences in apoptosis and proliferation. These results suggest that PLC plays crucial roles in intestinal tumorigenesis through two distinct mechanisms, augmentation of angiogenesis and inflammation, depending on the tumor stage.

  M Oka , H Edamatsu , M Kunisada , L Hu , N Takenaka , S Dien , M Sakaguchi , R Kitazawa , K Norose , T Kataoka and C. Nishigori

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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