NADPH oxidase-associated transition from Barrett's esophagus to adenocarcinoma

NADPH 氧化酶相关的巴雷特食管向腺癌的转变

• 批准号: 7765562
• 负责人: WEIBIAO CAO
• 金额: $ 30.59万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7765562
• 关键词: Acids; Adenocarcinoma; Adenocarcinoma Cell; Adult; Affect; Age-Years; American; Apoptosis; Barrett Esophagus; Biochemistry; Biological Markers; Biopsy; Cell Cycle; Cell Line; Cell Proliferation; Cells; Cessation of life; Cyclic AMP-Responsive DNA-Binding Protein; Cyclin D1; DNA Damage; DNA-dependent protein kinase; Data; Death Domain; Development; Dysplasia; Early Diagnosis; Enzymes; Esophageal; Esophageal Adenocarcinoma; Esophageal Intraepithelial Neoplasia; Esophageal mucous membrane; Esophagus; Fetal Kidney; Figs - dietary; Free Radicals; Funding; G1 Phase; Gastroesophageal reflux disease; Grant; Human; Hydrogen Peroxide; Inferior esophageal sphincter structure; Inflammation; Inflammation Mediators; Inflammatory; Intestinal Metaplasia; Investigation; Journals; Lead; Lipids; Malignant Neoplasms; Malignant neoplasm of esophagus; Manuscripts; Mediating; Metaplasia; Metaplastic Cell; Mitogens; Modeling; Mucous Membrane; Mutation; NADP; NADPH Oxidase; NF-kappa B; Nuclear; Oxidases; Pathway interactions; Patients; Phosphorylation; Physiologic pulse; Physiology; Platelet Activating Factor; Play; Prevention approach; Principal Investigator; Production; Protein Isoforms; Proteins; Publishing; Reactive Oxygen Species; Reflux; Regulation; Research; Retinoblastoma Protein; Rho-associated kinase; Risk; Risk Factors; Role; STAT protein; Signal Pathway; Signal Transduction Pathway; Small Interfering RNA; Smooth Muscle; Source; Structure; Testing; Thymidine; Tissues; Up-Regulation; cyclooxygenase 2; design; genetic regulatory protein; human CYBA protein; novel; overexpression; prevent; public health relevance; therapeutic target; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): Gastroesophageal reflux disease (GERD) affects more than one in ten adults over 40 years of age and one in four adults over 60. Approximately 10% of GERD patients develop Barrett's esophagus (BE), which is associated with nearly a 30-125-fold increased risk for the development of esophageal adenocarcinoma (EA). The mechanism of progression from BE to dysplasia and to EA is unknown. We will therefore examine some of the pathways that may be involved in this progression. Reactive oxygen species (ROS) are elevated in BE and EA, and may play a key role in the progression from BE to EA. We found that a novel isoform of NADPH oxidase NOX5-S is overexpressed in EA cell lines, EA tissues, and BE mucosa with high grade dysplasia. NOX5-S was first identified in human fetal kidney and has not been described in other tissues. In SEG1 EA cells pulsed acid exposure causes upregulation of NOX5-S and increases H2O2 production. NOX5-S-derived ROS contribute to increased cell proliferation and decreased apoptosis in SEG1 cells. However, the mechanisms of acid-induced NOX5-S upregulation and NOX5-S-dependent increase in cell proliferation and decrease in apoptosis are not fully understood. We will therefore test the hypothesis that acid exposure upregulates NADPH oxidases via activation of Rho kinases and MAP kinases in Barrett's metaplastic cells, causing overproduction of free radicals, which in turn may further enhance the expression of NADPH oxidases through activation of the nuclear factor kappaB (NF-kB). In addition, ROS may upregulate cyclin D1 and the silencer of the death domain (SODD). Upregulation of cyclin D1 and SODD will increase cell proliferation and decrease apoptosis in these cells. Thus the persistent acid reflux present in BE patients may cause high levels of ROS, increased cell proliferation and decreased apoptosis, which may lead to DNA damage and increased mutations, contributing to the progression from BE to dysplasia and to EA. To test this hypothesis we will: 1) Examine the signal transduction pathway of acid-induced expression of NADPH oxidases in a BE cell line, in Barrett's mucosal biopsies, and in EA cells (SEG1, FLO, and OE33). We will focus on the role of Rho kinase, MAP kinases and NF-kB. 2) Examine the mechanisms of NADPH oxidase-dependent increase in cell proliferation and decrease in apoptosis, concentrating on the role of cyclin D1 and SODD, and examine whether NADPH oxidase-derived ROS cause DNA damage. 3) Examine the regulatory proteins required for NOX5-S to function, focusing on Rac1 and p22phox. A better understanding of the signal transduction pathway of acid induced upregulation of NADPH oxidases, leading to increased cell proliferation and decreased apoptosis, may provide a rational approach to the prevention of development of EA. In addition, NOX5-S may be a potential biomarker for early detection of esophageal dysplasia. Our model may also be applicable to other inflammation-associated cancers. PUBLIC HEALTH RELEVANCE: This proposal studies the role of a particular enzyme NOX5-S in the progression from Barrett's esophagus, a condition where cells in the esophagus have been altered by acid reflux, to esophageal cancer. This project is designed to find potential therapeutic targets to prevent this progression.

