Therapeutic application of c-myc gene transcriptional repressor via its apoptotic function for cancer treatment

C-myc的高表达已在多种人类癌症中被检测到，这表明该癌基因在肿瘤的发生发展中起着关键作用。最近，FIR(FBP相互作用抑制因子)与TFIIH/p89/XPB解旋酶的相互作用被发现抑制c-myc的转录，因此可能在抑制肿瘤形成中起重要作用。在这项研究中，我们发现FIR的增强表达诱导了细胞的凋亡。FIR氨基末端抑制域的缺失使细胞免于凋亡，c-Myc和FIR的共表达也是如此，因此抑制myc介导了FIR诱导的细胞凋亡。令人惊讶的是，在人类原发性结直肠癌中经常发现一种FIR剪接变体，它既不能抑制c-myc，也不能促进细胞凋亡，但在邻近的正常组织中却没有。该剪接变异体与抑制子功能的FIR共表达，不仅抑制了c-Myc的抑制，而且抑制了细胞的凋亡。这些结果强烈表明，这种剪接变异体的表达通过抑制FIR抑制来维持高水平的c-Myc，并反对结直肠癌中的细胞凋亡，从而促进了肿瘤的发展。

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, 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 to sustain high levels of c-Myc and oppose apoptosis in colorectal cancer.