Gene Summary

Gene:NFE2L2; nuclear factor, erythroid 2 like 2
Aliases: NRF2, HEBP1, IMDDHH
Summary:This gene encodes a transcription factor which is a member of a small family of basic leucine zipper (bZIP) proteins. The encoded transcription factor regulates genes which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to injury and inflammation which includes the production of free radicals. Multiple transcript variants encoding different isoforms have been characterized for this gene. [provided by RefSeq, Sep 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:nuclear factor erythroid 2-related factor 2
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NFE2L2 (cancer-related)

Oronsky B, Scribner C, Aggarwal R, Cabrales P
RRx-001 protects normal tissues but not tumors via Nrf2 induction and Bcl-2 inhibition.
J Cancer Res Clin Oncol. 2019; 145(8):2045-2050 [PubMed] Related Publications
BACKGROUND: RRx-001, a minimally toxic next-generation checkpoint inhibitor that targets myeloid suppressor cells in the tumor microenvironment, has also been shown to protect normal tissues from the cytotoxic effects of chemotherapy and radiation. The following experiments were carried out to determine whether the cytoprotective functions of RRx-001 in normal cells were operative in tumor cells.
DESIGN: The effects of RRx-001 on normal cells, and ovarian cancer A2780 and UWB1 cells were evaluated with a colony-forming assay. Western blot densitometry was used to measure Nrf2 nuclear translocation in Caco2 cells after exposure to RRx-001. Following incubation with RRx-001, levels of the antioxidant, NQO1, were determined in Caco2 cells by measuring absorbance over 300 min at 440 nm. RRx-001-mediated cytotoxicity in HCT-116 colorectal cancer cells was evaluated with an MTT assay. In addition, the effect of RRx-001 incubation on the protein expression of Nrf2, PARP, cleaved PARP, procaspases 3, 8, and 9, Bcl-2, and Bax in HCT-116 colorectal cells was determined by western blot analysis.
RESULTS: RRx-001 is demonstrated to induce Nrf2 in normal tissues, mediating protection, and to downregulate the Nrf2-controlled antiapoptotic target gene, B-cell lymphoma 2 (Bcl-2) in tumors, mediating cytotoxicity.
CONCLUSION: Through Nrf2 induction in normal cells and inhibition of Bcl-2 in tumor cells, RRx-001 selectively protects normal cells against lethality in normal cells, but induces apoptosis in tumor cells.

Sprouse ML, Welte T, Boral D, et al.
PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Intratumoral infiltration of myeloid-derived suppressor cells (MDSCs) is known to promote neoplastic growth by inhibiting the tumoricidal activity of T cells. However, direct interactions between patient-derived MDSCs and circulating tumors cells (CTCs) within the microenvironment of blood remain unexplored. Dissecting interplays between CTCs and circulatory MDSCs by heterotypic CTC/MDSC clustering is critical as a key mechanism to promote CTC survival and sustain the metastatic process. We characterized CTCs and polymorphonuclear-MDSCs (PMN-MDSCs) isolated in parallel from peripheral blood of metastatic melanoma and breast cancer patients by multi-parametric flow cytometry. Transplantation of both cell populations in the systemic circulation of mice revealed significantly enhanced dissemination and metastasis in mice co-injected with CTCs and PMN-MDSCs compared to mice injected with CTCs or MDSCs alone. Notably, CTC/PMN-MDSC clusters were detected in vitro and in vivo either in patients' blood or by longitudinal monitoring of blood from animals. This was coupled with in vitro co-culturing of cell populations, demonstrating that CTCs formed physical clusters with PMN-MDSCs; and induced their pro-tumorigenic differentiation through paracrine Nodal signaling, augmenting the production of reactive oxygen species (ROS) by PMN-MDSCs. These findings were validated by detecting significantly higher Nodal and ROS levels in blood of cancer patients in the presence of naïve, heterotypic CTC/PMN-MDSC clusters. Augmented PMN-MDSC ROS upregulated Notch1 receptor expression in CTCs through the ROS-NRF2-ARE axis, thus priming CTCs to respond to ligand-mediated (Jagged1) Notch activation. Jagged1-expressing PMN-MDSCs contributed to enhanced Notch activation in CTCs by engagement of Notch1 receptor. The reciprocity of CTC/PMN-MDSC bi-directional paracrine interactions and signaling was functionally validated in inhibitor-based analyses, demonstrating that combined Nodal and ROS inhibition abrogated CTC/PMN-MDSC interactions and led to a reduction of CTC survival and proliferation. This study provides seminal evidence showing that PMN-MDSCs, additive to their immuno-suppressive roles, directly interact with CTCs and promote their dissemination and metastatic potency. Targeting CTC/PMN-MDSC heterotypic clusters and associated crosstalks can therefore represent a novel therapeutic avenue for limiting hematogenous spread of metastatic disease.

