Development of gene therapy for gastrointestinal cancers by using c-myc transcriptional suppressor FUSE Binding Protein-Interacting Repressor, FIR

利用 c-myc 转录抑制因子 FUSE 结合蛋白相互作用抑制因子 (FIR) 开发胃肠癌基因治疗

• 批准号: 16591292
• 负责人: MATSUZHITA Kazuyuki
• 金额: $ 2.24万
• 依托单位: Chiba 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-16591292/
• 关键词: c-myc gene; Transcriptional repressor; alternative splicing variats; cancer gene therapy; apotosis; 癌治療

Elevated expression of c-myc has been detected in a broad range of human cancers, indicating a key role for this oncogene in tumor development. Recently, an interaction between FIR (FBP Interacting Repressor) and TFIIH/p89/XPB helicase was found to repress c-myc transcription and so might be important for suppressing tumor formation. In this study, we showed that enforced expression of FIR induced apoptosis. Deletion of FIR's amino terminal repression domain rescued the cells from apoptosis, as did co-expression of c-Myc with FIR ; thus repression of Myc mediates FIR-driven apoptosis. Surprisingly, a splicing variant of FIR unable to repress c-myc nor to drive apoptosis was frequently discovered in human primary colorectal cancers, but not in the adjacent normal tissues. Coexpression of this splicing variant with repressor-competent FIR, either in HeLa cells or in the colon cancer cell line SW480,not only abrogated c-Myc suppression but inhibited apoptosis. These results strongly suggest the expression of this splicing variant promotes tumor development by disabling FIR-repression and so sustaining high levels of c-Myc and opposing apoptosis in colorectal cancer. One route to the development of cancer therapies directed against c-Myc may go through FIR and its variants

在广泛的人类癌症中检测到c-myc表达升高，表明该癌基因在肿瘤发展中起关键作用。最近，研究发现FIR （FBP相互作用抑制因子）与TFIIH/p89/XPB解旋酶之间的相互作用抑制c-myc转录，因此可能对抑制肿瘤形成很重要。在本研究中，我们发现强制表达FIR诱导细胞凋亡。FIR氨基末端抑制域的缺失使细胞免于凋亡，c-Myc与FIR的共表达也是如此；因此Myc的抑制介导了fir驱动的细胞凋亡。令人惊讶的是，在人类原发性结直肠癌中经常发现一种不能抑制c-myc也不能驱动细胞凋亡的FIR剪接变体，但在邻近的正常组织中却没有发现。在HeLa细胞或结肠癌细胞系SW480中，这种剪接变体与抑制因子能力强的FIR共表达，不仅消除了c-Myc抑制，而且抑制了细胞凋亡。这些结果强烈表明，在结直肠癌中，这种剪接变异体的表达通过禁用fir抑制从而维持高水平的c-Myc并抑制细胞凋亡来促进肿瘤的发展。开发针对c-Myc的癌症疗法的一条途径可能是通过FIR及其变体

项目成果

An essential role of alternative splicing of c-myc suppressor FUSE-binding protein-interacting repressor in carcinogenesis

• DOI: 10.1158/0008-5472.can-04-4459
• 发表时间: 2006-02-01
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: Matsushita, K;Tomonaga, T;Ochiai, T
• 通讯作者: Ochiai, T

FIRを用いた癌治療法およびFIRバリアントによる癌診断

使用 FIR 进行癌症治疗和使用 FIR 变体进行癌症诊断

• 发表时间: 2006