Activation of EGFR-DNA-PKcs pathway by IGFBP2 protects esophageal adenocarcinoma cells from acidic bile salts-induced DNA damage

Zhou, Zhangjian; Lu, Heng; Zhu, Shoumin; Gomaa, Ahmed R.; Chen, Zheng; Jin, Yan; Washington, Kay; El-Rifai, Wael; Dang, Chengxue; Peng, Dunfa

doi:10.1186/s13046-018-1021-y

Cited by 27 publications

(22 citation statements)

References 53 publications

(71 reference statements)

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“…We and others have reported that exposure of esophageal cells to acidic bile salts (ABS), mimicking GERD episodes, induced significant ROS and oxidative stress [ [30] , [31] , [32] , [33] ]. Therefore, neoplastic esophageal cells must develop mechanisms to survive in this harsh oxidative environment.…”

Section: Resultsmentioning

confidence: 99%

Activation of NRF2 by APE1/REF1 is redox-dependent in Barrett's related esophageal adenocarcinoma cells

Sriramajayam

Peng

et al. 2021

Redox Biology

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Background Chronic gastroesophageal reflux disease (GERD) is a major risk factor for the development of metaplastic Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC). Uncontrolled accumulation of reactive oxygen species (ROS) in response to acidic bile salts (ABS) in reflux conditions can be lethal to cells. In this study, we investigated the role of APE1/REF1 in regulating nuclear erythroid factor-like 2 (NRF2), the master antioxidant transcription factor, in response to reflux conditions. Results We found that APE1 protein was critical for protecting against cellular ROS levels, oxidative DNA damage, double strand DNA breaks, and cell death in response to conditions that mimic reflux. Analysis of cell lines and de-identified tissues from patients with EAC demonstrated overexpression of both APE1 and NRF2 in EAC cells, as compared to non-neoplastic esophageal cells. Using reflux conditions, we detected concordant and prolonged increases of APE1 and NRF2 protein levels for several hours, following transient short exposure to ABS (20 min). NRF2 transcription activity, as measured by ARE luciferase reporter, and expression of its target genes (HO-1 and TRXND1) were similarly increased in response to ABS. Using genetic knockdown of APE1, we found that APE1 was required for the increase in NRF2 protein stability, nuclear localization, and transcription activation in EAC. Using knockdown of APE1 with reconstitution of wild-type and a redox-deficient mutant (C65A) of APE1, as well as pharmacologic APE1 redox inhibitor (E3330), we demonstrated that APE1 regulated NRF2 in a redox-dependent manner. Mechanistically, we found that APE1 is required for phosphorylation and inactivation of GSK-3β, an important player in the NRF2 degradation pathway. Conclusion APE1 redox function was required for ABS-induced activation of NRF2 by regulating phosphorylation and inactivation of GSK-3β. The APE1-NRF2 network played a critical role in protecting esophageal cells against ROS and promoting cell survival under oxidative reflux conditions.

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Section: Resultsmentioning

confidence: 99%

Activation of NRF2 by APE1/REF1 is redox-dependent in Barrett's related esophageal adenocarcinoma cells

Sriramajayam

Peng

et al. 2021

Redox Biology

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“…Recurrent episodes of reflux of gastric juice and bile salts mixture into the lower esophagus are the unique characteristics of GERD-BE and EAC spectrum. We have demonstrated that a short-time exposure of esophageal cells to the acidic bile salts (ABS) to mimic a GERD episode led to significant generation of H 2 O 2 levels and rapid elevation of intracellular ROS levels [ 22 , [25] , [26] , [27] , [28] ]. Subsequently, oxidative DNA damage levels (detected by 8-OHdG) and double strand DNA breaks (detected by γH2AX) were significantly increased after ABS exposure [ 22 , 25 ].…”