Yang W, Liu H, Duan B, et al.
Three novel genetic variants in NRF2 signaling pathway genes are associated with pancreatic cancer risk.
Cancer Sci. 2019; 110(6):2022-2032 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer (PanC) is one of the most lethal solid malignancies, and metastatic PanC is often present at the time of diagnosis. Although several high- and low-penetrance genes have been implicated in PanC, their roles in carcinogenesis remain only partially elucidated. Because the nuclear factor erythroid2-related factor2 (NRF2) signaling pathway is involved in human cancers, we hypothesize that genetic variants in NRF2 pathway genes are associated with PanC risk. To test this hypothesis, we assessed associations between 31 583 common single nucleotide polymorphisms (SNP) in 164 NRF2-related genes and PanC risk using three published genome-wide association study (GWAS) datasets, which included 8474 cases and 6944 controls of European descent. We also carried out expression quantitative trait loci (eQTL) analysis to assess the genotype-phenotype correlation of the identified significant SNP using publicly available data in the 1000 Genomes Project. We found that three novel SNP (ie, rs3124761, rs17458086 and rs1630747) were significantly associated with PanC risk (P = 5.17 × 10

Jin M, Wang J, Ji X, et al.
MCUR1 facilitates epithelial-mesenchymal transition and metastasis via the mitochondrial calcium dependent ROS/Nrf2/Notch pathway in hepatocellular carcinoma.
J Exp Clin Cancer Res. 2019; 38(1):136 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mitochondrial Ca
METHODS: The effect of MCUR1 expression on epithelial-mesenchymal transition (EMT) in HCC cells was first evaluated by immunofluorescent staining and Western blot. Then, in vitro invasion and in vivo metastasis assays were used to evaluate the function of MCUR1 in HCC metastasis. The underlying mechanism has also been explored by investigating the effect of MCUR1 on ROS/Nrf2/Notch1 pathway.
RESULTS: MCUR1 expression was significantly higher in HCC with metastasis and associated with tumor progression. MCUR1 promoted in vitro invasion and in vivo metastasis of HCC cells by promoting EMT via Snail. Mechanistically, MCUR1-mediated mitochondrial Ca
CONCLUSIONS: Our study provides evidence supporting a metastasis-promoting role for MCUR1-dependent mitochondrial Ca

Huang H, Wu Y, Fu W, et al.
Downregulation of Keap1 contributes to poor prognosis and Axitinib resistance of renal cell carcinoma via upregulation of Nrf2 expression.
Int J Mol Med. 2019; 43(5):2044-2054 [PubMed] Free Access to Full Article Related Publications
Kelch‑like ECH‑associated protein 1 (Keap1)/nuclear factor erythroid 2‑related factor 2 (Nrf2) signaling has a protective effect on normal cells. A number of previous studies demonstrated that Keap1/Nrf2 signaling is associated with drug resistance in numerous tumors. The aim of the present study was to investigate the roles of Keap1 in renal cell carcinoma (RCC) and its effect on sensitivity to chemotherapy. Reverse transcription‑quantitative polymerase chain reaction was used to detect the mRNA expression of Keap1 in 45 cases of RCC tumors and adjacent normal tissues. A total of five randomly selected patients with RCC, five RCC cell lines and normal renal tubular cells were examined to detect the protein and mRNA expressions of Keap1. The 5‑year survival rate was analyzed by Kaplan‑Meier analysis. The cell viability was assessed by a Cell Counting kit‑8 assay. The cell apoptosis and reactive oxygen species (ROS) were determined by flow cytometry. The expressions of associated proteins were determined by western blot analysis. It was identified that in RCC tissues and RCC cell lines, the expression of Keap1 was downregulated, which was considered to be associated with poor prognosis. In total, 1 µM Axitinib significantly decreased cell viability, promoted ROS release and induced cell apoptosis in ACHN cells. Silencing Keap1 was able to reverse the inhibitory effect of Axitinib and enhance the protein expressions of Nrf2, NAD(P)H dehydrogenase [quinone] 1 and heme oxygenase 1. However, silencing Nrf2 increased the cell sensitivity to Axitinib. Under Axitinib condition, overexpressing Nrf2 was able to increase cell viability; however, overexpressing Keap1 resulted in an opposite effect. Keap1 serves as a tumor suppressor; its low expression was associated with poor prognosis and a decreased sensitivity of RCC cells to Axitinib. A possible mechanism underlying Axitinib resistance may involve Nrf2 overexpression.

Park SY, Lee SJ, Han JH, Koh YW
Association between 18F-FDG uptake in PET/CT, Nrf2, and NQO1 expression and their prognostic significance in non-small cell lung cancer.
Neoplasma. 2019; 2019:619-626 [PubMed] Related Publications
Two pentose phosphate pathway-related proteins, NF-E2-related factor 2 (Nrf2)/ NAD(P)H dehydrogenase (Quinone) 1 (NQO1) regulate the expression of glucose metabolism and antioxidant genes. We evaluated the prognostic significance of NRF2, NQO1 and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) parameter and their relationship with non-small cell lung cancer (NSCLC) histology. A total of 241 patients, who underwent surgical resection for NSCLC, were reviewed retrospectively. Preoperative 18F-FDG PET and immunohistochemical results of Nrf2 and NQO1 were evaluated. In SQCC, the maximum standardized uptake value (SUVmax) was significantly higher in NQO1-high than in NQO1-low expression (p=0.023). In adenocarcinoma, SUVmax was not correlated with NQO1 expression. Patients with a high NQO1 expression showed poor recurrence-free survival (RFS) and overall survival (OS) than patients with a low NQO1 expression in squamous cell carcinoma (SQCC) (p=0.002 and p=0.014, respectively). NQO1 expression was not associated with clinical outcome in adenocarcinoma. Nrf2 expression was not correlated with prognosis in two types of NSCLC. High SUVmax was associated with poor RFS (p=0.03) but is not related to poor OS (p=0.569) in SQCC. In multivariate analyses, NQO1 expression and SUVmax were not independent prognostic factors in SQCC. However, in multivariate analysis combining NQO1 and SUVmax values, both low SUVmax and low NQO1 was independent prognostic factor for RFS and OS (HR= 3.790, p = 0.033 and HR= 2.961, p = 0.045, respectively). In conclusion, both low SUVmax and low NQO1 was an independent prognostic factor in SQCC alone. The sample size was small but there was a positive correlation between NQO1 expression and SUVmax in SQCC.

