Development of novel cancer diagnosis and treatment targeting splicing variants of c-myc transcriptional suppressor FIR

远上游元件(FUSE)结合蛋白相互作用抑制子(FIR)是一种c-myc转录抑制因子，在大量表达c-Myc的结直肠癌组织中交替剪接和无效产生。人类恶性胸膜间皮瘤(HMPM)对常规治疗高度耐药，因此需要新的治疗方法。我们以前报道过，FIR的过表达通过抑制c-Myc诱导细胞凋亡，因此是一种合适的癌症治疗方法。在目前的临床前试验中，制备了编码FIR的融合基因缺失的仙台病毒载体(SeV/ΔF/FIR)，并评价了其与顺铂联合应用对HMPM原位移植模型的细胞毒活性。SEV/ΔF/FIR显着降低了3种HMPM细胞系的细胞活力，但对非肿瘤永生化间皮细胞的作用较弱。SEV/ΔF/FIR细胞毒作用部分是通过抑制c-Myc诱导细胞凋亡。

Far UpStream Element (FUSE)-binding protein-interacting repressor (FIR), a c-myc transcriptional suppressor, is alternatively spliced and futilely produced in colorectal cancer tissues that abundantly express c-Myc. Human malignant pleural mesothelioma (HMPM) is highly resistant to conventional therapy, and novel therapies are thus required. We previously reported that overexpression of FIR induces apoptosis via c-Myc suppression, and is thus a suitable cancer therapy. In the current preclinical trial, a fusion gene deleted non-transmissible Sendai virus vector encoding FIR (SeV/ΔF/FIR) was prepared and its cytotoxic activity against an orthotopic xenograft model of HMPM, in combination with cisplatin, was assessed. SeV/ΔF/FIR significantly reduced cell viability in 3 HMPM cell lines but was less effective in non-tumor immortalized mesothelial cells. SeV/ΔF/FIR cytotoxicity was partly due to apoptosis induction via c-Myc supression.