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

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.

MMP12 serves as an immune cell–related marker of disease status and prognosis in lung squamous cell carcinoma

“…MMP12 was significantly and positively correlated with immune cell levels, and immune cell scores were higher in the MMP12 high-expression group, suggesting that MMP12 was very closely associated with immune cells. We further validated this using the TIMER algorithm ( Chen et al., 2022c ; Li et al., 2020 ; Li et al., 2022b ; Liu et al., 2022a ) and multicenter single-cell sequencing, and the results were mostly consistent with our expectations; upregulation of MMP12 expression was not only associated with increased infiltration levels of five immune cell types but was also widely present in DCs as well as monocytes/macrophages. DCs are involved in antitumor immunity by activating T cells, and macrophages can participate in immune regulation through phagocytosis, antigen presentation, and the secretion of cytokines ( Wynn & Vannella, 2016 ).…”

“…The Tumor Immune Estimation Resource (TIMER) ( Li et al., 2020 ; Chen et al., 2022c ; Liu et al., 2022a ; Li et al., 2022b ) is an online database that allows comprehensive detection of immune cell infiltration levels. The data for six immune-infiltrating cells were downloaded from the database.…”

HBx promotes tumorigenicity through RRM2-mediated autophagy in hepatocellular carcinoma

“…Using the Kaplan-Meier survival curve and the log-rank test, overall survival in relation to RRM2 expression in HCC patients was examined. By calculating the receiver operating characteristic (ROC) and the area under the curves (AUCs), the diagnostic value of RRM2 was obtained using the "time ROC" and "ggplot2" R packages [7]. We used the "R-forestplot" and "R-survival" packages to analyze and illustrate the univariate and multivariate Cox regression analysis.…”

“…Additionally, RRM2 was reported to be predictive of lung adenocarcinoma prognosis. Our previous study has demonstrated that RRM2 is involved in HBVrelated hepatocellular carcinoma (HCC), whereas its precise functions and mechanisms in HCC caused by HBV still unclear [7].…”

A Transcriptomic Analysis of Smoking-Induced Gene Expression Alterations in Coronary Artery Disease Patients

“…This mechanism could potentially provide a plausible rationale for the upregulated RCAN3 gene among smokers with CAD. Furthermore, TRAV4 , which encodes T-cell receptor alpha variable 4, and JCHAIN , which encodes Ig J Chain, have been reported to be related to adenocarcinoma [ 38 , 39 ]. However, no previous studies have examined their connection to CAD or smoking.…”