Zhang B, Wu J, Cai Y, et al.
TCF7L1 indicates prognosis and promotes proliferation through activation of Keap1/NRF2 in gastric cancer.
Acta Biochim Biophys Sin (Shanghai). 2019; 51(4):375-385 [PubMed] Free Access to Full Article Related Publications
Gastric cancer is one of the most common cancers worldwide and is the third leading cause of cancer-related deaths globally. Although significant progress has been made in the diagnosis and treatment for the cancer, less improvement has been made in overall survival rate. Thus, there is an urgent need for a better understanding of the biological aspects of the cancer. The transcription factor transcription factor 7-like 1 (TCF7L1) is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in gastric cancer has seldom been discussed. In the present study, by using the Cancer Genome Atlas dataset analysis, we demonstrated that patients with higher expression of TCF7L1 could be used to reflect prognosis. An examination of the mechanisms demonstrated that TCF7L1 could positively regulate antioxidant response in gastric cancer cells by positively regulating Keap1/NRF2 [Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2] pathway. Collectively, our data demonstrated that TCF7L1 is a novel marker for predicting overall survival of gastric cancer and provided the possible underlying molecular mechanism.

Shao S, Duan W, Xu Q, et al.
Curcumin Suppresses Hepatic Stellate Cell-Induced Hepatocarcinoma Angiogenesis and Invasion through Downregulating CTGF.
Oxid Med Cell Longev. 2019; 2019:8148510 [PubMed] Free Access to Full Article Related Publications
Microenvironment plays a vital role in tumor progression; we focused on elucidating the role of hepatic stellate cells (HSCs) in hepatocarcinoma (HCC) aggressiveness and investigated the potential protective effect of curcumin on HSC-driven hepatocarcinoma angiogenesis and invasion. Our data suggest that HSCs increase HCC reactive oxygen species (ROS) production to upregulate hypoxia-inducible factor-1

Zhang J, Yang S, Xu B, et al.
p62 functions as an oncogene in colorectal cancer through inhibiting apoptosis and promoting cell proliferation by interacting with the vitamin D receptor.
Cell Prolif. 2019; 52(3):e12585 [PubMed] Related Publications
OBJECTIVES: The role of p62 in cancer is controversial. Evidence has shown that p62 is upregulated in different cancers and promotes tumour growth, such as in liver cancer and lung cancer. However, a recent study showed that the downregulation of p62 in hepatic stellate cells (HSCs) promotes hepatocellular carcinoma (HCC) development. How p62 is regulated in colorectal cancer (CRC) remains largely unknown. In this study, we aimed to investigate the roles and molecular mechanisms of p62 in CRC.
MATERIALS AND METHODS: The expression levels of p62 in CRC tissues and adjacent non-tumour tissues were determined by immunohistochemistry (IHC). Stable p62-overexpression HCT116 cells and p62-knockdown SW480 cells were established with lentiviral vectors. The role of p62 in CRC was investigated in in vitro and in vivo functional studies. The relationship between p62 and the vitamin D receptor (VDR) was investigated by coimmunoprecipitation (Co-IP) assays.
RESULTS: p62 was significantly upregulated in CRC, and a high p62 level was an independent risk factor for a poor prognosis in CRC patients. p62 promoted CRC migration and invasion by inhibiting apoptosis and promoting cell proliferation in vitro, and p62 aggravated tumour growth and metastasis in vivo. Co-IP assays indicated that p62 interacts with the VDR and may target the NRF2-NQO1 axis.
CONCLUSIONS: Our study suggested that p62 functions as an oncogene in CRC through inhibiting apoptosis and promoting cell proliferation by interacting with the VDR.

Al-Gayyar MMH, Bagalagel A, Noor AO, et al.
The therapeutic effects of nicotinamide in hepatocellular carcinoma through blocking IGF-1 and effecting the balance between Nrf2 and PKB.
Biomed Pharmacother. 2019; 112:108653 [PubMed] Related Publications
Insulin growth factor (IGF) family and their receptors play a great role in tumors' development. In addition, IGF-1 enhances cancer progression through regulating cell proliferation, angiogenesis, immune modulation and metastasis. Moreover, nicotinamide is association with protection against cancer. Therefore, we conducted this research to examine the therapeutic effects of nicotinamide against hepatocellular carcinoma (HCC) both in vivo and in vitro through affecting IGF-1 and the balance between PKB and Nrf2. HCC was induced in rats by 200 mg/kg, ip thioacetamide. The rat survival, number and size of tumors and serum α-fetoprotein (AFP) were measured. The gene and protein levels of IGF-1, Nrf2, PKB and JNK-MAPK were assessed in rat livers. In addition, HepG2 cells, human HCC cell lines, were treated with different concentrations of nicotinamide. We found that nicotinamide enhanced the rats' survival and reduced the number and size of hepatic tumors as well as it reduced serum AFP and HepG2 cells survival. Nicotinamide ameliorated HCC-induced reduction in the expression of Nrf2. Moreover, nicotinamide blocked HCC-induced elevation in IGF-1, PKB and JNK-MAPK. In conclusion, nicotinamide produced cytotoxic effects against HCC both in vivo and in vitro. The cytotoxic activity can be explained by inhibition of HCC-induced increased in the expression of IGF-1 and leads to disturbances in the balance between the cell death signal by PKB and MAPK; and the cell survival signal by Nrf2, directing it towards cell survival signals in normal liver cells providing more protection for body against tumor.

