Identification of RFC4 as a Potential Biomarker for Pan-Cancer - Prognosis, Tumour Immune Microenvironment and Drugs

Sep 21, 2026

Uploaded by Maeve

RFC4 is required for DNA polymerase δ and DNA polymerase ε to initiate DNA template expansion. Downregulated RFC4 suppresses tumour proliferation by triggering S-phase arrest and inhibiting mitosis. A comprehensive pan-cancer evaluation of RFC4, including expression, prognosis, methylation, splicing, immune infiltration links and immunotherapy response, was performed using multiple public databases and functional experiments in HCC. RFC4 was upregulated in most tumours and high levels predicted poor prognosis. RFC4 showed abnormal methylation and splicing, correlated with immune checkpoints and infiltration patterns, and reflected immunotherapy efficacy and sensitivity to selected small-molecule drugs, supported by cell experiments.

LanguageEnglish

CategoryResearch & Report

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Abstract

Introduction

DOI: 10. 1111/jcmm.18478 OR I G I NAL ART I C L E Identification of RFC4 as a potential biomarker for pan-cancer involving prognosis, tumour immune microenvironment and drugs Lei Yu1 | Jing Li1 | Mingyang Zhang1 | Yu Li1 | Jing Bai1 | Pengxia Liu1 | Jia Yan2 | Changshan Wang1 1School of Life Science, Inner Mongolia University, Hohhot, China 2School of Basic medical, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China Correspondence Changshan Wang and Pengxia Liu, School of Life Science, Inner Mongolia University, Hohhot 010020, China. Email: [changshanwang@imu.edu.cn](changshanwang@imu.edu.cn) and [liupengxia@imu.edu.cn](liupengxia@imu.edu.cn) Jia Yan, School of Basic medical, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China. [Email:](Email: yanjia0781@126.com)[ yanjia0781@126.com](Email: yanjia0781@126.com) Funding information Natural Science Foundation of Inner Mongolia, Grant/Award Number: 2020MS08096, 2020MS03007 and 2023MS08033; National Natural Science Foundation of China (CN), Grant/Award Number: 81660024 and 32060156 Abstract RFC4 is required for DNA polymerase δ and DNA polymerase ε to initiate DNA template expansion. Downregulated RFC4 inhibits tumour proliferation by causing Sphase arrest and inhibiting mitosis, resulting in the reduction of tumour cells. RFC4 has been implicated that it plays an important role in the initiation and progression of cancers, but a comprehensive analysis of the role of RFC4 in cancer has not been performed. We comprehensively analysed the expression, prognosis, methylation level, splicing level, relationship of RFC4 and immune infiltration, and pan-cancer immunotherapy response used various databases (including TCGA, GTEx, UALCAN, Oncosplicing, TIDE, TISCH, HPA and CAMOIP), and experimented its biological function in HCC. Through pan-cancer analysis, we found that RFC4 is significantly upregulated in most tumours. The tumour patients with high expression of RFC4 have poor prognosis. The methylation level and variable splicing level of RFC4 were abnormal in most tumours compared with the adjacent tissues. Furthermore, RFC4 was closely associated with immune cell infiltration in various cancers. RFC4 was significantly coexpressed with immune checkpoints and other immune-related genes. The expression of RFC4 could indicate the immunotherapy efficacy of some tumours. The RFC4 expression was associated with sensitivity to specific small molecule drugs. Cell experiments have shown that downregulated RFC4 can inhibit cell cycle and tumour cell proliferation. We conducted a systematic pan-cancer analysis of RFC4, and the results showed that RFC4 can serve as a biomarker for cancer diagnosis and prognosis. These findings open new perspectives for precision medicine. K E Y WO R D S bioinformatics analysis, biomarker, immunity therapy, pan-cancer, prognosis, RFC4 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2024 The Author(s) . Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. J Cell Mol Med. 2024;28:e18478 . [https://doi.org/10.1111/jcmm.18478](https://doi.org/10.1111/jcmm.18478) [wileyonlinelibrary.com/journal/jcmm](wileyonlinelibrary.com/journal/jcmm) 1 of 16 1 | INTRODUCTION RFC4 is necessary for DNA polymerase δ and DNA polymerase ε to extend primed DNA templates. The RFC family functions as clamp loaders during DNA synthesis, loading PCNA onto DNA through an ATP-dependent process.1–3 During the S phase of DNA replication, RFCs activate polymerase assembly and cell cycle checkpoint control. Upon DNA damage, they activate their mismatch and excision repair mechanisms after forming complexes with PCNA. Thus, RFCs play a crucial role in DNA repair activities following DNA damage.4–

FAQs

What biological role does RFC4 play in DNA replication?

RFC4 is necessary for DNA polymerase δ and ε to extend primed DNA templates. It functions as a clamp loader during DNA synthesis by loading PCNA onto DNA, supporting S-phase replication and checkpoint control.

How does downregulation of RFC4 affect tumour cells?

Downregulated RFC4 inhibits tumour proliferation by causing S-phase arrest and suppressing mitosis. Cell experiments also indicate reduced cell cycle progression and tumour cell proliferation.

How is RFC4 linked to prognosis and cancer immunotherapy?

High RFC4 expression is associated with poor patient prognosis across tumours. RFC4 correlates with immune cell infiltration and immune checkpoint genes, and its expression can indicate immunotherapy efficacy as well as drug sensitivity.

Sep 21, 2026

Uploaded by Maeve