Fancello Laura, Kampen Kim R, Hofman Isabel J F, Verbeeck Jelle, De Keersmaecker Kim
KU Leuven-University of Leuven, Department of Oncology, LKI-Leuven Cancer Institute, Leuven, Belgium.
Oncotarget. 2017 Feb 28;8(9):14462-14478. doi: 10.18632/oncotarget.14895.
For many years, defects in the ribosome have been associated to cancer. Recently, somatic mutations and deletions affecting ribosomal protein genes were identified in a few leukemias and solid tumor types. However, systematic analysis of all 81 known ribosomal protein genes across cancer types is lacking. We screened mutation and copy number data of respectively 4926 and 7322 samples from 16 cancer types and identified six altered genes (RPL5, RPL11, RPL23A, RPS5, RPS20 and RPSA). RPL5 was located at a significant peak of heterozygous deletion or mutated in 11% of glioblastoma, 28% of melanoma and 34% of breast cancer samples. Moreover, patients with low RPL5 expression displayed worse overall survival in glioblastoma and in one breast cancer cohort. RPL5 knockdown in breast cancer cell lines enhanced G2/M cell cycle progression and accelerated tumor progression in a xenograft mouse model. Interestingly, our data suggest that the tumor suppressor role of RPL5 is not only mediated by its known function as TP53 or c-MYC regulator. In conclusion, RPL5 heterozygous inactivation occurs at high incidence (11-34%) in multiple tumor types, currently representing the most common somatic ribosomal protein defect in cancer, and we demonstrate a tumor suppressor role for RPL5 in breast cancer.
多年来，核糖体缺陷一直与癌症相关。最近，在一些白血病和实体瘤类型中发现了影响核糖体蛋白基因的体细胞突变和缺失。然而，缺乏对所有81种已知核糖体蛋白基因在不同癌症类型中的系统分析。我们筛选了来自16种癌症类型的4926个样本和7322个样本的突变及拷贝数数据，鉴定出6个发生改变的基因（RPL5、RPL11、RPL23A、RPS5、RPS20和RPSA）。RPL5位于杂合缺失的显著峰值处，或在11%的胶质母细胞瘤、28%的黑色素瘤和34%的乳腺癌样本中发生突变。此外，RPL5表达较低的胶质母细胞瘤患者和一个乳腺癌队列中的患者总体生存率较差。在乳腺癌细胞系中敲低RPL5可增强G2/M期细胞周期进程，并在异种移植小鼠模型中加速肿瘤进展。有趣的是，我们的数据表明，RPL5的肿瘤抑制作用不仅由其作为TP53或c-MYC调节因子的已知功能介导。总之，RPL5杂合失活在多种肿瘤类型中发生率较高（11%-34%），目前是癌症中最常见的体细胞核糖体蛋白缺陷，并且我们证明了RPL5在乳腺癌中的肿瘤抑制作用。
