Expression of RSUME is Associated With Poor Prognosis in Clear Cell Renal Carcinoma: Involvement of ROS Related Metabolism

• Published in: Clinical genitourinary cancer 2023-06, Vol.21 (3), p.393-402.e5
• Main Authors: Gonilski-Pacin, David, Ciancio del Giudice, Nicolas, Elguero, Belen, Arzt, Eduardo
• Format: Article
• Language: English
• Subjects: Carcinoma, Renal Cell - pathology; ccRCC; Clinical prognosis; Humans; Kidney Neoplasms - pathology; Prognosis; Reactive Oxygen Species; RWDD3; TCGA; Transcription Factors - genetics; Transcription Factors - metabolism; VHL; von Hippel-Lindau Disease
• ISSN: 1558-7673; 1938-0682
• DOI: 10.1016/j.clgc.2023.03.008

RSUME (RWD domain-containing protein SUMO Enhancer), RWD domain containing 3 (RWDD3) gene product, is upregulated by hypoxia and expressed in organs prone to develop von Hippel-Lindau (VHL) syndrome tumors. We evaluated RSUME prognostic value in clear cell renal cell carcinoma (ccRCC) based mainly on the dataset (KIRC) from patients in The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test and one-way analysis of variance (ANOVA) followed by Tukey's test were used to evaluate relationships between clinicopathological features and RSUME expression and univariate and multivariate Cox regression analysis methods were used to evaluate prognostic factors. The biological function of RSUME was assessed by gene set enrichment analysis (GSEA). For validation, total amount of ROS was detected in ccRCC cell lines using dichlorofluorescin diacetate. RSUME is highly expressed in tumor tissues compared with normal tissues (P = .006, P = .039, P = .002, P = .036, P < .001) and associates with tumor T (P = .018) and tumor M (P = .036) advanced stages and higher extent cysts (P = .005). RSUME expression appears to be an independent risk factor for overall survival (OS) (P = .002) and disease-specific survival (DSS) (P = .026) in ccRCC patients. GSEA showed enrichment of relevant glycerophospholipid- and ROS-related pathways in RSUME high-expression phenotype. ROS diminished levels in RSUME-silenced ccRCC cell lines validated RSUME relevance in ROS-related pathways. RSUME high expression may predict poor prognosis in ccRCC and impact through its action on metabolism and ROS related pathways. RSUME-RWDD3 gene has been shown to be involved in tumorigenesis and angiogenesis by its negative regulation of the von Hippel-Lindau (VHL) protein. Using different clear cell renal cell carcinoma (ccRCC) patient datasets, including TCGA-KIRC, the present study explores RSUME expression as an independent and adverse factor in ccRCC acting on metabolic and ROS pathways.