描述（由申请人提供）：胃食管反流疾病（GERD）影响40岁以上的十分之一以上的成年人，四分之一的成年人超过60岁。大约10％的GERD患者会发展与Barrett的食管（BE），这与这是相关的食管腺癌（EA）的发展风险近30-125倍。从BE到发育异常到EA的进展机制尚不清楚。因此，我们将研究可能参与此进展的一些途径。活性氧（ROS）在BE和EA中升高，并且可能在从BE到EA的发展中起关键作用。我们发现，NADPH氧化酶NOX5-S的新型同工型在EA细胞系，EA组织中过表达，并且具有高级发育不良的粘膜。 NOX5-S首先在人类胎儿肾脏中鉴定出来，尚未在其他组织中描述。在SEG1 EA细胞中，脉冲酸暴露会导致NOX5-S的上调，并增加H2O2的产生。 NOX5-S衍生的ROS有助于SEG1细胞中细胞增殖的增加和凋亡减少。但是，尚未完全了解酸诱导的NOX5-S上调和NOX5-S依赖性增加的机制和细胞凋亡的降低。因此，我们将检验以下假设：酸暴露通过激活Rho激酶和MAP激酶在Barrett的化生细胞中上调NADPH氧化酶，从而导致自由基的过度生产，从而进一步增强了NADPH氧化酶的表达，从NF-KB）。此外，ROS可能会上调细胞周期蛋白D1和死亡结构域（SODD）的消音器。细胞周期蛋白D1和SODD的上调将增加细胞增殖并减少这些细胞的凋亡。因此，患者存在的持续胃酸反流可能会导致高水平的ROS，增加细胞增殖并减少凋亡，这可能导致DNA损伤并增加突变，从而导致从BE发育不良和EA的发展。为了检验这一假设，我们将：1）检查酸诱导的NADPH氧化酶在BE细胞系，Barrett的粘膜活检和EA细胞中的信号转导途径（SEG1，FLO和OE33）。我们将重点关注Rho激酶，MAP激酶和NF-KB的作用。 2）检查NADPH氧化酶依赖性增加细胞增殖的机制和凋亡减少，集中于细胞周期蛋白D1和SODD的作用，并检查NADPH氧化酶衍生的ROS是否会导致DNA损伤。 3）检查NOX5-S功能所需的调节蛋白，重点是Rac1和P22Phox。更好地了解酸诱导的NADPH氧化酶上调的信号转导途径，从而导致细胞增殖增加和凋亡减少，这可能为预防EA发育的发展提供了合理的方法。此外，NOX5-S可能是早期检测食管发育不良的潜在生物标志物。我们的模型也可能适用于其他与炎症相关的癌症。 公共卫生相关性：该提案研究了特定酶NOX5-S在Barrett食管进展中的作用，在这种情况下，食管中食道细胞已通过胃酸反流改变了食管癌的疾病。该项目旨在找到潜在的治疗靶标，以防止这种进展。