Identification of C3 and FN1 as potential biomarkers associated with progression and prognosis for clear cell renal cell carcinoma

Abstract

Background Clear cell renal cell carcinoma (ccRCC) is one of the most lethal urological malignancies, but the pathogenesis and prognosis of ccRCC remain obscure, which need to be better understand. Methods Differentially expressed genes were identified and function enrichment analyses were performed using three publicly available ccRCC gene expression profiles downloaded from the Gene Expression Omnibus database. The protein-protein interaction and the competing endogenous RNA (ceRNA) networks were visualized by Cytoscape. Multivariate Cox analysis was used to predict an optimal risk mode, and the survival analysis was performed with the Kaplan-Meier curve and log-rank test. Protein expression data were downloaded from Clinical Proteomic Tumor Analysis Consortium database and Human Protein Atlas database, and the clinical information as well as the corresponding lncRNA and miRNA expression data were obtained via The Cancer Genome Atlas database. The co-expressed genes and potential function of candidate genes were explored using data exacted from the Cancer Cell Line Encyclopedia database. Results Of the 1044 differentially expressed genes shared across the three datasets, 461 were upregulated, and 583 were downregulated, which significantly enriched in multiple immunoregulatory-related biological process and tumor-associated pathways, such as HIF-1, PI3K-AKT, P53 and Rap1 signaling pathways. In the most significant module, 36 hub genes were identified and were predominantly enriched in inflammatory response and immune and biotic stimulus pathways. Survival analysis and validation of the hub genes at the mRNA and protein expression levels suggested that these genes, particularly complement component 3 (C3) and fibronectin 1 (FN1), were primarily responsible for ccRCC tumorigenesis and progression. Increased expression of C3 or FN1 was also associated with advanced clinical stage, high pathological grade, and poor survival in patients with ccRCC. Univariate and multivariate Cox regression analysis qualified the expression levels of the two genes as candidate biomarkers for predicting poor survival. FN1 was potentially regulated by miR-429, miR-216b and miR-217, and constructed a bridge to C3 and C3AR1 in the ceRNA network, indicating a critical position of FN1. Conclusions The biomarkers C3 and FN1 could provide theoretical support for the development of a novel prognostic tool to advance ccRCC diagnosis and targeted therapy.

Inside-Out of Complement in Cancer

“…Conversely, high CD59 expression is associated with better outcomes ( 29 , 80 , 122 ). Further support for the role of C3 in RCC comes from Dong and colleagues, who demonstrated that high mRNA and protein expression levels of C3 and fibronectin 1 (FN1) in cancer cells were primarily responsible for RCC tumorigenesis and progression ( 123 ). Furthermore, increased expression of C3 was also associated with the advanced clinical stage, high pathological grade, and poor survival.…”

New insights into fibrotic signaling in renal cell carcinoma

“…CAF-induced fibronectin promotes the proliferation and inhibits the apoptosis of precancerous bronchial epithelial and carcinoma cells through the activation of PI3K/AKT signaling in the lung . As for RCC patients, higher fibronectin 1 expression showed an increased disease-related mortality rate (Steffens et al, 2012) and a more advanced clinical stage (Dong et al, 2021). Competing endogenous RNA networks further proved the direct correlations between FN1 and C3, FN1 and pro-fibrotic signaling pathways, including WNT, HIF, PI3K/AKT, MAPK, and TGF-β pathways, in ccRCC (Dong et al, 2021).…”

“…As for RCC patients, higher fibronectin 1 expression showed an increased disease-related mortality rate (Steffens et al, 2012) and a more advanced clinical stage (Dong et al, 2021). Competing endogenous RNA networks further proved the direct correlations between FN1 and C3, FN1 and pro-fibrotic signaling pathways, including WNT, HIF, PI3K/AKT, MAPK, and TGF-β pathways, in ccRCC (Dong et al, 2021). The TGF-β1/Src axis is a well-studied pro-fibrotic signaling pathway that promotes renal fibrosis and tumor progression by promoting macrophage-tomyofibroblast transition (MMT) (Meng et al, 2016;Tang et al, 2018).…”

Characterization of myeloid signature genes for predicting prognosis and immune landscape in Ewing sarcoma

“…31 The aberrant expression of FN1 has been proven to be associated closely with the invasion and prognosis of a variety of solid tumors, including renal, gastric, and lung cancers. 32,33 FN1 upregulation was strongly associated with M2 macrophage polarization and might be implicated in the progression of HNSCC through the Akt and MAPK signaling pathways. 34 Besides, Zhang et al demonstrated that FN1 increased the sensitivity of OS cells to cisplatin to promote cell apoptosis.…”