Cheng LC, Lin CJ, Liu HJ, Li LA
Health risk of metal exposure via inhalation of cigarette sidestream smoke particulate matter.
Environ Sci Pollut Res Int. 2019; 26(11):10835-10845 [PubMed] Related Publications
Cigarette sidestream smoke particulate matter (CSSP) is a major source of airborne metals in the indoor environment. However, the health impacts of inhalation of CSSP-bound metals are rarely studied. In this study, we quantify the amount of 37 metals discharged through CSSP from a leading Taiwan brand of cigarette, Long Life. We also estimate cancer and non-cancer risks due to inhalation of these metals and investigate possible modes of toxic action. Long Life CSSP exhibits a distinctive carcinogenic metal profile compared with Western brands. When released to a 60-m

Zhang L, Guo Y, Wang H, et al.
Edaravone reduces Aβ-induced oxidative damage in SH-SY5Y cells by activating the Nrf2/ARE signaling pathway.
Life Sci. 2019; 221:259-266 [PubMed] Related Publications
AIMS: Edaravone potentially alleviates cognitive deficits in a mouse model of Alzheimer's disease (AD). However, the mechanism of edaravone in suppressing AD progression remains unclear. We aim to investigate the mechanism of edaravone in suppressing oxidative stress-mediated AD progression in vitro.
MAIN METHODS: Human neuroblastoma SH-SY5Y cells were pretreated with different concentrations of edaravone prior to the induction by Aβ
KEY FINDINGS: The results showed that apoptosis and reactive oxygen species levels significantly increased in Aβ
SIGNIFICANCE: Activation of the Nrf2/ARE signaling pathway may underlie the protective effects of edaravone against the oxidative damage associated with Alzheimer's disease.

Tsai YS, Jou YC, Tsai HT, et al.
Prothymosin-α enhances phosphatase and tensin homolog expression and binds with tripartite motif-containing protein 21 to regulate Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 signaling in human bladder cancer.
Cancer Sci. 2019; 110(4):1208-1219 [PubMed] Free Access to Full Article Related Publications
Prothymosin-α (PTMA) is a small, acidic protein that is usually transported into the nucleus and involves many cellular and immunological functions. Previous studies demonstrated that aberrant location of PTMA expression exists in human bladder cancer, but the role of PTMA protein expression remains elusive. In this study, we created ectopic nuclear or cytoplasmic PTMA expression in human bladder cancer cells by infecting lentiviruses carrying wild type or deleted nuclear localization signal of the PTMA gene. The in vivo tumorigenesis assay showed PTMA protein with deleted nuclear localization signal promotes J82 xenograft tumor growth in mice and shortens their survival more so than the wild type. Chromatin immunoprecipitation showed that wild-type PTMA protein binds to the PTEN promoter and enhances phosphatase and tensin homolog (PTEN) expression. Through immunoblot proteomics and in vivo ubiquitination studies, PTMA protein can bind with tripartite motif-containing protein 21 (TRIM21) and block its ubiquitination. Also, TRIM21 can downregulate both forms of PTMA protein. In human bladder tumors, loss of nuclear PTMA expression was an unfavorable prognostic indicator for shorter disease-free survival (hazard ratio, 1.54; P = 0.009). Our data support that nuclear PTMA protein serves as a tumor suppressor in bladder cancer through upregulating PTEN and orchestrating TRIM21 for the regulation of Nrf2 signaling.

Quaas A, Heydt C, Waldschmidt D, et al.
Alterations in ERBB2 and BRCA and microsatellite instability as new personalized treatment options in small bowel carcinoma.
BMC Gastroenterol. 2019; 19(1):21 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma.
METHODS: We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2).
RESULTS: In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations - one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions.
CONCLUSION: Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.

Li O, Ma Q, Li F, et al.
Progress of small ubiquitin-related modifiers in kidney diseases.
Chin Med J (Engl). 2019; 132(4):466-473 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Small ubiquitin-related modifiers (SUMOs) are a group of post-translational modification proteins extensively expressed in eukaryotes. Abnormal SUMOylation can lead to the development of various diseases. This article summarizes the progress on research of the role of SUMOs in various types of kidney diseases to further increase the understanding of the regulatory functions of SUMOylation in the pathogenesis of kidney diseases.
DATA SOURCES: This review was based on articles published in the PubMed databases up to January 2018, using the keywords including "SUMOs," "SUMOylation," and "kidney diseases."
STUDY SELECTION: Original articles and critical reviews about SUMOs and kidney disease were selected for this review. A total of 50 studies were in English.
RESULTS: SUMO participates in the activation of NF-κB inflammatory signaling pathway, playing a central regulatory role in the inflammation and progression of DN, and the secretion of various chemokines in AKI. SUMO involves in the regulation of TG2 and Nrf2 antioxidant stress, affecting renal tubular injury in AKI. SUMO affects the MAPK/ERK pathway, regulating intracellular signal transduction, modulating the transcription and expression of effector molecules in DN. SUMO contributes to the TGF-β/Smad pathway, leading to fibrosis of the kidney. The conjugate combination of SUMO and p53 regulates cell proliferation and apoptosis, and participates in the regulation of tumorigenesis. In addition, SUMOylation of MITF modulates renal tumors secondary to melanoma, Similarly, SUMOylation of tumor suppressor gene VHL regulates the occurrence of renal cell carcinoma in VHL syndrome.
CONCLUSIONS: Tissue injury, inflammatory responses, fibrosis, apoptosis, and tumor proliferation in kidney diseases all involve SUMOs. Further research of the substrate SUMOylation and regulatory mechanisms of SUMO in kidney diseases will improve and develop new treatment measures and strategies targeting kidney diseases.

