Huang Bifen, Zheng Jianqing, Chen Bizhen, Wu Min, Xiao Lihua
Department of Obstetrics and Gynecology, People's Hospital Affiliated of Quanzhou Medical College, Quanzhou, Fujian, China.
Department of Radiation Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
Front Genet. 2025 May 19;16:1514383. doi: 10.3389/fgene.2025.1514383. eCollection 2025.
Replication factor C subunit 4 (RFC4) plays a critical role in the initiation and progression of some cancers; however, its relationship with tumor-infiltrating immune cells in cervical cancer (CC) has not been comprehensively analyzed. This study aimed to determine whether RFC4 overexpression affects overall survival in CC and to explore its impact and potential mechanisms on the tumor immune microenvironment.
Data from Genotype-Tissue Expression database (GTEx) and Cancer Genome Atlas (TCGA) database were used as the exploration set. Datasets from the Gene Expression Omnibus (GEO) were used as the validation set. We also validated the expression of the RFC4 protein in the Human Protein Atlas (HPA) database and a real cohort. Clinical data on CC were evaluated for their association with RFC4 using TCGA and GEO databases. Possible relationships amongst RFC4, immune cells, and related genes were investigated using Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression (ESTIMATE). GO and KEGG pathway enrichment analyses were used to explore potential mechanisms. Tumor immune dysfunction and exclusion (TIDE) scores were used to predict the immunotherapeutic response to RFC4.
In the exploration, validation, and real cohort datasets, RFC4 expression was significantly elevated in CC tissues compared to that in normal tissues. Survival analysis based on TCGA and GEO datasets showed that CC patients with high RFC4 expression had a better prognosis than those with low expression. RFC4 expression was strongly correlated with some immunostimulators and immunoinhibitors. RFC4 expression was significantly negatively correlated with activated mast cell immune infiltration, activated CD4 memory T cells, M0 macrophages, and resting natural killer (NK) cells and significantly positively associated with activated dendritic cells, resting dendritic cells, and plasma cells.
RFC4 is highly expressed in CC tissues. However, patients with high RFC4 expression in CC have a better prognosis, possibly because RFC4 exerts antitumor effects by affecting the immunostimulatory tumor microenvironment, such as immunostimulatory and dendritic cell infiltration.
复制因子C亚基4（RFC4）在某些癌症的发生和发展中起关键作用；然而，其与宫颈癌（CC）中肿瘤浸润免疫细胞的关系尚未得到全面分析。本研究旨在确定RFC4过表达是否影响CC患者的总生存期，并探讨其对肿瘤免疫微环境的影响及潜在机制。
来自基因型-组织表达数据库（GTEx）和癌症基因组图谱（TCGA）数据库的数据用作探索集。来自基因表达综合数据库（GEO）的数据集用作验证集。我们还在人类蛋白质图谱（HPA）数据库和一个真实队列中验证了RFC4蛋白的表达。使用TCGA和GEO数据库评估CC的临床数据与RFC4的相关性。使用通过估计RNA转录本相对子集进行细胞类型鉴定（CIBERSORT）和利用表达估计恶性肿瘤组织中的基质和免疫细胞（ESTIMATE）研究RFC4、免疫细胞和相关基因之间的可能关系。采用GO和KEGG通路富集分析来探索潜在机制。使用肿瘤免疫功能障碍和排除（TIDE）评分来预测对RFC4的免疫治疗反应。
在探索集、验证集和真实队列数据集中，与正常组织相比，CC组织中RFC4表达显著升高。基于TCGA和GEO数据集的生存分析表明，RFC4高表达的CC患者预后优于低表达患者。RFC4表达与一些免疫刺激剂和免疫抑制剂密切相关。RFC4表达与活化肥大细胞免疫浸润、活化CD4记忆T细胞、M0巨噬细胞和静息自然杀伤（NK）细胞显著负相关，与活化树突状细胞、静息树突状细胞和浆细胞显著正相关。
RFC4在CC组织中高表达。然而，CC中RFC4高表达的患者预后较好，可能是因为RFC4通过影响免疫刺激肿瘤微环境（如免疫刺激和树突状细胞浸润）发挥抗肿瘤作用。
