A pan-cancer analysis of the oncogenic role of ribonucleotide reductase subunit M2 in human tumors

Author:

Li Yaqun1,Fu Wenhuan1,Geng Zikai2,Song Yun1,Yang Xionggang3,He Tianye1,Wu Jian1,Wang Bin1

Affiliation:

1. Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China

2. Pharmacy School, Binzhou Medical University, Shandong, China

3. Department of Orthopedic Surgery, Huashan Hospital, Fudan University, Shanghai, China

Abstract

Background Recent studies have identified ribonucleotide reductase subunit M2 (RRM2) as a putative promoter of tumors. However, no systematic analysis of its carcinogenicity has been conducted. Methods The potential functions of RRM2 in various tumor types were investigated using data from the Genotype-Tissue Expression (GTEx), the Clinical Proteomic Tumor Analysis Consortium (CPTAC), the Cancer Genome Atlas (TCGA), the Human Protein Atlas (HPA), cBioPortal, GEPIA, String, and Gene Set Enrichment Analysis (GSEA). We analyzed the difference in mRNA and protein expression, pathological stage, survival, mutation, tumor microenvironment (TME), and immune cell infiltration in relation to RRM2. Meanwhile, using TCGA and the Tumor Immune Estimation Resource 2 (TIMER 2), the associations between RRM2 expression, immune infiltration, and immune-related genes were assessed. Additionally, CCK-8, Edu and RT-PCR assays were used to validate that RRM2 acts as an oncogene in liver cancer cells and its association with HBx. A cohort of liver hepatocellular carcinoma (LIHC) patients (n=154) from Huashan Hospital was analyzed for the expression of RRM2 and the association between RRM2 and immune infiltration. Results Using the GTEx and TCGA databases, we discovered that 28 tumors expressed RRM2 at significantly higher levels than the corresponding normal tissues. Increased RRM2 expression may be predictive of a poor overall survival (OS) in patients with seven different cancers. GO, KEGG, and GSEA analyses revealed that the biological process of RRM2 was associated with the regulation of carcinogenic processes and immune pathways in a variety of tumor types. The expression of RRM2 was highly correlated with maker genes involved in immune activation and immunosuppression, immune checkpoints, DNA mismatch repair system (MMR), and the infiltration levels of Tregs and macrophages (TAMs), suggesting that the carcinogenic effect of RRM2 may be achieved by regulating immune related genes. Moreover, as demonstrated by CCK-8 and Edu assays, RRM2 was an oncogene in liver cancer cells. We confirmed for the first time that RRM2 was significantly upregulated by HBx, suggesting that RRM2 may be a key regulator of LIHC induced by HBV. IHC analysis validated the upregulated expression of RRM2 protein and its correlation with immune infiltration makers in a LIHC patient cohort. Conclusion RRM2 may be a valuable molecular biomarker for predicting prognosis and immunotherapeutic efficacy in pan-cancer, particularly in LIHC.

Funder

National Natural Science Foundation of China

Shanghai Municipal Health Commission

Natural Science Foundation of Shandong Province

Clinical Research Foundation of Wu Jieping Medical Foundation

Shanghai Key Clinical Specialities-Clinical Pharmacy Education

Publisher

PeerJ

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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