Marampon F, Codenotti S, Megiorni F, et al.
NRF2 orchestrates the redox regulation induced by radiation therapy, sustaining embryonal and alveolar rhabdomyosarcoma cells radioresistance.
J Cancer Res Clin Oncol. 2019; 145(4):881-893 [PubMed] Related Publications
PURPOSE: Tumor cells generally exhibit higher levels of reactive oxygen species (ROS), however, when stressed, tumor cells can undergo a process of 'Redox Resetting' to acquire a new redox balance with stronger antioxidant systems that enable cancer cells to become resistant to radiation therapy (RT). Here, we describe how RT affects the oxidant/antioxidant balance in human embryonal (RD) and alveolar (RH30) rhabdomyosarcoma (RMS) cell lines, investigating on the molecular mechanisms involved.
METHODS: Radiations were delivered using an x-6 MV photon linear accelerator and their effects were assessed by vitality and clonogenic assays. The expression of specific antioxidant-enzymes, such as Superoxide Dismutases (SODs), Catalase (CAT) and Glutathione Peroxidases 4 (GPx4), miRNAs (miR-22, -126, -210, -375, -146a, -34a) and the transcription factor NRF2 was analyzed by quantitative polymerase chain reaction (q-PCR) and western blotting. RNA interference experiments were performed to evaluate the role of NRF2.
RESULTS: Doses of RT higher than 2 Gy significantly affected RMS clonogenic ability by increasing ROS production. RMS rapidly and efficiently brought back ROS levels by up-regulating the gene expression of antioxidant enzymes, miRNAs as well as of NRF2. Silencing of NRF2 restrained the RMS ability to counteract RT-induced ROS accumulation, antioxidant enzyme and miRNA expression and was able to increase the abundance of γ-H2AX, a biomarker of DNA damage, in RT-treated cells.
CONCLUSIONS: Taken together, our data suggest the strategic role of oxidant/antioxidant balance in restraining the therapeutic efficiency of RT in RMS treatment and identify NRF2 as a new potential molecular target whose inhibition might represent a novel radiosensitizing therapeutic strategy for RMS clinical management.

Daga M, Pizzimenti S, Dianzani C, et al.
Ailanthone inhibits cell growth and migration of cisplatin resistant bladder cancer cells through down-regulation of Nrf2, YAP, and c-Myc expression.
Phytomedicine. 2019; 56:156-164 [PubMed] Related Publications
BACKGROUND: Ailanthone (Aila) is a natural active compound isolated from the Ailanthus altissima, which has been shown to possess an "in vitro" growth-inhibitory effect against several cancer cell lines. Advanced bladder cancer is a common disease characterized by a frequent onset of resistance to cisplatin-based therapy. The cisplatin (CDDP) resistance is accompanied by an increase in Nrf2 protein expression which contributes to conferring resistance. Recently, we demonstrated a cross-talk between Nrf2 and YAP. YAP has also been demonstrated to play an important role in chemoresistance of bladder cancer.
PURPOSE: We analyzed the antitumor effect of Aila in sensitive and CDDP-resistant bladder cancer cells and the molecular mechanisms involved in Aila activity.
STUDY DESIGN: Sensitive and CDDP-resistant 253J B-V and 253J bladder cancer cells, intrinsically CDDP-resistant T24 bladder cancer cells and HK-2 human renal cortex cells were used. Cells were treated with diverse concentrations of Aila and proliferation, cell cycle, apoptosis and gene expressions were determined.
METHODS: Aila toxicity and proliferation were determined by MTT and colony forming methods, respectively. Cell cycle was determined by cytofluorimetric analysis through PI staining method. Apoptosis was detected using Annexin V and PI double staining followed by quantitative flow cytometry. Expressions of Nrf2, Yap, c-Myc, and house-keeping genes were determined by western blot with specific antibodies. Cell migration was detected by wound healing and Boyden chamber analysis.
RESULTS: Aila inhibited the growth of sensitive and CDDP-resistant bladder cancer cells with the same effectiveness. On the contrary, the growth of HK-2 cells was only slightly reduced by Aila. Cell cycle analysis revealed an accumulation of Aila-treated bladder cancer cells in the G0/G1 phase. Interestingly, Aila strongly reduced Nrf2 expression in these cell lines. Moreover, Aila significantly reduced YAP, and c-Myc protein expression. The random and the oriented migration of bladder cancer cells were strongly inhibited by Aila treatment, in particular in CDDP-resistant cells.
CONCLUSION: Aila inhibited proliferation and invasiveness of bladder cancer cells. Its high effectiveness in CDDP resistant cells could be related to the inhibition of Nrf2, YAP, and c-Myc expressions. Aila could represent a new tool to treating CDDP-resistant bladder cancers.

Zhai X, Yuan S, Yang X, et al.
Chitosan Oligosaccharides Induce Apoptosis in Human Renal Carcinoma via Reactive-Oxygen-Species-Dependent Endoplasmic Reticulum Stress.
J Agric Food Chem. 2019; 67(6):1691-1701 [PubMed] Related Publications
In recent years, various studies have confirmed the role of natural products as effective cancer prevention and treatment drugs. The present study demonstrated that chitosan oligosaccharide (COS) from shells of shrimp and crab caused an inhibitory effect on the proliferation of human renal carcinoma in vitro and in vivo. First, the in vivo biodistribution of COS was investigated by the synthesis of cyanine-7-labeled COS (COS-Cy7) following tail vein injection. The kidney was found to be a major target organ. Then, the impacts on renal carcinoma cell proliferation, apoptosis, and reactive oxygen species (ROS) production were observed in vitro, and an orthotopic xenograft tumor model was designed to evaluate the antitumor efficacy of COS in vivo. In renal carcinoma cells, COS induced G2/M phase arrest and apoptosis in a ROS-dependent fashion. COS significantly promoted mRNA expression of nuclear factor erythroid 2-related factor (Nrf2) and Nrf2 target genes, such as heme oxygenase 1, modifier subunit of glutamate cysteine ligase, and solute carrier family 7 member 11. Additionally, COS significantly upregulated the protein expression of glucose-regulated protein 78, protein RNA-like endoplasmic reticulum (ER) kinase, eukaryotic initiation factor 2α, activating transcription factor 4, C/EBP homologous protein, and cytochrome c, which justified the activation of the ER stress signaling pathway. In vivo, COS repressed tumor growth and induced apoptosis and ROS accumulation, consistent with the in vitro results. Taken together, COS repressed human renal carcinoma growth and induced apoptosis both in vitro and in vivo, mainly via ROS-dependent ER stress pathways.

