Research Paper Volume 14, Issue 19 pp 7890—7905

Comprehensive bioinformatics analysis of ribonucleoside diphosphate reductase subunit M2(RRM2) gene correlates with prognosis and tumor immunotherapy in pan-cancer

Liyuan Wu1,2, *, , Le Yin3, *, , Linxiang Ma4, *, , Jiarui Yang5, , Feiya Yang1,2, , Baofa Sun6, #, , Xing Nianzeng1,2,7, #, ,

  • 1 Department of Urology, National Cancer Center/National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
  • 2 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
  • 3 Research and Development Department, Allife Medicine Inc., Beijing 100176, China
  • 4 Department of Urology, Weifang Hospital of Traditional Chinese Medicine, Weifang 261000, Shandong, China
  • 5 Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University, Xiqing, Tianjin 300382, China
  • 6 Department of Zoology, College of Life Science, Nankai University, Nankai, Tianjin 300071, China
  • 7 Department of Urology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Shanxi, Taiyuan 030013, China
* Equal contribution
# Co-first author

Received: February 6, 2022       Accepted: August 31, 2022       Published: October 3, 2022
How to Cite

Copyright: © 2022 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Ribonucleotide reductase (RNR) small subunit M2 (RRM2) levels are known to regulate the activity of RNR, a rate-limiting enzyme in the synthesis of deoxyribonucleotide triphosphates (dNTPs) and essential for both DNA replication and repair. The high expression of RRM2 enhances the proliferation of cancer cells, thereby implicating its role as an anti-cancer agent. However, little research has been performed on its role in the prognosis of different types of cancers. This pan-cancer study aimed to evaluate the effect of high expression of RRM2 the tumor prognosis based on clinical information collected from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) databases. We found RRM2 gene was highly expressed in 30 types of cancers. And we performed a pan-cancer analysis of the genetic alteration status and methylation of RRM2. Results indicated that RRM2 existed hypermethylation, associated with m6A, m1A, and m5C related genes. Subsequently, we explored the microRNAs (miRNA), long non-coding RNAs (lncRNA), and the transcription factors responsible for the high expression of RRM2 in cancer cells. Results indicated that has-miR-125b-5p and has-miR-30a-5p regulated the expression of RRM2 along with transcription factors, such as CBFB, E2F1, and FOXM. Besides, we established the competing endogenous RNA (ceRNA) diagram of lncRNAs-miRNAs-circular RNAs (circRNA) involved in the regulation of RRM2 expression. Meanwhile, our study demonstrated that high-RRM2 levels correlated with patients’ worse prognosis survival and immunotherapy effects through the consensus clustering and risk scores analysis. Finally, we found RRM2 regulated the resistance of immune checkpoint inhibitors through the PI3K-AKT single pathways. Collectively, our findings elucidated that high expression of RRM2 correlates with prognosis and tumor immunotherapy in pan-cancer. Moreover, these findings may provide insights for further investigation of the RRM2 gene as a biomarker in predicting immunotherapy’s response and therapeutic target.


ACC: Adrenocortical carcinoma; BLCA: Bladder cancer; BRCA: Breast invasive carcinoma; CHOL: Cholangiocarcinoma; COAD: Colon adenocarcinoma; ESCA: Esophageal carcinoma; GBM: Esophageal carcinoma; NSC: Head and neck squamous cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; KIRC: Kidney renal clear cell carcinoma; LUAD: Lung adenocarcinoma; LIHC: Liver hepatocellular carcinoma; LUSC: Lung squamous cell carcinoma; PRAD: Prostate adenocarcinoma; READ: Rectum adenocarcinoma; STAD: Stomach adenocarcinoma; THCA: Thyroid carcinoma; UCEC: Uterine Corpus Endometrial Carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; PCPG: Pheochromocytoma and Paraganglioma; DLBC: Lymphoid neoplasm diffuse large B-cell lymphoma; LGG: Brain lower-grade glioma; OV: Ovarian serous cystadenocarcinoma; UCS: Uterine Carcinosarcoma; SARC: Sarcoma; SKCM: Skin cutaneous melanoma; THYM: Thymoma; TGCT: Testicular germ cell tumors; KICH: Kidney Chromophobe; PAAD: Pancreatic adenocarcinoma; RRM2: ribonucleoside diphosphate reductase subunit M2; RNR: Ribonucleotide reductase; OS: Overall survival; DFS: Disease-free survival; PFI: Progression-free interval; PD-1: programmed cell death protein-1; CTLA-4: cytotoxic T-lymphocyte antigen-4; PD-L1: programmed cell death ligand 1; PD-L2: programmed cell death ligand 2; LAG-3: lymphocyte activation gene-3; TIM-3: T cell immunoglobulin and mucin domain-3; TIGIT: T cell immunoreceptor with Ig and ITIM domains.