Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, de Boelelaan 1118, Amsterdam, The Netherlands.
Amsterdam UMC, Vrije Universiteit Amsterdam, Epidemiology and Biostatistics, Netherlands Bioinformatics Center, de Boelelaan 1118, Amsterdam, The Netherlands.
Oncogene. 2019 May;38(21):4142-4153. doi: 10.1038/s41388-019-0711-z. Epub 2019 Jan 31.
Novel therapeutic strategies for non-small-cell lung cancer (NSCLC) are urgently needed. RNA splicing, orchestrated by the spliceosome, is deregulated in many forms of cancer, including NSCLC. Here, we performed high-throughput screening with a small interfering RNA library targeting all annotated human spliceosome proteins to identify cancer-selective lethal targets in the RNA splicing machinery. Silencing of several spliceosome proteins reduced cell viability in a panel of NSCLC cell lines, but not in non-malignant lung fibroblasts and epithelial cells. Interestingly, the cancer-selective lethal target set comprised all seven Sm proteins that, together with small nuclear RNA, form the core structure of most spliceosome subunits. Interfering with Sm protein expression induced apoptosis in NSCLC cells, but not in non-malignant cells. In silico analysis revealed that Sm proteins are frequently upregulated in NSCLC. For several Sm proteins, increased expression showed a positive correlation with disease severity. Together, our results suggest that the Sm proteins represent particularly useful novel targets for selective treatment of NSCLC.
我们迫切需要针对非小细胞肺癌（NSCLC）的新型治疗策略。剪接体调控的 RNA 剪接在包括 NSCLC 在内的许多癌症中失调。在这里，我们使用针对所有注释的人类剪接体蛋白的小干扰 RNA 文库进行了高通量筛选，以鉴定 RNA 剪接机制中的癌症选择性致死靶标。沉默几种剪接体蛋白可降低 NSCLC 细胞系中的细胞活力，但对非恶性肺成纤维细胞和上皮细胞没有影响。有趣的是，癌症选择性致死靶标集包含了所有七个 Sm 蛋白，这些蛋白与小核 RNA 一起构成了大多数剪接体亚基的核心结构。干扰 Sm 蛋白表达会诱导 NSCLC 细胞凋亡，但不会诱导非恶性细胞凋亡。计算机分析显示，Sm 蛋白在 NSCLC 中经常上调。对于几种 Sm 蛋白，表达增加与疾病严重程度呈正相关。总之，我们的研究结果表明，Sm 蛋白是 NSCLC 选择性治疗的特别有用的新型靶标。
