Zhang Jiheng, Xu Lei, Yan Xiuwei, Hu Jiahe, Gao Xin, Zhao Hongtao, Geng Mo, Wang Nan, Hu Shaoshan
Cancer Center, Department of Neurosurgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Discov Oncol. 2024 Aug 20;15(1):361. doi: 10.1007/s12672-024-01093-y.
Pseudouridine widely affects the stability and function of RNA. However, our knowledge of pseudouridine properties in tumors is incomplete. We systematically analyzed pseudouridine synthases (PUSs) expression, genomic aberrations, and prognostic features in 10907 samples from 33 tumors. We found that the pseudouridine-associated pathway was abnormal in tumors and affected patient prognosis. Dysregulation of the PUSs expression pattern may arise from copy number variation (CNV) mutations and aberrant DNA methylation. Functional enrichment analyses determined that the PUSs expression was closely associated with the MYC, E2F, and MTORC1 signaling pathways. In addition, PUSs are involved in the remodeling of the tumor microenvironment (TME) in solid tumors, such as kidney and lung cancers. Particularly in lung cancer, increased expression of PUSs is accompanied by increased immune checkpoint expression and Treg infiltration. The best signature model based on more than 112 machine learning combinations had good prognostic ability in ACC, DLBC, GBM, KICH, MESO, THYM, TGCT, and PRAD tumors, and is expected to guide immunotherapy for 19 tumor types. The model was also effective in identifying patients with tumors amenable to etoposide, camptothecin, cisplatin, or bexarotene treatment. In conclusion, our work highlights the dysregulated features of PUSs and their role in the TME and patient prognosis, providing an initial molecular basis for future exploration of pseudouridine. Studies targeting pseudouridine are expected to lead to the development of potential diagnostic strategies and the evaluation and improvement of antitumor therapies.
假尿苷广泛影响RNA的稳定性和功能。然而，我们对肿瘤中假尿苷特性的了解并不完整。我们系统分析了来自33种肿瘤的10907个样本中的假尿苷合成酶（PUSs）表达、基因组畸变和预后特征。我们发现肿瘤中与假尿苷相关的途径异常，并影响患者预后。PUSs表达模式的失调可能源于拷贝数变异（CNV）突变和异常的DNA甲基化。功能富集分析确定PUSs表达与MYC、E2F和MTORC1信号通路密切相关。此外，PUSs参与实体瘤（如肾癌和肺癌）的肿瘤微环境（TME）重塑。特别是在肺癌中，PUSs表达增加伴随着免疫检查点表达增加和调节性T细胞浸润。基于112种以上机器学习组合的最佳特征模型在ACC、DLBC、GBM、KICH、MESO、THYM、TGCT和PRAD肿瘤中具有良好的预后能力，有望指导19种肿瘤类型的免疫治疗。该模型在识别适合接受依托泊苷、喜树碱、顺铂或贝沙罗汀治疗的肿瘤患者方面也很有效。总之，我们的工作突出了PUSs的失调特征及其在TME和患者预后中的作用，为未来假尿苷的探索提供了初步的分子基础。针对假尿苷的研究有望推动潜在诊断策略的开发以及抗肿瘤治疗的评估和改进。
