Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, SAR; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, SAR.
J Pathol. 2013 Oct;231(2):158-67. doi: 10.1002/path.4240.
Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer which is prevalent in southern China, south-east Asia and northern Africa. The development and stepwise progression of NPC involves accumulation of multiple gross genetic changes during the clonal expansion of Epstein-Barr virus (EBV)-infected nasopharyngeal epithelial cell population. Here, using paired-end whole-transcriptome sequencing, we discovered a number of chimeric fusion transcripts in a panel of EBV-positive tumour lines. Among these transcripts, a novel fusion of ubiquitin protein ligase E3 component n-recognin 5 (UBR5) on 8q22.3 and zinc finger protein 423 (ZNF423) on 16q12.1, identified from the NPC cell line C666-1, was recurrently detected in 12/144 (8.3%) of primary tumours. The fusion gene contains exon 1 of UBR5 and exons 7-9 of ZNF423 and produces a 94 amino acid chimeric protein including the original C-terminal EBF binding domain (ZF29-30) of ZNF423. Notably, the growth of NPC cells with UBR5-ZNF423 rearrangement is dependent on expression of this fusion protein. Knock-down of UBR5-ZNF423 by fusion-specific siRNA significantly inhibited the cell proliferation and colony-forming ability of C666-1 cells. The transforming ability of UBR5-ZNF423 fusion was also confirmed in NIH3T3 fibroblasts. Constitutive expression of UBR5-ZNF423 in NIH3T3 fibroblasts significantly enhanced its anchorage-independent growth in soft agar and induced tumour formation in a nude mouse model. These findings suggest that expression of UBR5-ZNF423 protein might contribute to the transformation of a subset of NPCs, possibly by altering the activity of EBFs (early B cell factors). Identification of the oncogenic UBR5-ZNF423 provides new potential opportunities for therapeutic intervention in NPC.
鼻咽癌（NPC）是一种独特的头颈部癌症，在中国南方、东南亚和北非地区较为普遍。NPC 的发生和逐步发展涉及 EBV 感染的鼻咽上皮细胞群体克隆扩增过程中多种遗传改变的积累。在这里，我们使用配对末端全转录组测序，在一组 EBV 阳性肿瘤系中发现了一些嵌合融合转录本。在这些转录本中，从 NPC 细胞系 C666-1 中鉴定出的一种新型锌指蛋白 423（ZNF423）位于 16q12.1 和泛素蛋白连接酶 E3 成分 n-识别蛋白 5（UBR5）位于 8q22.3 的融合，在 144 个原发性肿瘤中的 12/144（8.3%）中反复检测到。融合基因包含 UBR5 的外显子 1 和 ZNF423 的外显子 7-9，并产生一种 94 个氨基酸的嵌合蛋白，包括 ZNF423 的原始 C 末端 EBF 结合结构域（ZF29-30）。值得注意的是，具有 UBR5-ZNF423 重排的 NPC 细胞的生长依赖于该融合蛋白的表达。融合特异性 siRNA 敲低 UBR5-ZNF423 显著抑制了 C666-1 细胞的增殖和集落形成能力。UBR5-ZNF423 融合的转化能力也在 NIH3T3 成纤维细胞中得到证实。UBR5-ZNF423 在 NIH3T3 成纤维细胞中的组成性表达显著增强了其在软琼脂中的无锚定生长能力，并在裸鼠模型中诱导肿瘤形成。这些发现表明，UBR5-ZNF423 蛋白的表达可能通过改变 EBFs（早期 B 细胞因子）的活性，促进 NPC 的转化。鉴定出致癌性的 UBR5-ZNF423 为 NPC 的治疗干预提供了新的潜在机会。
