RNA 修饰调控因子共表达评分（RMRCoeS）预测前列腺癌的生化复发和治疗反应：一项多组学和实验验证研究。

RNA modification Regulators' Co-Expression Score (RMRCoeS) predicts biochemical recurrence and therapy response in prostate cancer: A multi-omics and experimental validation study.

机构信息

Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, China.

Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, China; Department of Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, 510700, Guangzhou, China; The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, 510700, Guangzhou, China.

出版信息

Int Immunopharmacol. 2024 Sep 30;139:112723. doi: 10.1016/j.intimp.2024.112723. Epub 2024 Jul 24.

DOI:10.1016/j.intimp.2024.112723

PMID:39053228

Abstract

BACKGROUND

Owing to the heterogeneity of prostate cancer (PCa), the clinical indicators traditionally fall short of meeting the requirements for personalized medicine. The realm of RNA modification has emerged as an increasingly relevant domain, shedding light on its pivotal role in tumor heterogeneity. However, the specific contributions of RNA modification regulators within the context of PCa remain largely unexplored.

METHODS

In this study, we undertook a literature review to summarize the common 8 types of RNA modifications (ac4c, AI, APA, m1A, m5c, m6A, m7G, Ψ) encompassing a total of 84 regulators. Moreover, we integrated multi-center cohorts with Ridge regression to develop the Regulators' Co-Expression Score (RMRCoeS). Then we assessed the role of RMRCoeS in several clinical aspects such as biochemical recurrence (BCR), responses to chemotherapy, androgen receptor signaling inhibitor (ARSI) therapy and immunotherapy in PCa. Finally, we validated the cancer-promoting performance of five hub genes through immunohistochemistry and in vitro assays.

RESULTS

Within the mutation landscape of RNA modification regulators, we observed a relatively low overall mutation rate. Remarkably, RMRCoeS, comprising 81 RNA modification regulators, exhibited a notable capability for accurately predicting the prognosis and therapeutic responses in PCa patients subjected to BCR, chemotherapy, ARSI therapy, and immunotherapy. A high RMRCoeS was indicative of a poor prognosis and unfavorable therapy responses. Functional enrichment analysis unveiled that RMRCoeS may exert its influence on PCa progression through various metabolic pathways. Furthermore, a higher RMRCoeS showed a positive correlation with elevated CNV mutations. Lastly, we validated the oncogene effects of CPSF4, WBSCR22, RPUSD3, TRMT61A, and NSUN5-five hub regulators-within the context of PCa.

CONCLUSION

The function of different RNA modifications is interconnected. Comprising eight distinct RNA modifications' regulators, RMRCoeS exhibits multifaceted roles in various aspects of PCa, including disease progression, prognosis, and responses to multiple therapies. Furthermore, we provide the initial validation of the oncogene effect associated with WBSCR22, RPUSD3, TRMT61A and NSUN5 in PCa. Our findings offer novel insights into the significance of RNA modifications in PCa personalized medicine.

摘要

背景

由于前列腺癌（PCa）的异质性，传统的临床指标难以满足个性化医疗的要求。RNA 修饰领域的出现为其提供了重要的研究方向，揭示了其在肿瘤异质性中的关键作用。然而，RNA 修饰调控因子在 PCa 中的具体作用仍有待进一步研究。

方法

本研究通过文献综述，总结了常见的 8 种 RNA 修饰类型（ac4c、AI、APA、m1A、m5c、m6A、m7G、Ψ）共 84 种调控因子。此外，我们整合了多中心队列数据，采用 Ridge 回归构建了调控因子共表达评分（RMRCoeS）。然后，我们评估了 RMRCoeS 在 PCa 患者生化复发（BCR）、化疗反应、雄激素受体信号抑制剂（ARSI）治疗和免疫治疗等多个临床方面的作用。最后，我们通过免疫组化和体外实验验证了五个关键基因的促癌作用。

结果

在 RNA 修饰调控因子的突变图谱中，我们观察到总体突变率相对较低。值得注意的是，由 81 个 RNA 修饰调控因子组成的 RMRCoeS，能够准确预测 PCa 患者 BCR、化疗、ARSI 治疗和免疫治疗的预后和治疗反应。高 RMRCoeS 与不良预后和治疗反应相关。功能富集分析表明，RMRCoeS 可能通过多种代谢途径影响 PCa 的进展。此外，较高的 RMRCoeS 与更高的 CNV 突变呈正相关。最后，我们验证了 CPSF4、WBSCR22、RPUSD3、TRMT61A 和 NSUN5 这五个关键调控因子在 PCa 中的致癌作用。

结论

不同 RNA 修饰的功能相互关联。由八种不同的 RNA 修饰调控因子组成的 RMRCoeS，在 PCa 的多个方面发挥着多方面的作用，包括疾病进展、预后和对多种治疗的反应。此外，我们初步验证了 WBSCR22、RPUSD3、TRMT61A 和 NSUN5 在 PCa 中的致癌作用。我们的研究结果为 RNA 修饰在 PCa 个性化医学中的意义提供了新的见解。