Cheng H, Huang C, Tang G, et al.
Emerging role of EPHX1 in chemoresistance of acute myeloid leukemia by regurlating drug-metabolizing enzymes and apoptotic signaling.
Mol Carcinog. 2019; 58(5):808-819 [PubMed] Related Publications
Microsomal epoxide hyrolase 1 (EPHX1) is a critical biotransformation enzyme and participants in both the detoxification and activation of potentially genotoxic epoxides. In this study, we firstly aimed to investigate the role of EPHX1 in the chemoresistance of acute myeloid leukemic cells to aclarubicin (ACM) and mitoxantrone (MIT). EPHX1 mRNA expression and prognosis were measured in acute myeloid leukemia (AML) patients, and the function of EPHX1 in leukemic cell viability and apoptosis induced by ACM and MIT was also measured. Our results found that EPHX1 expression is obviously associated with recurrence rate, overall survival and time of obtaining first complete remission in AML patients. EPHX1 silencing promoted ACM and MIT induced decrease in cell viability and cell apoptosis of HL-60, K562, and THP-1 that was inhibited by EPHX1 overexpression. EPHX1 reduced the susceptibility of leukemic cells to ACM and MIT by regulating drug-metabolizing enzymes (CYP1A1, GSTM1, and GSTT1) and apoptotic signaling (Bax, Bcl-2, Caspase-3, Caspase-9, and PARP1). Moreover, Nrf2 overexpression significantly increased EPHX1 expression and leukemic cell viability and decreased leukemic cell apoptosis. Taken together, we summarized the recent findings about the chemoresistance-promoting role of EPHX1, and the potential of targeting EPHX1 was proposed to counteract drug resistance in leukemia treatment.

Czauderna C, Palestino-Dominguez M, Castven D, et al.
Ginkgo biloba induces different gene expression signatures and oncogenic pathways in malignant and non-malignant cells of the liver.
PLoS One. 2018; 13(12):e0209067 [PubMed] Free Access to Full Article Related Publications
Ginkgo biloba (EGb761) is a widely used botanical drug. Several reports indicate that EGb761 confers preventive as well as anti-tumorigenic properties in a variety of tumors, including hepatocellular carcinoma (HCC). We here evaluate functional effects and molecular alterations induced by EGb761 in hepatoma cells and non-malignant hepatocytes. Hepatoma cell lines, primary human HCC cells and immortalized human hepatocytes (IH) were exposed to various concentrations (0-1000 μg/ml) of EGb761. Apoptosis and proliferation were evaluated after 72h of EGb761 exposure. Response to oxidative stress, tumorigenic properties and molecular changes were further investigated. While anti-oxidant effects were detected in all cell lines, EGb761 promoted anti-proliferative and pro-apoptotic effects mainly in hepatoma cells. Consistently, EGb761 treatment caused a significant reduction in colony and sphere forming ability in hepatoma cells and no mentionable changes in IH. Transcriptomic changes involved oxidative stress response as well as key oncogenic pathways resembling Nrf2- and mTOR signaling pathway. Taken together, EGb761 induces differential effects in non-transformed and cancer cells. While treatment confers protective effects in non-malignant cells, EGb761 significantly impairs tumorigenic properties in cancer cells by affecting key oncogenic pathways. Results provide the rational for clinical testing of EGb761 in preventive and therapeutic strategies in human liver diseases.

Yin Y, Liu H, Xu J, et al.
miR‑144‑3p regulates the resistance of lung cancer to cisplatin by targeting Nrf2.
Oncol Rep. 2018; 40(6):3479-3488 [PubMed] Related Publications
Chemotherapeutic drug resistance is correlated with treatment failure and poor prognosis among lung cancer patients. Numerous studies indicate the relevance of miRNAs in inducing certain drug resistance. In the course of the study, we unexpectedly found that miR‑144‑3p could regulate the cisplatin resistance of lung cancer cells via Nrf2. However, Nrf2 also could reverse activate the expression of miR‑144‑3p by binding to the ARE box in the miR‑144‑3p promoter. This may be a self‑protection mechanism of the body. In addition, we also found that in other cancer cell lines, such as HepG2, miR‑144‑3p also had the function of regulating cisplatin resistance. These findings may provide some theoretical reference for the clinical inhibition of cisplatin resistance.

