A novel oxidative stress-related genes signature associated with clinical prognosis and immunotherapy responses in clear cell renal cell carcinoma

Abstract

BackgroundOxidative stress plays a significant role in the tumorigenesis and progression of tumors. We aimed to develop a prognostic signature using oxidative stress-related genes (ORGs) to predict clinical outcome and provide light on the immunotherapy responses of clear cell renal cell carcinoma (ccRCC).MethodsThe information of ccRCC patients were collected from the TCGA and the E-MTAB-1980 datasets. Univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) were conducted to screen out overall survival (OS)-related genes. Then, an ORGs risk signature was built by multivariate Cox regression analyses. The performance of the risk signature was evaluated with Kaplan-Meier (K-M) survival. The ssGSEA and CIBERSORT algorithms were performed to evaluate immune infiltration status. Finally, immunotherapy responses was analyzed based on expression of several immune checkpoints.ResultsA prognostic 9-gene signature with ABCB1, AGER, E2F1, FOXM1, HADH, ISG15, KCNMA1, PLG, and TEK. The patients in the high risk group had apparently poor survival (TCGA: p < 0.001; E-MTAB-1980: p < 0.001). The AUC of the signature was 0.81 at 1 year, 0.76 at 3 years, and 0.78 at 5 years in the TCGA, respectively, and was 0.8 at 1 year, 0.82 at 3 years, and 0.83 at 5 years in the E-MTAB-1980, respectively. Independent prognostic analysis proved the stable clinical prognostic value of the signature (TCGA cohort: HR = 1.188, 95% CI =1.142-1.236, p < 0.001; E-MTAB-1980 cohort: HR =1.877, 95% CI= 1.377-2.588, p < 0.001). Clinical features correlation analysis proved that patients in the high risk group were more likely to have a larger range of clinical tumor progression. The ssGSEA and CIBERSORT analysis indicated that immune infiltration status were significantly different between two risk groups. Finally, we found that patients in the high risk group tended to respond more actively to immunotherapy.ConclusionWe developed a robust prognostic signature based on ORGs, which may contribute to predict survival and guide personalize immunotherapy of individuals with ccRCC.

ISG15 promotes tumor progression via IL6/JAK2/STAT3 signaling pathway in ccRCC

“…Furthermore, the biological activity of ISG15 has been found to vary across different cancer types [ 29 – 34 ]. Moreover, recent studies indicate that ISG15 may serve as a potential prognostic factor for adverse outcomes in individuals with ccRCC [ 35 , 36 ]. Consequently, it is crucial to investigate the precise biological role of ISG15 in ccRCC.…”

The Cellular Stress and Cutaneous Manifestations in Renal Cell Carcinomas—A Narrative Review

“…An increase in ROS results in the activation of the NLRP3 inflammasome and the release of pro-inflammatory cytokines, which suppress immune surveillance, allowing tumor progression. Persistent stress increases susceptibility to cancer and enhances RCC's capacity to develop secondary manifestations through a variety of mechanisms: tumor signaling, TME reorganization, immune evasion, invasion and metastasis, DNA mutations, angiogenesis, treatment response, and induction of cellular ferroptosis/apoptosis [13,[25][26][27]. Potential inducers of cellular stress from within and outside cells are excessive amounts of oxidants [15].…”

“…For instance, activating transcription factor 3 (ATF3 were correlated with RCC progression [28], genes ABCB1, AGER, E2F1, FOXM1, HADH ISG15, KCNMA1, PLG, and TEK were correlated with the clinical outcome and immune status of ccRCC patients [27], genes UCN, PLG, FOXM1, and HRH2 were associated with the ccRCC prognosis [29], long non-coding RNAs (lncRNA) SPART-AS1, AL162586.1 Based on bioinformatic analysis, several current studies have identified sets of genes related to oxidative stress (ORG). For instance, activating transcription factor 3 (ATF3) were correlated with RCC progression [28], genes ABCB1, AGER, E2F1, FOXM1, HADH, ISG15, KCNMA1, PLG, and TEK were correlated with the clinical outcome and immune status of ccRCC patients [27], genes UCN, PLG, FOXM1, and HRH2 were associated with the ccRCC prognosis [29], long non-coding RNAs (lncRNA) SPART-AS1, AL162586.1, LINC00944, LINC01550, HOXB-AS4, LINC02027, and DOCK9-DT were associated with ccRCC aggressiveness [30,31], mitochondrial genes ACAD11, ACADSB, BID, PYCR1, SLC25A27, and STAR were linked to the ccRCC prognosis [12], and genes ADAM8, CGN, EIF4EBP1, FOXM1, G6PC, HAMP, HTR2C, ITIH4, LTB4R, MMP3, PLG, PRKCG, SAA1, and VWF, and microRNAs related to the redox status and ccRCC progression [12], were found to be essential for the response to oxidative stress. Recently, a transcription factor for the oxidative stress response, broad complex-tramtrack-bric-a-brac and cap 'n' collar homology 1 (BACH1), has been labeled an essential factor involved in RCC progression in vivo [32].…”

“…A recently detected set of genes associated with cellular metabolism has been identified as involved in ccRCC distant metastasis [2,26]. Metabolic alterations (hyperglycemia, hyperlipidemia), anomalies in calcium-dependent signaling, mutational changes, ROSinduced damage, heat shock, and exposure to toxins/medications [14,26,27] can lead to the activation of cellular stress, called the unfolded protein response [14].…”