Function of REIC/Dkk-3, a putative Wntregulator in normal skin and cancer

REIC/Dkk-3（一种假定的 Wnt 调节因子）在正常皮肤和癌症中的功能

• 批准号: 18591249
• 负责人: KATAOKA Ken
• 金额: $ 2.24万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591249/
• 关键词: REIC; Dkk-3; Wnt; Tumor suppressor gene; Skin

1. The screening of genes which expression level were elevated after the infection of an adenovirus canying REIC/Dkk-3 (Ad-REIC) into normal human keratinocytes showed that a specific cytokine was strongly induced. After in vitro and in vivo experiments, we conclude that Ad-REIC treatment activates immune reaction against cancer cells through the cytokine in vivo.2. When over expressed using Ad-REIC, REIC/Dkk-3 induced apoptosisin cancer cells but not in normal cells. Ad-REIC was effective on human prostate cancer (PC3), testicular cancer (NCCIT) and mouse renal carcinoma (RENCA), but not all cancers are sensitive to Ad-REIC. To know the crucial mechanism of Ad-REIC sensitivity, we compared Ad-REIC sensitive renal cancer cells (RENCA) with normal fibroblast (N1H3T3). We found that the expression level of Hsp70/72 affected on tumor-cell specific induction of apoptosis by Ad-REIC.3. We established Ad-REIC-resistant sub-lines from a prostate cancer cell line (PC3). A micro array analysis to overview the expression profile of these lines is on the way. After the comparison of ER stress response after Ad-REIC treatment, we found a key molecule to be responsible for the Ad-REIC sensitivity.4. We also established a method for the purification of REIC/Dkk-3 protein from human fibroblasts. We are comparing addition of this type of purified protein with forced expression system by Ad-REIC.5. Generation of REIC/Dkk-3 knockout mouse is under way. We already got knockout ES cells and we are waiting chimera littermates.

1.对携带REIC/Dkk-3的腺病毒（Ad-REIC）感染正常人角质形成细胞后表达水平升高的基因的筛选表明，一种特异性细胞因子被强烈诱导。通过体内外实验，我们得出结论：Ad-REIC治疗通过体内细胞因子激活针对癌细胞的免疫反应.当使用Ad-REIC过表达时，REIC/Dkk-3在癌细胞中诱导了凋亡，而在正常细胞中没有。Ad-REIC对人前列腺癌（PC 3）、睾丸癌（NCCIT）和小鼠肾癌（RENCA）有效，但并非所有癌症都对Ad-REIC敏感。为了了解Ad-REIC敏感性的重要机制，我们将Ad-REIC敏感的肾癌细胞（RENCA）与正常成纤维细胞（N1 H3 T3）进行了比较。发现Hsp 70/72的表达水平影响Ad-REIC诱导肿瘤细胞凋亡的特异性。我们从前列腺癌细胞系（PC 3）建立了Ad-REIC抗性亚系。一个微阵列分析，以概述这些线的表达谱是在路上。通过比较Ad-REIC对ER应激反应的影响，我们发现了一个与Ad-REIC敏感性相关的关键分子.我们还建立了从人成纤维细胞中纯化REIC/Dkk-3蛋白的方法。我们正在比较添加这种类型的纯化蛋白与Ad-REIC强制表达系统。REIC/Dkk-3基因敲除小鼠的产生正在进行中。我们已经得到了敲除胚胎干细胞，我们正在等待嵌合体的出生。

项目成果

Heat shock proteins play a crucial role in tumor-specific apoptosis by REIC/Dkk-3.

• DOI: 10.3892/ijmm.20.1.37
• 发表时间: 2007-07
• 期刊: International journal of molecular medicine
• 影响因子: 5.4
• 作者: F. Abarzúa;M. Sakaguchi;R. Tanimoto;Hiroyuki Sonegawa;Dai Li;K. Edamura;Tomoko Kobayashi;Masami Watanabe;Y. Kashiwakura;H. Kaku;T. Saika;K. Nakamura;Y. Nasu;H. Kumon;N. Huh

Involvement of deterioration in S100C/A11-mediated pathway in resistance of human squamous cancer cell lines to TGFβ-induced growth suppression

• DOI: 10.1007/s00109-007-0180-7
• 发表时间: 2007-05
• 期刊: Journal of Molecular Medicine
• 作者: Hiroyuki Sonegawa;T. Nukui;Dai Li;M. Takaishi;M. Sakaguchi;N. Huh

S100A11, a Dual Mediator for Growth Regulation of Human Keratinocytes

S100A11，人类角质形成细胞生长调节的双重介质

• 发表时间: 2008
• 期刊: Mol Biol Cell 19
• 作者: Sakaguchi;et. al.
• 通讯作者: et. al.

Truncation of annexin Al is a regulatory lever for linking epidermal growth factor signaling with cytosolic phospholipase A2 in normal and malignant squamous epithelial cells

膜联蛋白A1的截短是连接正常和恶性鳞状上皮细胞中表皮生长因子信号转导与胞质磷脂酶A2的调节杠杆

• 发表时间: 2007
• 期刊: J Biol Chem 282
• 作者: Sakaguchi;et. al.
• 通讯作者: et. al.

Truncation of annexin A1 is a regulatory lever for linking epidermal growth factor signaling with cytosolic phospholipase A2 in normal and malignant squamous epithelial cells

• DOI: 10.1074/jbc.m707538200
• 发表时间: 2007-12-07
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Sakaguchi, Masakiyo;Murata, Hitoshi;Huh, Nam-ho
• 通讯作者: Huh, Nam-ho