Dong J, Li Y, Xiao H, et al.
Cordycepin sensitizes breast cancer cells toward irradiation through elevating ROS production involving Nrf2.
Toxicol Appl Pharmacol. 2019; 364:12-21 [PubMed] Related Publications
Radiation therapy toward malignancies is often ineffective owing to radioresistance of cancer cells. On the basis of anti-tumor properties of cordycepin, we examined the effects of cordycepin on sensitizing breast cancer cells toward radiotherapy. Cordycepin administration promoted G2/M arrest and apoptosis of MCF-7 and MDA-MB-231 cells resulting in restraining the proliferation of the cells in vitro and in vivo following irradiation. Mechanistic investigations showed that the breast cancer cells cultured with cordycepin harbored higher levels of intracellular reactive oxygen species (ROS) and incremental numbers of γ-H2AX foci after irradiation exposure. Importantly, cordycepin treatment down-regulated the expression levels of Nuclear factor erythroid 2-related factor (Nrf2) and a series of downstream genes, such as heme oxygenase-1 (HO-1), to enhance ROS in breast cancer cells exposed to irradiation. Together, our observations demonstrate that cordycepin treatment sensitizes breast carcinoma cells toward irradiation via Nrf2/HO-1/ROS axis. Thus, our findings provide novel insights into the function and the underlying mechanism of cordycepin in radiotherapy, and suggest that cordycepin might be employed as a radiosensitizer during radiotherapy toward breast cancer in a pre-clinical setting.

Nachliely M, Trachtenberg A, Khalfin B, et al.
Dimethyl fumarate and vitamin D derivatives cooperatively enhance VDR and Nrf2 signaling in differentiating AML cells in vitro and inhibit leukemia progression in a xenograft mouse model.
J Steroid Biochem Mol Biol. 2019; 188:8-16 [PubMed] Related Publications
Acute myeloid leukemia (AML) is one of the deadliest hematological malignancies without effective treatment for most patients. Vitamin D derivatives (VDDs) - active metabolites 1α,25-dihydroxyvitamin D

Nunziato M, Esposito MV, Starnone F, et al.
A multi-gene panel beyond BRCA1/BRCA2 to identify new breast cancer-predisposing mutations by a picodroplet PCR followed by a next-generation sequencing strategy: a pilot study.
Anal Chim Acta. 2019; 1046:154-162 [PubMed] Related Publications
By analyzing multiple gene panels, next-generation sequencing is more effective than conventional procedures in identifying disease-related mutations that are useful for clinical decision-making. Here, we aimed to test the efficacy of an 84 genes customized-panel in BRCA1 and BRCA2 mutation-negative patients. Twenty-four patients were enrolled in this study. DNA libraries were prepared using a picodroplet PCR-based approach and sequenced with the MiSeq System. Highly putative pathogenic mutations were identified in genes other than the commonly tested BRCA1/2: 2 pathogenic mutations one in TP53 and one in MUTYH; 2 missense variants in MSH6 and ATM, respectively; 2 frameshift variants in KLLN, and ATAD2, respectively; an intronic variant in ANPEP, and 3 not functionally known variants (a frameshift variant in ATM a nonsense variant in ATM and a missense variant in NFE2L2). Our results show that this molecular screening will increase diagnostic sensitivity leading to a better risk assessment in breast cancer patients and their families. This strategy could also reveal genes that have a higher penetrance for breast and ovarian cancers by matching gene mutation with familial and clinical data, thereby increasing information about hereditary breast and ovarian cancer genetics and improving cancer prevention measures or therapeutic approaches.

Cai MC, Chen M, Ma P, et al.
Clinicopathological, microenvironmental and genetic determinants of molecular subtypes in KEAP1/NRF2-mutant lung cancer.
Int J Cancer. 2019; 144(4):788-801 [PubMed] Related Publications
Somatic KEAP1-NRF2 pathway alterations are frequently detected in both lung adenocarcinomas and squamous cell carcinomas. However, the biological characteristics and molecular subtypes of KEAP1/NRF2-mutant lung cancer remain largely undefined. Here, we performed a stepwise, integrative analytic and experimental interrogation of primary tumors and cancer cell lines harboring KEAP1 or NFE2L2 (encoding NRF2) gene mutations. First, we discovered that KEAP1/NRF2-mutant lung cancer presented APOBEC-mediated mutational signatures, impaired tumor angiogenesis, elevated hypoxic stress and deficient immune-cell infiltrates. Second, gene expression-based subtyping revealed three molecular subsets of KEAP1/NRF2-mutant lung adenocarcinomas and two molecular subsets of KEAP1/NRF2-mutant lung squamous cell carcinomas, each associated with distinguishing genetic, differentiation, immunological and clinicopathological properties. Third, single-sample prediction allowed for de novo identification of KEAP1/NRF2-active tumors within KEAP1/NRF2-wild-type samples. Our data demonstrate that KEAP1/NRF2-mutant lung cancer is a microenvironmentally distinct, biologically heterogeneous, and clinically underestimated disease. These new pathological and molecular insights may accelerate the development of efficacious therapeutic strategies against human malignancies featured by KEAP1-NRF2 pathway activation.

Fu J, Xiong Z, Huang C, et al.
Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus.
J Biol Chem. 2019; 294(1):327-340 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Mutations in the genes encoding nuclear factor (erythroid-derived 2)-like 2 (NRF2), Kelch-like ECH-associated protein 1 (KEAP1), and cullin 3 (CUL3) are commonly observed in human esophageal squamous cell carcinoma (ESCC) and result in activation of the NRF2 signaling pathway. Moreover, hyperactivity of the transcription factor Nrf2 has been found to cause esophageal hyperproliferation and hyperkeratosis in mice. However, the underlying mechanism is unclear. In this study, we aimed to understand the molecular mechanisms of esophageal hyperproliferation in mice due to hyperactive Nrf2. Esophageal tissues were obtained from genetically modified mice that differed in the status of the

