背景:由于前列腺癌(PCa)的异质性,传统上,临床指标无法满足个性化医疗的要求。RNA修饰的领域已经成为一个越来越相关的领域,阐明其在肿瘤异质性中的关键作用。然而,RNA修饰调节因子在PCa中的具体作用仍未被研究.
方法:在本研究中,我们进行了文献综述,总结了常见的8种RNA修饰类型(ac4c,AI,APA,m1A,m5c,M6A,m7G,Φ)涵盖总共84个监管机构。此外,我们将多中心队列与Ridge回归进行整合,以建立调节因子共表达评分(RMCCoeS).然后,我们评估了RMSCoeS在几个临床方面的作用,如生化复发(BCR),对化疗的反应,雄激素受体信号传导抑制剂(ARSI)治疗和免疫治疗PCa。最后,我们通过免疫组织化学和体外试验验证了5种hub基因的促癌性能.
结果:在RNA修饰调节因子的突变景观中,我们观察到总体突变率相对较低.值得注意的是,RMCCoeS,包含81个RNA修饰调节因子,在接受BCR的PCa患者中表现出准确预测预后和治疗反应的显着能力,化疗,ARSI治疗,和免疫疗法。高RMSCoeS表明预后不良和不利的治疗反应。功能富集分析揭示了RMCCoeS可能通过各种代谢途径对PCa的进展产生影响。此外,较高的RMSCoeS与CNV突变升高呈正相关.最后,我们验证了CPSF4,WBSCR22,RPUSD3,TRMT61A,和NSUN5-五个中心监管机构-在PCa的背景下。
结论:不同RNA修饰的功能是相互关联的。包含八个不同的RNA修饰调节因子,RMCCoeS在PCa的各个方面表现出多方面的作用,包括疾病进展,预后,以及对多种疗法的反应。此外,我们提供了PCa中与WBSCR22、RPUSD3、TRMT61A和NSUN5相关的癌基因效应的初步验证。我们的发现为RNA修饰在PCa个性化医疗中的意义提供了新的见解。
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.
CONCLUSIONS: 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.