Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Sydney, Australia.
School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
Commun Biol. 2024 Oct 14;7(1):1322. doi: 10.1038/s42003-024-06899-8.
MYCN amplification predicts poor prognosis in childhood neuroblastoma. To identify MYCN oncogenic signal dependencies we performed N-ethyl-N-nitrosourea (ENU) mutagenesis on the germline of neuroblastoma-prone TH-MYCN transgenic mice to generate founders which had lost tumorigenesis. Sequencing of the mutant mouse genomes identified the Ring Finger Protein 121 (RNF121) gene mutated to RNF associated with heritable loss of tumorigenicity. While the RNF121 protein localised predominantly to the cis-Golgi Complex, the RNF121 mutation in Helix 4 of its transmembrane domain caused reduced RNF121 protein stability and absent Golgi localisation. RNF121 expression markedly increased during TH-MYCN tumorigenesis, whereas hemizygous RNF121 gene deletion reduced TH-MYCN tumorigenicity. The RNF121-enhanced growth of MYCN-amplified neuroblastoma cells depended on RNF121 transmembrane Helix 5. RNF121 directly bound MYCN protein and enhanced its stability. High RNF121 mRNA expression associated with poor prognosis in human neuroblastoma tissues and another MYC-driven malignancy, laryngeal cancer. RNF121 is thus an essential oncogenic cofactor for MYCN and a target for drug development.
MYCN 扩增预示着儿童神经母细胞瘤预后不良。为了确定 MYCN 致癌信号的依赖性，我们对易发生神经母细胞瘤的 TH-MYCN 转基因小鼠的种系进行了 N-乙基-N-亚硝脲（ENU）诱变，以产生失去致瘤性的启动子。突变小鼠基因组的测序确定了 Ring Finger Protein 121（RNF121）基因发生突变，导致与遗传性失瘤性相关的 RNF 突变。虽然 RNF121 蛋白主要定位于顺式高尔基体复合物，但跨膜结构域第 4 螺旋中的 RNF121 突变导致 RNF121 蛋白稳定性降低和高尔基体定位缺失。RNF121 在 TH-MYCN 肿瘤发生过程中表达明显增加，而 RNF121 基因杂合缺失则降低了 TH-MYCN 的致瘤性。RNF121 增强了 MYCN 扩增神经母细胞瘤细胞的生长，这取决于 RNF121 跨膜螺旋 5。RNF121 直接结合 MYCN 蛋白并增强其稳定性。在人类神经母细胞瘤组织和另一种 MYC 驱动的恶性肿瘤喉癌中，高 RNF121 mRNA 表达与预后不良相关。因此，RNF121 是 MYCN 的必需致癌辅助因子，也是药物开发的靶点。
