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Increased Nrf2 expression by renal cell carcinoma is associated with postoperative chronic kidney disease and an unfavorable prognosis.

ABSTRACT: Chronic kidney disease (CKD) is a worldwide health problem, and prevention of CKD is important for preservation of renal function after kidney surgery. There is evidence that transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has a vital antioxidant and detoxifying role in protecting the kidneys against various diseases. Impaired activation of Nrf2 is associated with oxidative stress related to CKD, and Nrf2 is also a key player in the development of cancer. However, the clinical impact of Nrf2 has not been investigated in patients with renal cell carcinoma (RCC). A retrospective study was performed in 89 patients undergoing nephrectomy for RCC. The estimated glomerular filtration rate (eGFR) and serum uric acid (SUA) were investigated over time after surgery. We investigated Nrf2 protein expression in all tumors and single nucleotide polymorphisms (SNPs) of the Nrf2 gene in 7 tumors. In patients whose tumors showed higher Nrf2 expression, there was a more rapid decrease of eGFR and increase of SUA after nephrectomy. Multivariate analysis confirmed that increased Nrf2 expression was an independent poor prognostic factor related to shorter overall survival. Among the 7 tumor samples, an SNP on exon 5 of the Nrf2 gene in one tumor and three genotypes (C/C, C/A, and A/A) of rs6721961 at the promoter region of the Nrf2 gene were observed. Although the mechanisms underlying the influence of Nrf2 are still unclear, our findings suggested that elevated tumor expression of Nrf2 was associated with postoperative CKD and biologically aggressive RCC with an unfavorable prognosis.

SUBMITTER: Yuki H

PROVIDER: S-EPMC6033338 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Increased Nrf2 expression by renal cell carcinoma is associated with postoperative chronic kidney disease and an unfavorable prognosis.

Yuki Hideo H Kamai Takao T Murakami Satoshi S Higashi Satoru S Narimatsu Takahiro T Kambara Tsunehito T Betsunoh Hironori H Abe Hideyuki H Arai Kyoko K Shirataki Hiromichi H Yoshida Ken-Ichiro KI

Oncotarget 20180619 47

Chronic kidney disease (CKD) is a worldwide health problem, and prevention of CKD is important for preservation of renal function after kidney surgery. There is evidence that transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has a vital antioxidant and detoxifying role in protecting the kidneys against various diseases. Impaired activation of Nrf2 is associated with oxidative stress related to CKD, and Nrf2 is also a key player in the development of cancer. However, the cli ...[more]

PMID: 29983865

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Project description:BackgroundKidney renal clear cell carcinoma (KIRC) is the most common pathological subtype of renal cell cancer. APOBEC3 activity has been identified in a variety of human cancers. Although its involvement in cancer has been studied widely, its influence on the tumor immune microenvironment remains poorly understood. Therefore, this study aimed to focus on the effect of APOBEC3 on tumor immune microenvironment of KIRC.MethodsIn this study, we comprehensively analyzed the expression and prognostic significance of the APOBEC3 family in pan-cancer using multiple databases. The functions of key APOBEC3 family members were further investigated in KIRC, with APOBEC3G determined to be a candidate biomarker for unfavorable prognosis. We subsequently explored the correlation of APOBEC3G with the tumor immune environment in KIRC by analyzing the Cancer Genome Atlas (TCGA) dataset, then validated the prognostic significance and PD-L1 correlation of APOBEC3G by using tissue microarrays which included 233 primary tumor samples from patients with renal clear cell carcinoma.ResultsThe APOBEC3 family was overexpressed in KIRC and high APOBEC3 expression predicted poor prognosis. In addition, APOBEC3G was positively correlated with the expression of immunoinhibitors such as TIGIT, LAG3, CD96, PD-1, and CTLA4. In addition, APOBEC3G had a positive correlation with immunosuppressive cells, including regulatory T cell and myeloid-derived suppressor cell. Finally, based on 233 clinical samples, we validated that high expression of APOBEC3G contributed to a poor prognosis for KIRC patients and the positive relationship between APOBEC3G and PD-L1 expression. High APOBEC3G expression was also found to be more common in patients with sarcomatoid histology (P = 0.0026).ConclusionsOur study showed that APOBEC3G was a prognostic biomarker correlated with the immune response in KIRC. In addition, APOBE3G had a positive correlation with PD-L1 expression and sarcomatoid histology, perhaps suggesting the potential impact of APOBEC3G on immunotherapy.

Project description:BackgroundRunt-related transcription factor 1 (RUNX1) was previously reported to play a dual role in promoting or suppressing tumorigenesis in various malignancies. A public dataset from The Cancer Genome Atlas (TCGA) was used to evaluate the role of RUNX1 in clear cell renal cell carcinoma (ccRCC).MethodsThe Wilcoxon signed-rank test was used to compare the expression of RUNX1 in ccRCC tissues and normal tissues. The Wilcoxon signed-rank test and logistic regression were utilized to investigate the relationship between clinicopathological factors and RUNX1 expression. Additionally, we analysed the differences in prognosis between patients with high and low expression of RUNX1 via the Kaplan-Meier method and Cox regression. Gene set enrichment analysis (GSEA) was performed to explore the mechanisms of RUNX1 in ccRCC.ResultsThe expression of RUNX1 in ccRCC tissues was significantly higher than that in normal tissues. High expression of RUNX1 was significantly associated with gender (p = 0.003), clinical stage (p < 0.001), tissue infiltration (p < 0.001), lymph node metastasis (p = 0.037) and histological grade (p < 0.001). Logistic regression analysis showed that high RUNX1 expression was significantly correlated with gender (OR = 1.71 for male vs. female, p = 0.004), histological grade (OR = 11.61 for grade IV vs. I, p < 0.001), clinical stage (OR = 1.55 for stage III/IV vs. I/II, p = 0.014) and tissue infiltration (OR = 1.54 for positive vs. negative, p = 0.018). Kaplan-Meier survival curves revealed that the prognosis of patients with ccRCC with high RUNX1 expression was worse than that of patients with ccRCC with low RUNX1 expression (p < 0.001). Univariate Cox regression analysis showed that high RUNX1 expression was strongly correlated with poor prognosis (HR = 1.60, 95% CI [1.31-1.97], p < 0.001). In addition, high expression of RUNX1 was an independent prognostic factor for poor overall survival (OS), with an HR of 1.50 (95% CI [1.20-1.87], p < 0.001) in multivariate Cox analysis. GSEA showed that the apoptosis, B cell receptor signalling pathway, calcium signalling pathway, chemokine signalling pathway, JAK/STAT signalling pathway, MAPK signalling pathway, p53 signalling pathway, pathways in cancer, T cell receptor signalling pathway, Toll-like receptor signalling pathway, VEGF signalling pathway, and Wnt signalling pathway were significantly enriched in the RUNX1 high-expression phenotype. In conclusion, RUNX1 can be used as a novel prognostic factor and therapeutic target in ccRCC.

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Increased Nrf2 expression by renal cell carcinoma is associated with postoperative chronic kidney disease and an unfavorable prognosis.

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Increased Nrf2 expression by renal cell carcinoma is associated with postoperative chronic kidney disease and an unfavorable prognosis.

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