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Clinical implication of Keap1 and phosphorylated Nrf2 expression in hepatocellular carcinoma.

ABSTRACT: In this paper, variation tendency of phosphorylated Nrf2, as the activated form of native Nrf2, was studied in 107 primary hepatocellular carcinoma (HCC) specimens treated by curative hepatectomy. Moreover, the coexpression of oxidative stress markers Keap1 and pNrf2, and their association with pathological features were also evaluated based on those specimens. The results showed that preserved cytoplasmic Keap1 expression of cancer cells was observed in 59 HCCs, while reduced Keap1 expression was determined in remaining 48 ones. With regarding to nuclear pNrf2 expression, 75 HCCs were defined as high and the other 32 ones as low. There was a significant association between Keap1 and pNrf2 expression in HCCs. Higher pNrf2 expression was observed, at a more substantial proportion, in those specimens with reduced Keap1 expression, compared to those with preserved Keap1 expression. The subset with higher pNrf2 and reduced Keap1 expression was defined as pNrf2⁺ Keap1^- . According to the analysis of prognosis, this subset was significantly associated with poor 5-year overall survival and worse disease-free survival in HCCs, indicating that pNrf2 and Keap1 were two-functional biomolecules, not only the oxidative stress markers but also biomarkers for prognosis of HCCs.

SUBMITTER: Chen J

PROVIDER: S-EPMC5083719 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Clinical implication of Keap1 and phosphorylated Nrf2 expression in hepatocellular carcinoma.

Chen Jiang J Yu Yaojun Y Ji Tong T Ma Rui R Chen Mingming M Li Gaofeng G Li Feibo F Ding Qiong Q Kang Qingsong Q Huang Diyu D Liang Xiao X Lin Hui H Cai Xiujun X

Cancer medicine 20160920 10

In this paper, variation tendency of phosphorylated Nrf2, as the activated form of native Nrf2, was studied in 107 primary hepatocellular carcinoma (HCC) specimens treated by curative hepatectomy. Moreover, the coexpression of oxidative stress markers Keap1 and pNrf2, and their association with pathological features were also evaluated based on those specimens. The results showed that preserved cytoplasmic Keap1 expression of cancer cells was observed in 59 HCCs, while reduced Keap1 expression w ...[more]

PMID: 27650414

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Project description:BackgroundGlutathione S-transferase zeta 1 (GSTZ1) is the penultimate enzyme in phenylalanine/tyrosine catabolism. GSTZ1 is dysregulated in cancers; however, its role in tumorigenesis and progression of hepatocellular carcinoma (HCC) is largely unknown. We aimed to assess the role of GSTZ1 in HCC and to reveal the underlying mechanisms, which may contribute to finding a potential therapeutic strategy against HCC.MethodsWe first analyzed GSTZ1 expression levels in paired human HCC and adjacent normal tissue specimens and the prognostic effect of GSTZ1 on HCC patients. Thereafter, we evaluated the role of GSTZ1 in aerobic glycolysis in HCC cells on the basis of the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Furthermore, we assessed the effect of GSTZ1 on HCC proliferation, glutathione (GSH) concentration, levels of reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (NRF2) signaling via gain- and loss- of GSTZ1 function in vitro. Moreover, we investigated the effect of GSTZ1 on diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) induced hepatocarcinogenesis in a mouse model of HCC.ResultsGSTZ1 was downregulated in HCC, thus indicating a poor prognosis. GSTZ1 deficiency significantly promoted hepatoma cell proliferation and aerobic glycolysis in HCC cells. Moreover, loss of GSTZ1 function depleted GSH, increased ROS levels, and enhanced lipid peroxidation, thus activating the NRF2-mediated antioxidant pathway. Furthermore, Gstz1 knockout in mice promoted DEN/CCl4-induced hepatocarcinogenesis via activation of the NRF2 signaling pathway. Furthermore, the antioxidant agent N-acetylcysteine and NRF2 inhibitor brusatol effectively suppressed the growth of Gstz1-knockout HepG2 cells and HCC progression in Gstz1-/- mice.ConclusionsGSTZ1 serves as a tumor suppressor in HCC. GSH depletion caused by GSTZ1 deficiency elevates oxidative stress, thus constitutively activating the NRF2 antioxidant response pathway and accelerating HCC progression. Targeting the NRF2 signaling pathway may be a promising therapeutic approach for this subset of HCC.

Project description:BackgroundNucleolar protein 16 (NOP16) is present in the protein complex of the nucleolus. The NOP16 promoter contains a c-Myc binding site, and the transcriptional regulation by c-Myc directly regulates NOP16 expression levels.ObjectiveDysregulation of NOP 16 is currently reported in only a small number of cancers. In this study, the expression profile of NOP 16 in hepatocellular carcinoma (LIHC) and its clinical significance were analyzed.MethodsNOP16 expression in hepatocellular carcinoma (LIHC) and its relationship with the clinical characters of LIHC were examined using the Cancer Genome Atlas (TCGA), the Gene Expression comprehensive database (GEO), Kaplan-Meier survival analysis, univariate Cox analysis, multivariate Cox analysis, ROC curve analysis of KEGG enrichment, GSEA enrichment, in vitro experiments (e.g., siRNA interference of NOP16 expression in hepatoma cells, Keap1-Nrf2 pathway, cell cycle, cell apoptosis and Transwell assays), and LIHC single-cell sequencing (scRNA).ResultsPan-cancer analysis revealed that NOP16 was highly expressed in 20 cancer types, including LIHC, and high NOP16 expression was an independent adverse prognostic factor in LIHC patients. The expression levels of NOP16 mRNA and protein were significantly increased in tumour tissues of LIHC patients compared to normal tissues. The functions of co-expressed genes were primarily enriched in the cell cycle and reactive oxygen species metabolism. The experimental results showed that knockdown of NOP16 activated the Keap/Nrf2 signalling pathway and inhibited the invasion, migration, and EMT progression of LIHC cells. LIHC scRNA-seq data showed that NOP16 was primarily expressed in T lymphocytes.ConclusionsNOP16 promoted cancer development in LIHC and caused an imbalance in Keap/Nrf2 signalling, which subsequently caused the aberrant expression of genes typical for EMT, cell cycle progression and apoptosis. NOP16 is a potential prognostic marker and therapeutic target for hepatocellular carcinoma progression.

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Clinical implication of Keap1 and phosphorylated Nrf2 expression in hepatocellular carcinoma.

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Clinical implication of Keap1 and phosphorylated Nrf2 expression in hepatocellular carcinoma.

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