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

在广泛的人类癌症中检测到c-myc的表达升高，表明该癌基因在肿瘤发展中起关键作用。近年来，人们发现FIR（FBP Interacting Repressor）和TFIIH/p89/XPB解旋酶之间的相互作用抑制c-myc的转录，因此可能对抑制肿瘤形成具有重要意义。在这项研究中，我们发现，FIR的强制表达诱导细胞凋亡。删除FIR的氨基末端抑制结构域拯救细胞免于凋亡，正如c-Myc与FIR的共表达一样;因此Myc的抑制介导FIR驱动的凋亡。令人惊讶的是，FIR的剪接变异体不能抑制c-myc也不能驱动细胞凋亡，经常发现在人类原发性结直肠癌，但不是在邻近的正常组织。在HeLa细胞或结肠癌细胞系SW 480中，这种剪接变体与有阻遏物能力的FIR的共表达不仅废除了c-Myc抑制，而且抑制了细胞凋亡。这些结果强烈表明，这种剪接变体的表达通过使FIR抑制失效从而维持高水平的c-Myc并对抗结直肠癌中的细胞凋亡来促进肿瘤发展。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

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