RCC2 regulates the cell cycle and may be associated with EMT [9–10,25]. Its overexpression can lead to tumor formation and poor prognosis in various cancers [3,13]. In this study, R software and several gene-related analysis online-tools such as cBioPortal were employed to analyze over 10,000 samples based on TCGA, GTEx, and CPTAC cohorts across many cancer types. The data analyzed RCC2 genetic alteration, gene expression, prognosis, and immune infiltration. In addition, gene enrichment analysis was performed using the combined RCC2-interacted and RCC2-correlated genes, which could be helpful in exploring the possible mechanism between RCC2 expression and cancer formation.
RCC2 was overexpressed in most tumors including BRCA, ESCA, and LIHC, which correlated with previous studies [9,13,26]. However, RCC2 expression in normal tissues was higher than that in KICH and LAML tumorous tissues. Consequently, RCC2 might be a “double-edged sword” across all tumors because it may be an oncogene in most cancers, and a tumor suppressor gene in tumors such as KICH. Despite RCC2 was overexpressed in both lung cancer subtypes (LUAD and LUSC), it was linked to poor OS only in LUAD. This indicates that the prognostic ability of RCC2 may depend on the lung cancer subtype, or may also be present in other cancers. Further studies are required to confirm this hypothesis. OS was previously viewed as one of the best indices in cancer treatment as it might be used to evaluate treatment outcome, with DFS playing an important role in surgical treatment together with radiotherapy [20]. The present study indicated that RCC2 was positively associated with OS and DFS in some tumors such as ACC. Hence, RCC2 may be a promising biomarker for those tumors.
RCC2 was positively related to AUNIP, CCNF, MSH2, TIMELESS, and WDHD1 in most cancers. These five genes are linked to tumor formation, invasion, and DNA replication, with RCC2 and MSH2 previously regarded as molecular signatures for lung cancer malignancy [27–32]. In this work, RRP1B and SERBP1 oncogenes were obtained via intersection analysis of RCC2-interacted and RCC2-correlated genes. These oncogenes may be linked to EMT in some tumors [33–36]. This might reveal the potential mechanism by which RCC2 leads to cancer formation and metastasis. Our previous study showed that PTTG1 is associated with the cell cycle and could be linked to cancer formation via EMT [37]. RCC2 is a cell cycle regulator that promotes EMT in BRCA, LUAD and PAAD [9–10,38–39]. EMT appears in normal tissue during wound repair or fibrosis and might be associated with tumor formation or even cancer metastasis [40]. During EMT, normal epithelial cells invade and abandon polarity [39]. High RCC2 expression promoted cell proliferation, DNA replication, and mismatch repair. In addition, the GSEA demonstrated that high expression of RCC2 was associated with signature oncogenes, such as E2F, KRAS, and TBK1. The roles of E2F and KRAS in cancer have been extensively studied [40–41]. TBK1 was selectively essential in cells that harbor mutant KRAS [42]. Emerging evidence showed that TBK1 plays important role in the pathogenesis of cancer [43–44]. Thus, our findings suggested that RCC2 could be a novel oncogene in human cancer.
Immune infiltration plays a crucial role in anti-cancer therapy because it rebuilds the tumor microenvironment and regulates anti-cancer responses [45–46]. This study indicated that RCC2 was positively related to ImmuneScore, StromalScore, and ESTIMATEScore in KICH, KIRC, LGG, PAAD, and PCPG. Thus, RCC2 overexpression was associated with the high immune and stromal cell infiltration and low tumor purity in the tumor mass. RCC2 expression was negatively correlated with all the scores in tumors such as BLCA, ESCA, and GBM indicating that there was poor immune infiltration. Consequently, RCC2-targeted treatment should depend on the tumor types rather than “one for all” therapy. Further research is required into immune infiltration and the tumor microenvironment.
Insights into the immune checkpoint (ICP) in tumor treatment may lead to revolutionary outcomes [47–49]. Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and PD-1 are two of the best targets for tumor therapy [50–51]. Inhibitors of these two targets have achieved great success in tumor therapy [52–53]. This study showed that RCC2 expression was positively related to these two targets in many cancers, including STAD, PRAD, and BRCA, indicating that RCC2 could be a novel biomarker for PD-1 and CTLA-4 in those tumors. The latest findings show that TMB is a good biomarker for the assessment of the response to ICP inhibitor [54–55]. Thus, the relationship between RCC2 expression and MSI/TMB could be a potential biomarker for ICP inhibitors, such as PD-1 or CTLA-4. Consequently, the mixture of MSI and tumor microenvironment could be a new method for predicting the outcome of ICP inhibitor treatment for cancers [56–57]. In this study, RCC2 expression was positively associated with TMB/MSI in LUAD and SARC but negatively related to TMB/MSI in HNSC. Hence, RCC2 may be a good biomarker for ICP inhibitor treatment of these tumors.
This study presented the results of the systemic pan-cancer analysis of RCC2. It is the first analysis combining RCC2 expression, survival, gene enrichment, immune infiltration, ICP, and TMB/MSI analysis in human pan-cancer. This provides new insights into the possible mechanisms of RCC2 in cancer formation, invasion, and prognostic ability.
Pan-cancer analysis of RCC2 showed that its expression is associated with tumor formation, immune infiltration, and prognosis. RCC2 may be used as a novel biomarker for ICP inhibitors across multiple tumors. This data may be helpful in understanding the potential role of RCC2 in carcinogenesis and antitumor therapy.