The ribosomal protein gene RPL5 is a haploinsufficient tumor suppressor in multiple cancer types.
The ribosomal protein gene RPL5 is a haploinsufficient tumor suppressor in multiple cancer types.
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DOI：
10.18632/oncotarget.14895
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发表时间：
2017-02-28
期刊：
影响因子：
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通讯作者：
De Keersmaecker K
中科院分区：
文献类型：
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作者：
Fancello L;Kampen KR;Hofman IJ;Verbeeck J;De Keersmaecker K
多年来，核糖体的缺陷与癌症有关。最近，在几种白血病和实体肿瘤类型中鉴定出影响核糖体蛋白基因的体细胞突变和缺失。但是，缺乏对跨癌症类型的所有81种已知核糖体蛋白基因的系统分析。我们筛选了16种癌症类型的4926和7322个样品的突变和拷贝数数据，并确定了6种改变的基因（RPL5，RPL11，RPL23A，RPL23A，RPS5，RPS5，RPS20和RPSA）。 RPL5位于杂合缺失的显着峰值或11％的胶质母细胞瘤，28％的黑色素瘤和34％的乳腺癌样品中突变。此外，RPL5表达低的患者在胶质母细胞瘤和一个乳腺癌队列中的总体生存率较差。乳腺癌细胞系中的RPL5敲低增强了异种移植小鼠模型中的G2/M细胞周期进程和加速肿瘤进展。有趣的是，我们的数据表明，RPL5的肿瘤抑制作用不仅是由已知的TP53或C-MYC调节剂介导的。总之，RPL5杂合灭活发生在多种肿瘤类型的高发病率（11-34％），目前代表了癌症中最常见的体细胞核糖体蛋白缺陷，我们证明了RPL5在乳腺癌中的肿瘤抑制作用。
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.