Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, 69120, Heidelberg, Germany.
Shanghai University of Medicine and Health Sciences, Shanghai, 201318, PR China.
Oncogene. 2021 Feb;40(5):909-921. doi: 10.1038/s41388-020-01570-y. Epub 2020 Dec 7.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide underlining the urgent need for new biomarkers and therapeutic targets for this disease. Long noncoding RNAs are critical players in NSCLC but the role of small RNA species is not well understood. In the present study, we investigated the role of H/ACA box small nucleolar RNAs (snoRNAs) and snoRNA-bound ribonucleoproteins (snoRNPs) in the tumorigenesis of NSCLC. H/ACA box snoRNPs including the NOP10 core protein were highly expressed in NSCLC. High levels of either NOP10 mRNA or protein were associated with poor prognosis in NSCLC patients. Loss of NOP10 and subsequent reduction of H/ACA box snoRNAs and rRNA pseudouridylation inhibited lung cancer cell growth, colony formation, migration, and invasion. A focused CRISPR/Cas9 snoRNA knockout screen revealed that genomic deletion of SNORA65, SNORA7A, and SNORA7B reduced proliferation of lung cancer cells. In line, high levels of SNORA65, SNORA7A, and SNORA7B were observed in primary lung cancer specimens with associated changes in rRNA pseudouridylation. Knockdown of either SNORA65 or SNORA7A/B inhibited growth and colony formation of NSCLC cell lines. Our data indicate that specific H/ACA box snoRNAs and snoRNA-associated proteins such as NOP10 have an oncogenic role in NSCLC providing new potential biomarkers and therapeutic targets for the disease.
非小细胞肺癌（NSCLC）是全球癌症死亡的主要原因，这凸显了迫切需要针对这种疾病的新生物标志物和治疗靶点。长链非编码 RNA 是 NSCLC 的关键参与者，但小分子 RNA 物种的作用尚未得到很好的理解。在本研究中，我们研究了 H/ACA 盒小核仁 RNA（snoRNA）和 snoRNA 结合的核糖核蛋白（snoRNP）在 NSCLC 肿瘤发生中的作用。H/ACA 盒 snoRNP 包括 NOP10 核心蛋白在 NSCLC 中高度表达。NSCLC 患者中 NOP10 mRNA 或蛋白水平高与预后不良相关。NOP10 的缺失及其随后的 H/ACA 盒 snoRNA 和 rRNA 假尿嘧啶化减少抑制了肺癌细胞的生长、集落形成、迁移和侵袭。CRISPR/Cas9 snoRNA 敲除筛选的焦点揭示了 SNORA65、SNORA7A 和 SNORA7B 的基因组缺失可降低肺癌细胞的增殖。与此一致，在原发性肺癌标本中观察到 SNORA65、SNORA7A 和 SNORA7B 水平升高，同时 rRNA 假尿嘧啶化也发生了相应变化。SNORA65 或 SNORA7A/B 的敲低抑制了 NSCLC 细胞系的生长和集落形成。我们的数据表明，特定的 H/ACA 盒 snoRNA 和 snoRNA 相关蛋白（如 NOP10）在 NSCLC 中具有致癌作用，为该疾病提供了新的潜在生物标志物和治疗靶点。