Enkhbat T, Nishi M, Yoshikawa K, et al.
Epigallocatechin-3-gallate Enhances Radiation Sensitivity in Colorectal Cancer Cells Through Nrf2 Activation and Autophagy.
Anticancer Res. 2018; 38(11):6247-6252 [PubMed] Related Publications
BACKGROUND/AIM: Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. EGCG plays a potential role in radio-sensitizing cancer cells. The combined effect of EGCG and radiation was investigated in a colorectal cancer cell line, focusing on nuclear factor (erythroid-derived 2)-like 2 (Nrf2) autophagy signalling.
MATERIALS AND METHODS: HCT-116 cells were treated with 12.5 μM EGCG for different periods of time, 2 Gy radiation, or both. Cell viability was determined with the WST-8 assay. The number of colonies was determined with the colony formation assay. mRNA expression of LC3 and caspase-9 was analyzed with quantitative real-time polymerase chain reaction.
RESULTS: Combination treatment with EGCG and radiation significantly decreased the growth of HCT-116 cells. The number of colonies was reduced to 34.2% compared to the control group. Immunofluorescence microscopy images showed that nuclear translocation of Nrf2 was significantly increased when cells were treated with the combination of EGCG and radiation compared to the control and single-treatment groups. Combined treatment with EGCG and radiation significantly induced LC3 and caspase-9 mRNA expression.
CONCLUSION: EGCG increased the sensitivity of colorectal cancer cells to radiation by inhibiting cell proliferation and inducing Nrf2 nuclear translocation and autophagy.

Hassanein EHM, Shalkami AS, Khalaf MM, et al.
The impact of Keap1/Nrf2, P
Biomed Pharmacother. 2019; 109:47-56 [PubMed] Related Publications
Berberine (BBR) is a natural compound of plant origin belonging to isoquinoline type of alkaloid. Methotrexate (MTX) is an anti-metabolite used widely for a variety of tumors and autoimmune conditions. Clinical uses of MTX were severely limited by its concomitant renal intoxication. The current study was designed to investigate the efficacy of BBR against MTX-induced nephrotoxicity and for exploring the underlying molecular mechanisms through examining the Keap1/Nrf2, NF-κB/P

Cirone M
EBV and KSHV Infection Dysregulates Autophagy to Optimize Viral Replication, Prevent Immune Recognition and Promote Tumorigenesis.
Viruses. 2018; 10(11) [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Autophagy is a catabolic process strongly involved in the immune response, and its dysregulation contributes to the onset of several diseases including cancer. The human oncogenic gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), manipulate autophagy, either during the de novo infection or during the lytic reactivation, in naturally latently-infected lymphoma cells. In particular, the gammaherpesvirus infection reduces autophagy in immune cells, such as monocytes, resulting in the impairment of cell survival and cell differentiation into dendritic cells (DCs), which are essential for initiating and regulating the immune response. In the case of EBV, the reduction of autophagy in these cells, leading to p62 accumulation, activated the p62-NRF2-antioxidant response, reducing ROS, and further inhibiting autophagy. KSHV inhibits autophagy in monocytes by de-phosphorylating JNK2, altering the calpains⁻calpastatin balance and increasing the calpain activity responsible for the cleavage of ATG5. To further impair the immune response, KSHV also inhibits autophagy in differentiated DCs by hyper-phosphorylating STAT3. Conversely, when the lytic cycle is induced in vitro in latently-infected lymphoma B cells, both EBV and KSHV promote autophagy to enhance their replication, although the final autophagic steps are blocked through the down-regulation of Rab7. This strategy allows viruses to avoid the destructive environment of lysosomes, and to exploit the autophagic machinery for intracellular transportation. EBV and KSHV encode for proteins that may either inhibit or promote autophagy and, in addition, they can modulate the cellular pathways that control this process. In this review we will discuss the findings that indicate that autophagy is dysregulated by gammaherpesvirus to promote immune suppression, facilitate viral replication and contribute to the onset and maintenance of gammaherpesvirus-associated malignancies.

Bismeijer T, Canisius S, Wessels LFA
Molecular characterization of breast and lung tumors by integration of multiple data types with functional sparse-factor analysis.
PLoS Comput Biol. 2018; 14(10):e1006520 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Effective cancer treatment is crucially dependent on the identification of the biological processes that drive a tumor. However, multiple processes may be active simultaneously in a tumor. Clustering is inherently unsuitable to this task as it assigns a tumor to a single cluster. In addition, the wide availability of multiple data types per tumor provides the opportunity to profile the processes driving a tumor more comprehensively. Here we introduce Functional Sparse-Factor Analysis (funcSFA) to address these challenges. FuncSFA integrates multiple data types to define a lower dimensional space capturing the relevant variation. A tailor-made module associates biological processes with these factors. FuncSFA is inspired by iCluster, which we improve in several key aspects. First, we increase the convergence efficiency significantly, allowing the analysis of multiple molecular datasets that have not been pre-matched to contain only concordant features. Second, FuncSFA does not assign tumors to discrete clusters, but identifies the dominant driver processes active in each tumor. This is achieved by a regression of the factors on the RNA expression data followed by a functional enrichment analysis and manual curation step. We apply FuncSFA to the TCGA breast and lung datasets. We identify EMT and Immune processes common to both cancer types. In the breast cancer dataset we recover the known intrinsic subtypes and identify additional processes. These include immune infiltration and EMT, and processes driven by copy number gains on the 8q chromosome arm. In lung cancer we recover the major types (adenocarcinoma and squamous cell carcinoma) and processes active in both of these types. These include EMT, two immune processes, and the activity of the NFE2L2 transcription factor. We validate the breast cancer findings on the METABRIC set and demonstrate the translatability of the TCGA breast cancer factors to METABRIC. In summary, FuncSFA is a robust method to perform discovery of key driver processes in a collection of tumors through unsupervised integration of multiple molecular data types and functional annotation.

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