Section: Increased Oxidative Stress During Gerd-be-eac Cascadesmentioning

confidence: 99%

The antioxidant response in Barrett's tumorigenesis: A double-edged sword

et al. 2021

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Esophageal adenocarcinoma (EAC) is the dominant form of esophageal malignancies in the United States and other industrialized countries. The incidence of EAC has been rising rapidly during the past four decades. Barrett's esophagus (BE) is the main precancerous condition for EAC, where a metaplastic columnar epithelium replaces normal squamous mucosa of the lower esophagus. The primary risk factor for BE and EAC are chronic gastroesophageal reflux disease (GERD), obesity and smoking. During the BE-dysplasia-EAC sequence, esophageal cells are under a tremendous burden of accumulating reactive oxygen species (ROS) and oxidative stress. While normal cells have intact antioxidant machinery to maintain a balanced anti-tumorigenic physiological response, the antioxidant capacity is compromised in neoplastic cells with a pro-tumorigenic development antioxidant response. The accumulation of ROS, during the neoplastic progression of the GERD-BE-EAC sequence, induces DNA damage, lipid peroxidation and protein oxidation. Neoplastic cells adapt to oxidative stress by developing a pro-tumorigenic antioxidant response that keeps oxidative damage below lethal levels while promoting tumorigenesis, progression, and resistance to therapy. In this review, we will summarize the recent findings on oxidative stress in tumorigenesis in the context of the GERD-BE-EAC process. We will discuss how EAC cells adapt to increased ROS. We will review APE1 and NRF2 signaling mechanisms in the context of EAC. Finally, we will discuss the potential clinical significance of applying antioxidants or NRF2 activators as chemoprevention and NRF2 inhibitors in treating EAC patients.

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“…Insulin-like growth factor (IGF) binding protein 2(IGFBP2) is a developmental regulatory gene highly expressed in embryonic and fetal tissues and signi cantly reduced after birth. He is also considered a systemic regulator of IGF and controls the activity, distribution, and function of IGFs in the pericellular space (10,11,12). IGFBP2 is found in serum and in various biological uids, including amniotic membranes, follicles, cerebrospinal uid and semen, and milk.…”

Section: Discussionmentioning

confidence: 99%

Identification of potential core genes in atrial fibrillation based on bioinformatics analysis

Pan

Zhang

2020

Preprint

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OBJECTIVE:Atrial fibrillation (AF) is one of the most common arrhythmias, which is caused by a number of minorring disorders caused by the heart owner's guide. It is noted in almost all organic heart disease and can also occur in non-organic heart disease,causing serious complications, such as heart failure and arterial embolism, seriously threaten people's health.Atrial fibrillation can cause serious complications, such as heart failure and arterial embolism, which seriously threaten people's health. Clinically, according to the characteristics of atrial fibrillation, atrial fibrillation is divided into paroxysmal atrial fibrillation,persistent atrial fibrillation, permanent atrial fibrillation (cannot be converted to sinus rhythm).Among them, persistent atrial fibrillation poses the greatest threat to people's health.So the main purpose of this study is to identify the differential genes in patients with permanent atrial fibrillation. MATERIALS AND METHODS:To explore potential differential genes for permanent atrial fibrillation, we analyzed three microarray datasets GSE2240 derived from the Gene Expression Omnibus (GEO) database. We used the“limma”function package of R software to screen differentially expressed genes(DEGs), and used the“pheatmap”function package to construct heatmaps for the screened differential genes.Visualization and Integration Discovery (DAVID) ,Cytoscape ,BMKcloud and String platforms were utilized for Genome Ontology (GO) analysis,Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis , PPI(protein-proteinInteraction) network analysis ,module analysis,and identification hub genes based on the selected differential genes.RESULTS:74 DEGs in total were identified, including 41 up- and 33 downregulated genes. These DEGs were mainly enriched in PI3K-Akt signaling pathway ,cGMP-PKG signaling pathway, Focal adhesion, and so on. The module analysis filtered out 12 key genes, including PRL, CREB1, AGO2, NAMPT, IGFBP2, FGF7, ANGPT2, SYT13, NRXN1, AQP4, TCEAL2, and CPLX1. 2 Hub genes were identified, including IGFBP2, and FGF7.CONCLUSIONS:IGFBP2 and FGF7 were identified as Hub genes of AF, which helped us to understand more deeply the pathophysiological mechanism of AF.

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Activation of EGFR-DNA-PKcs pathway by IGFBP2 protects esophageal adenocarcinoma cells from acidic bile salts-induced DNA damage

Cited by 27 publications

References 53 publications

Activation of NRF2 by APE1/REF1 is redox-dependent in Barrett's related esophageal adenocarcinoma cells

Activation of NRF2 by APE1/REF1 is redox-dependent in Barrett's related esophageal adenocarcinoma cells

The antioxidant response in Barrett's tumorigenesis: A double-edged sword

Identification of potential core genes in atrial fibrillation based on bioinformatics analysis

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