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Development of novel therapeutic strategy based on malignant nature of colorectal cancer

基于结直肠癌恶性本质的新治疗策略的开发

基本信息

批准号：
16591313
负责人：
YAMAMOTO Hirofumi
金额：
$ 2.24万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591313/
关键词：
antisense cyclin D1 TCF decoy dominant negative TCF colorectal cancer liver metastasis Wnt signal cyclin D1

项目摘要

Beta-catenin and TCF complex is activated in a variety of gastrointestinal cancer. The down stream of this way contains cancer related gene including cyclin D1,MMP7,c-myc. To block this pathway may be useful strategy against cancer. We target TCF transcription and cyclin D1 oncogene.1.Adnovirus dominant negative TCFAdenovirus dominant negative TCF inhibited TCF transcription activity and the promoter activities of down stream genes including cyclin D1,MMP7,c-myc. It also inhibited in vivo subcutaneous tumor growth and liver metastasis. Therapeutic model for xenograft was also successful. These findings suggest that Adenovirus dominant negative TCF may be useful strategy for tumors that display high TCF transcription activity.2.TCF decoyTo block TCF activity in safer way, we developed a novel TCF DNA decoy. In vitro assays indicated it inhibited TCF activity and the promoter activities of down stream genes including cyclin D1,MMP7,c-myc. successfully. It inhibited growth of tumor cell, but not non-tumor cells. However problem still remains with regard to its stability in vivo. FITC labeling revealed TCF decoy accumulate into nucleus within 24 hr and remained till 48-72 hr. These findings will be published in Mol Cancer Ther (in press).3.Antisense cyclin D1Adenovirus antisense cyclin D1 inhibited tumor growth and tumor associated vessels. One of the mechanism for anti-tumor vessel is a direct effects of antisense to cyclin D1 on vascular endothelial cells. As another mechanism, cyclin D1 inhibition caused inhibition of STAT-3 transcription factor, which leaded to inhibition of VEGF promoter activity. This occurs in a certain tumor cell type. These findings will be published in Clin Cancer Res (in press).

β-连环蛋白和TCF复合体在多种胃肠道肿瘤中被激活。该途径的下游含有细胞周期蛋白D1、MMP7、c-myc等肿瘤相关基因。阻断这一途径可能是对抗癌症的有效策略。1.腺病毒显性阴性TCF腺病毒显性阴性TCF抑制TCF转录活性及下游基因Cyclin D1、MMP7、c-myc的启动子活性。它还能抑制体内皮下肿瘤生长和肝转移。异种移植的治疗模型也是成功的。这些发现表明，腺病毒显性的阴性TCF可能是对表现出高TCF转录活性的肿瘤有用的策略。2.TCF诱骗为了以更安全的方式阻断TCF活性，我们开发了一种新型的TCF DNA诱骗。体外实验表明，它抑制TCF活性和下游基因Cyclin D1、MMP7、c-myc的启动子活性。成功了。对肿瘤细胞生长有抑制作用，但对非肿瘤细胞无明显影响。然而，其在体内的稳定性仍然存在问题。FITC标记显示，TCF诱饵在24小时内积聚到细胞核中，并持续到48-72小时。这些发现将发表在《摩尔癌症杂志》上(正在出版)。3.反义细胞周期蛋白D1腺病毒反义细胞周期蛋白D1抑制肿瘤生长和肿瘤相关血管。反义细胞周期蛋白D1直接作用于血管内皮细胞是其抗肿瘤血管作用的机制之一。作为另一个机制，细胞周期蛋白D1的抑制导致STAT-3转录因子的抑制，从而导致血管内皮生长因子启动子活性的抑制。这发生在某种类型的肿瘤细胞中。这些发现将发表在《临床癌症研究》杂志(印刷中)上。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Wntシグナルを標的とした治療

针对 Wnt 信号的治疗

DOI：
发表时间：
2004
期刊：
現代医療 36(7)
影响因子：
0
作者：
関洋介;山本清文;他
通讯作者：
他

Construction of a novel DNA decoy that inhibits the oncogenic □-catenin/TCF pathway.

构建抑制致癌 □-catenin/TCF 途径的新型 DNA 诱饵。

DOI：
发表时间：
期刊：
Mol Cancer Ther. (in press)
影响因子：
0
作者：
Seki Y.;Yamamoto.;et al.
通讯作者：
et al.

Construction of a novel DNA decoy that inhibits the oncogenic β-catenin/TCF pathway

构建抑制致癌β-连环蛋白/TCF途径的新型DNA诱饵

DOI：
发表时间：
期刊：
Molecular Cancer Therapeutics (in press)
影响因子：
0
作者：
Seki Y;Yamamoto H;Ngan Chew Yee;Yasui M;Tomita N;Kitani K;Takemasa I;Ikeda M;Sekimoto M;Matsuura N;Chris Albanese;Kaneda Y;Richard G Pestell;Monden M.
通讯作者：
Monden M.