Guo Mengbiao, Li Feng, Zhao Linghao, Fang Zhengwen, Yu Huichuan, Songyang Zhou, Xiong Yuanyan
Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Front Oncol. 2023 Mar 9;13:1097667. doi: 10.3389/fonc.2023.1097667. eCollection 2023.
RNA editing is prevalent in the transcriptome and is important for multiple cellular processes. C-to-U RNA editing sites (RES) are relatively rare and understudied in humans, compared to A-to-I editing. However, the functional impact of C-to-U editing in human cancers also remains elusive. Here, we conducted the first comprehensive survey of pan-cancer C-to-U RESs. Surprisingly, we found that the same subset of RESs were associated with multiple features, including patient survival, cancer stemness, tumor mutation burden (TMB), and tumor-infiltrated immune cell compositions (ICC), suggesting an RES-mediated close relationship between these features. For example, editing sites for GALM or IFI6 that led to higher expression were linked to lower survival and more cancer stemness. Also, TMB was found to be lower in prostate cancer cases with ICC-associated RESs in CAVIN1 or VWA8 or higher in prostate cancer cases with thymoma. With experimental support, we also found RESs in CST3, TPI1, or TNC that are linked to immune checkpoint blockade by anti-PD1. We also confirmed through experiments that two C-to-U RESs in CSNK2B or RPS14 had different effects on colon cancer cells. Patients with CSNK2B editing, which increased the expression of the oncogene CLDN18, had a lower response to drugs. On the other hand, drugs worked better on people who had RPS14 editing, which greatly increased ribosome production. In summary, our study demonstrated the important roles of C-to-U RESs across cancers and shed light on personalized cancer therapy.
RNA编辑在转录组中普遍存在，对多种细胞过程至关重要。与A-to-I编辑相比，C-to-U RNA编辑位点（RES）在人类中相对罕见且研究较少。然而，C-to-U编辑在人类癌症中的功能影响也仍然难以捉摸。在这里，我们对泛癌C-to-U RES进行了首次全面调查。令人惊讶的是，我们发现相同的RES子集与多种特征相关，包括患者生存、癌症干性、肿瘤突变负担（TMB）和肿瘤浸润免疫细胞组成（ICC），这表明这些特征之间存在RES介导的密切关系。例如，导致更高表达的GALM或IFI6的编辑位点与更低的生存率和更多的癌症干性相关。此外，在CAVIN1或VWA8中具有ICC相关RES的前列腺癌病例中TMB较低，而在胸腺瘤的前列腺癌病例中TMB较高。在实验支持下，我们还在CST3、TPI1或TNC中发现了与抗PD1免疫检查点阻断相关的RES。我们还通过实验证实，CSNK2B或RPS14中的两个C-to-U RES对结肠癌细胞有不同影响。具有CSNK2B编辑的患者增加了癌基因CLDN18的表达，对药物的反应较低。另一方面，药物对具有RPS14编辑的人效果更好，这大大增加了核糖体的产生。总之，我们的研究证明了C-to-U RES在各种癌症中的重要作用，并为个性化癌症治疗提供了线索。
